The 100 most-cited articles in International Journal of Molecular Sciences, 2023

This review focuses on the multiple and reciprocal relationships that exist between oxidative stress, hyperglycemia and diabetes and related metabolic disorders. Human metabolism uses most of the consumed glucose under aerobic conditions. Oxygen is needed in the mitochondria to obtain energy, as well as for the action of microsomal oxidases and cytosolic pro-oxidant enzymes. This relentlessly generates a certain amount of reactive oxygen species (ROS). Although ROS are intracellular signals necessary for some physiological processes, their accumulation leads to oxidative stress, hyperglycemia, and progressive resistance to insulin. A cellular pro-oxidant versus an antioxidant equilibrium would regulate ROS levels, but oxidative stress, hyperglycemia, and pro-inflammatory conditions feed back to each other and the relevance of the interconnections tends to increase those conditions. Hyperglycemia promotes collateral glucose metabolism through protein kinase C, polyols and hexosamine routes. In addition, it also facilitates spontaneous glucose auto-oxidation and the formation of…

Metabolic syndrome is a cluster of conditions associated with the risk of diabetes mellitus type 2 and cardiovascular diseases (CVDs). Metabolic syndrome is closely related to obesity. Increased adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving metabolic syndrome components, namely insulin resistance, hypertension, and hyperlipidemia. An increasing number of studies confirm the importance of oxidative stress and chronic inflammation in the etiology of metabolic syndrome. However, few studies have reviewed the mechanisms underlying the role of oxidative stress in contributing to metabolic syndrome. In this review, we highlight mechanisms by which reactive oxygen species (ROS) increase mitochondrial dysfunction, protein damage, lipid peroxidation, and impair antioxidant function in metabolic syndrome. Biomarkers of oxidative stress can be used in disease diagnosis and evaluation of severity.

Exosomes are a subtype of membrane-contained vesicles 40-200 nm in diameter that are secreted by cells into their surroundings. By transporting proteins, lipids, mRNA, miRNA, lncRNA, and DNA, exosomes are able to perform such vital functions as maintaining cellular homeostasis, removing cellular debris, and facilitating intercellular and interorgan communication. Exosomes travel in all body fluids and deliver their molecular messages in autocrine, paracrine as well as endocrine manners. In recent years, there has been an increased interest in studying exosomes as diagnostic markers and therapeutic targets, since in many disease conditions this machinery becomes dysregulated or hijacked by pathological processes. Additionally, delivery of exosomes and exosomal miRNA has already been shown to improve systemic metabolism and inhibit progression of cancer development in mice. However, the subcellular machinery of exosomes, including their biogenesis, release and uptake, remains largely unknown. This review will bring molecular details of these processes up to date with the goal of…

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying…

In vitro determination of hemolytic properties is a common and important method for preliminary evaluation of cytotoxicity of chemicals, drugs, or any blood-contacting medical device or material. The method itself is relatively straightforward, however, protocols used in the literature vary substantially. This leads to significant difficulties both in interpreting and in comparing the obtained values. Here, we examine how the different variables used under different experimental setups may affect the outcome of this assay. We find that certain key parameters affect the hemolysis measurements in a critical manner. The hemolytic effect of compounds tested here varied up to fourfold depending on the species of the blood source. The use of different types of detergents used for generating positive control samples (i.e., 100% hemolysis) produced up to 2.7-fold differences in the calculated hemolysis ratios. Furthermore, we find an expected, but substantial, increase in the number of hemolyzed erythrocytes with increasing erythrocyte concentration and with prolonged incubation time, which…

mRNA vaccines have been demonstrated as a powerful alternative to traditional conventional vaccines because of their high potency, safety and efficacy, capacity for rapid clinical development, and potential for rapid, low-cost manufacturing. These vaccines have progressed from being a mere curiosity to emerging as COVID-19 pandemic vaccine front-runners. The advancements in the field of nanotechnology for developing delivery vehicles for mRNA vaccines are highly significant. In this review we have summarized each and every aspect of the mRNA vaccine. The article describes the mRNA structure, its pharmacological function of immunity induction, lipid nanoparticles (LNPs), and the upstream, downstream, and formulation process of mRNA vaccine manufacturing. Additionally, mRNA vaccines in clinical trials are also described. A deep dive into the future perspectives of mRNA vaccines, such as its freeze-drying, delivery systems, and LNPs targeting antigen-presenting cells and dendritic cells, are also summarized.

Natural products are compounds produced by living organisms and can be divided into two main categories: primary (PMs) and secondary metabolites (SMs). Plant PMs are crucial for plant growth and reproduction since they are directly involved in living cell processes, whereas plant SMs are organic substances directly involved in plant defense and resistance. SMs are divided into three main groups: terpenoids, phenolics and nitrogen-containing compounds. The SMs contain a variety of biological capabilities that can be used as flavoring agents, food additives, plant-disease control, strengthen plant defenses against herbivores and, additionally, it can help plant cells to be better adapted to the physiological stress response. The current review is mainly focusing on certain key elements related to the significance, biosynthesis, classification, biochemical characterization and medical/pharmaceutical uses of the major categories of plant SMs. In addition, the usefulness of SMs in controlling plant diseases, boosting plant resistance and as potential natural, safe, eco-friendly…

Phenolic compounds or polyphenols are among the most common compounds of secondary metabolism in plants. Their biosynthesis is characteristic of all plant cells and is carried out with the participation of the shikimate and acetate-malonate pathways. In this case, polyphenols of various structures are formed, such as phenylpropanoids, flavonoids, and various oligomeric and polymeric compounds of phenolic nature. Their number already exceeds 10,000. The diversity of phenolics affects their biological activity and functional role. Most of their representatives are characterized by interaction with reactive oxygen species, which manifests itself not only in plants but also in the human body, where they enter through food chains. Having a high biological activity, phenolic compounds are successfully used as medicines and nutritional supplements for the health of the population. The accumulation and biosynthesis of polyphenols in plants depend on many factors, including physiological-biochemical, molecular-genetic, and environmental factors. In the review, we present the latest…

Alzheimer's disease is one of the most commonly diagnosed cases of senile dementia in the world. It is an incurable process, most often leading to death. This disease is multifactorial, and one factor of this is inflammation. Numerous mediators secreted by inflammatory cells can cause neuronal degeneration. Neuritis may coexist with other mechanisms of Alzheimer's disease, contributing to disease progression, and may also directly underlie AD. Although much has been established about the inflammatory processes in the pathogenesis of AD, many aspects remain unexplained. The work is devoted in particular to the pathomechanism of inflammation and its role in diagnosis and treatment. An in-depth and detailed understanding of the pathomechanism of neuroinflammation in Alzheimer's disease may help in the development of diagnostic methods for early diagnosis and may contribute to the development of new therapeutic strategies for the disease.

Selenium (Se) is a naturally occurring metalloid element essential to human and animal health in trace amounts but it is harmful in excess. Se plays a substantial role in the functioning of the human organism. It is incorporated into selenoproteins, thus supporting antioxidant defense systems. Selenoproteins participate in the metabolism of thyroid hormones, control reproductive functions and exert neuroprotective effects. Among the elements, Se has one of the narrowest ranges between dietary deficiency and toxic levels. Its level of toxicity may depend on chemical form, as inorganic and organic species have distinct biological properties. Over the last decades, optimization of population Se intake for the prevention of diseases related to Se deficiency or excess has been recognized as a pressing issue in modern healthcare worldwide. Low selenium status has been associated with an increased risk of mortality, poor immune function, cognitive decline, and thyroid dysfunction. On the other hand, Se concentrations slightly above its nutritional levels have been shown to have adverse…

Osteoarthritis (OA) is a chronic disease and the most common orthopedic disorder. A vast majority of the social OA burden is related to hips and knees. The prevalence of knee OA varied across studies and such differences are reflected by the heterogeneity of data reported by studies conducted worldwide. A complete understanding of the pathogenetic mechanisms underlying this pathology is essential. The OA inflammatory process starts in the synovial membrane with the activation of the immune system, involving both humoral and cellular mediators. A crucial role in this process is played by the so-called "damage-associated molecular patterns" (DAMPs). Mesenchymal stem cells (MSCs) may be a promising option among all possible therapeutic options. However, many issues are still debated, such as the best cell source, their nature, and the right amount. Further studies are needed to clarify the remaining doubts. This review provides an overview of the most recent and relevant data on the molecular mechanism of cartilage damage in knee OA, including current therapeutic approaches in…

Abiotic stress is the adverse effect of any abiotic factor on a plant in a given environment, impacting plants' growth and development. These stress factors, such as drought, salinity, and extreme temperatures, are often interrelated or in conjunction with each other. Plants have evolved mechanisms to sense these environmental challenges and make adjustments to their growth in order to survive and reproduce. In this review, we summarized recent studies on plant stress sensing and its regulatory mechanism, emphasizing signal transduction and regulation at multiple levels. Then we presented several strategies to improve plant growth under stress based on current progress. Finally, we discussed the implications of research on plant response to abiotic stresses for high-yielding crops and agricultural sustainability. Studying stress signaling and regulation is critical to understand abiotic stress responses in plants to generate stress-resistant crops and improve agricultural sustainability.

Breast cancer is the most common cancer and the deadliest among women worldwide. Estrogen signaling is closely associated with hormone-dependent breast cancer (estrogen and progesterone receptor positive), which accounts for two-thirds of tumors. Hormone therapy using antiestrogens is the gold standard, but resistance to these treatments invariably occurs through various biological mechanisms, such as changes in estrogen receptor activity, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle dysregulations. All these factors have led to the development of new therapies, such as selective estrogen receptor degraders (SERDs), or combination therapies with cyclin-dependent kinases (CDK) 4/6 or PI3K inhibitors. Therefore, understanding the estrogen pathway is essential for the treatment and new drug development of hormone-dependent cancers. This mini-review summarizes current literature on the signalization, mechanisms of action and clinical implications of estrogen receptors in breast cancer.

Osteoporosis is characterized by the alteration of bone homeostasis due to an imbalance between osteoclastic bone resorption and osteoblastic bone formation. Estrogen deficiency causes bone loss and postmenopausal osteoporosis, the pathogenesis of which also involves oxidative stress, inflammatory processes, and the dysregulation of the expression of microRNAs (miRNAs) that control gene expression at post-transcriptional levels. Oxidative stress, due to an increase in reactive oxygen species (ROS), proinflammatory mediators and altered levels of miRNAs enhance osteoclastogenesis and reduce osteoblastogenesis through mechanisms involving the activation of MAPK and transcription factors. The present review summarizes the principal molecular mechanisms involved in the role of ROS and proinflammatory cytokines on osteoporosis. Moreover, it highlights the interplay among altered miRNA levels, oxidative stress, and an inflammatory state. In fact, ROS, by activating the transcriptional factors, can affect miRNA expression, and miRNAs can regulate ROS production and inflammatory processes.…

family. Due to their small size, simple structure, high antigen binding affinity, and remarkable stability in extreme conditions, nanobodies possess the potential to overcome several of the limitations of conventional monoclonal antibodies. For many years, nanobodies have been of great interest in a wide variety of research fields, particularly in the diagnosis and treatment of diseases. This culminated in the approval of the world's first nanobody based drug (Caplacizumab) in 2018 with others following soon thereafter. This review will provide an overview, with examples, of (i) the structure and advantages of nanobodies compared to conventional monoclonal antibodies, (ii) methods used to generate and produce antigen-specific nanobodies, (iii) applications for diagnostics, and (iv) ongoing clinical trials for nanobody therapeutics as well as promising candidates for clinical development.

Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the 'Warburg effect,' provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a…

In recent years, interest in nanotechnology has increased exponentially due to enhanced progress and technological innovation. In tissue engineering, the development of metallic nanoparticles has been amplified, especially due to their antibacterial properties. Another important characteristic of metal NPs is that they enable high control over the features of the developed scaffolds (optimizing their mechanical strength and offering the controlled release of bioactive agents). Currently, the main concern related to the method of synthesis of metal oxide NPs is the environmental impact. The physical and chemical synthesis uses toxic agents that could generate hazards or exert carcinogenicity/environmental toxicity. Therefore, a greener, cleaner, and more reliable approach is needed. Green synthetic has come as a solution to counter the aforementioned limitations. Nowadays, green synthesis is preferred because it leads to the prevention/minimization of waste, the reduction of derivatives/pollution, and the use of non-toxic (safer) solvents. This method not only uses biomass sources as…

Most chronic inflammatory illnesses include fibrosis as a pathogenic characteristic. Extracellular matrix (ECM) components build up in excess to cause fibrosis or scarring. The fibrotic process finally results in organ malfunction and death if it is severely progressive. Fibrosis affects nearly all tissues of the body. The fibrosis process is associated with chronic inflammation, metabolic homeostasis, and transforming growth factor-β1 (TGF-β1) signaling, where the balance between the oxidant and antioxidant systems appears to be a key modulator in managing these processes. Virtually every organ system, including the lungs, heart, kidney, and liver, can be affected by fibrosis, which is characterized as an excessive accumulation of connective tissue components. Organ malfunction is frequently caused by fibrotic tissue remodeling, which is also frequently linked to high morbidity and mortality. Up to 45% of all fatalities in the industrialized world are caused by fibrosis, which can damage any organ. Long believed to be persistently progressing and irreversible, fibrosis has now been…

Bioactive compounds, including terpenoids, polyphenols, alkaloids and other nitrogen-containing constituents, exert various beneficial effects arising from their antioxidant and anti-inflammatory properties. These compounds can be found in vegetables, fruits, grains, spices and their derived foods and beverages such as tea, olive oil, fruit juices, wine, chocolate and beer. Agricultural production and the food supply chain are major sources of food wastes, which can become resources, as they are rich in bioactive compounds. The aim of this review is to highlight recent articles demonstrating the numerous potential uses of products and by-products of the agro-food supply chain, which can have various applications.

Moringa oleifera, also known as the “tree of life” or “miracle tree,” is classified as an important herbal plant due to its immense medicinal and non-medicinal benefits. Traditionally, the plant is used to cure wounds, pain, ulcers, liver disease, heart disease, cancer, and inflammation. This review aims to compile an analysis of worldwide research, pharmacological activities, phytochemical, toxicological, and ethnomedicinal updates of Moringa oleifera and also provide insight into its commercial and phytopharmaceutical applications with a motive to help further research. The scientific information on this plant was obtained from various sites and search engines such as Scopus, Pub Med, Science Direct, BMC, Google Scholar, and other scientific databases. Articles available in the English language have only been referred for review. The pharmacological studies confirm the hepatoprotective, cardioprotective, and anti-inflammatory potential of the extracts from the various plant parts. It was found that bioactive constituents are present in every part of the plant. So far, more than…

The discovery and advances of medicines may be considered as the ultimate relevant translational science effort that adds to human invulnerability and happiness. But advancing a fresh medication is a quite convoluted, costly, and protracted operation, normally costing USD ~2.6 billion and consuming a mean time span of 12 years. Methods to cut back expenditure and hasten new drug discovery have prompted an arduous and compelling brainstorming exercise in the pharmaceutical industry. The engagement of Artificial Intelligence (AI), including the deep-learning (DL) component in particular, has been facilitated by the employment of classified big data, in concert with strikingly reinforced computing prowess and cloud storage, across all fields. AI has energized computer-facilitated drug discovery. An unrestricted espousing of machine learning (ML), especially DL, in many scientific specialties, and the technological refinements in computing hardware and software, in concert with various aspects of the problem, sustain this progress. ML algorithms have been extensively engaged for…

Classically, superoxide anion O2•− and reactive oxygen species ROS play a dual role. At the physiological balance level, they are a by-product of O2 reduction, necessary for cell signalling, and at the pathological level they are considered harmful, as they can induce disease and apoptosis, necrosis, ferroptosis, pyroptosis and autophagic cell death. This revision focuses on understanding the main characteristics of the superoxide O2•−, its generation pathways, the biomolecules it oxidizes and how it may contribute to their modification and toxicity. The role of superoxide dismutase, the enzyme responsible for the removal of most of the superoxide produced in living organisms, is studied. At the same time, the toxicity induced by superoxide and derived radicals is beneficial in the oxidative death of microbial pathogens, which are subsequently engulfed by specialized immune cells, such as neutrophils or macrophages, during the activation of innate immunity. Ultimately, this review describes in some depth the chemistry related to O2•− and how it is harnessed by the innate immune…

Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host’s immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) M. tb strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bedaquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB—the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years—reflecting the…

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the world. It is classified as familial and sporadic. The dominant familial or autosomal presentation represents 1–5% of the total number of cases. It is categorized as early onset (EOAD; <65 years of age) and presents genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or the Amyloid precursor protein (APP). Sporadic AD represents 95% of the cases and is categorized as late-onset (LOAD), occurring in patients older than 65 years of age. Several risk factors have been identified in sporadic AD; aging is the main one. Nonetheless, multiple genes have been associated with the different neuropathological events involved in LOAD, such as the pathological processing of Amyloid beta (Aβ) peptide and Tau protein, as well as synaptic and mitochondrial dysfunctions, neurovascular alterations, oxidative stress, and neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms associated with LOAD have been identified. This review aims to analyze the…

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Metabolic reprogramming is considered a new hallmark of cancer, but it remains unclearly described in HCC. The dysregulation of the PI3K/AKT/mTOR signaling pathway is common in HCC and is, therefore, a topic of further research and the concern of developing a novel target for liver cancer therapy. In this review, we illustrate mechanisms by which this signaling network is accountable for regulating HCC cellular metabolism, including glucose metabolism, lipid metabolism, amino acid metabolism, pyrimidine metabolism, and oxidative metabolism, and summarize the ongoing clinical trials based on the inhibition of the PI3K/AKT/mTOR pathway in HCC.

Venous thromboembolism (VTE) is the third most common cause of death worldwide. The incidence of VTE varies according to different countries, ranging from 1-2 per 1000 person-years in Western Countries, while it is lower in Eastern Countries (<1 per 1000 person-years). Many risk factors have been identified in patients developing VTE, but the relative contribution of each risk factor to thrombotic risk, as well as pathogenetic mechanisms, have not been fully described. Herewith, we provide a comprehensive review of the most common risk factors for VTE, including male sex, diabetes, obesity, smoking, Factor V Leiden, Prothrombin G20210A Gene Mutation, Plasminogen Activator Inhibitor-1, oral contraceptives and hormonal replacement, long-haul flight, residual venous thrombosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, trauma and fractures, pregnancy, immobilization, antiphospholipid syndrome, surgery and cancer. Regarding the latter, the incidence of VTE seems highest in pancreatic, liver and non-small cells lung cancer (>70 per 1000 person-years) and…

Endometriosis is a complex disease, which is defined by abnormal growth of endometrial tissue outside the uterus. It affects about 10% of women of reproductive age all over the world. Endometriosis causes symptoms that notably worsen patient's well-being-such as severe pelvic pain, dysfunction of the organs of pelvic cavity, infertility and secondary mental issues. The diagnosis of endometriosis is quite often delayed because of nonspecific manifestations. Since the disease was defined, several different pathogenetic pathways have been considered, including retrograde menstruation, benign metastasis, immune dysregulation, coelomic metaplasia, hormonal disbalance, involvement of stem cells and alterations in epigenetic regulation, but the true pathogenesis of endometriosis remains poorly understood. The knowledge of the exact mechanism of the origin and progression of this disease is significant for the appropriate treatment. Therefore, this review reports the main pathogenetic theories of endometriosis based on current studies.

Psoriasis is a chronic inflammatory skin disorder, and current treatments include topical therapies, phototherapy, systemic immune modulators, and biologics, aiming to alleviate symptoms and improve quality of life. However, challenges persist, such as adverse effects, treatment resistance, high costs, and variability in response among individuals. The future of psoriasis treatment shows promising emerging trends. New biologic agents targeting novel pathways, such as interleukin 23 inhibitors like mirikizumab, offer enhanced efficacy. Small molecule inhibitors like RORγt inhibitors and ROCK2 inhibitors provide additional treatment options. Combination therapies, including biologics with methotrexate, may improve treatment response. Advancements in topical treatments utilizing microneedles and nanoparticle-based carriers can enhance drug delivery and improve therapeutic outcomes. Biomarkers and multi-omics technologies hold potential for personalized treatment approaches, thus aiding in diagnosis, predicting treatment response, and guiding therapeutic decisions. Collaboration among…

Liposomes, the most widely studied nano-drug carriers in drug delivery, are sphere-shaped vesicles consisting of one or more phospholipid bilayers. Compared with traditional drug delivery systems, liposomes exhibit prominent properties that include targeted delivery, high biocompatibility, biodegradability, easy functionalization, low toxicity, improvements in the sustained release of the drug it carries and improved therapeutic indices. In the wake of the rapid development of nanotechnology, the studies of liposome composition have become increasingly extensive. The molecular diversity of liposome composition, which includes long-circulating PEGylated liposomes, ligand-functionalized liposomes, stimuli-responsive liposomes, and advanced cell membrane-coated biomimetic nanocarriers, endows their drug delivery with unique physiological functions. This review describes the composition, types and preparation methods of liposomes, and discusses their targeting strategies in cancer therapy.

Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are…

Urinary tract infections (UTIs) are common bacterial infections that represent a severe public health problem. They are often caused by Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumonia), Proteus mirabilis (P. mirabilis), Enterococcus faecalis (E. faecalis), and Staphylococcus saprophyticus (S. saprophyticus). Among these, uropathogenic E. coli (UPEC) are the most common causative agent in both uncomplicated and complicated UTIs. The adaptive evolution of UPEC has been observed in several ways, including changes in colonization, attachment, invasion, and intracellular replication to invade the urothelium and survive intracellularly. While antibiotic therapy has historically been very successful in controlling UTIs, high recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly reduce the efficacy of these treatments. Furthermore, the gradual global emergence of multidrug-resistant UPEC has highlighted the need to further explore its pathogenesis and seek alternative therapeutic and preventative strategies. Therefore, a thorough…

The tumor microenvironment (TME) is a critical regulator of tumor growth, progression, and metastasis. Among the innate immune cells recruited to the tumor site, macrophages are the most abundant cell population and are present at all stages of tumor progression. They undergo M1/M2 polarization in response to signals derived from TME. M1 macrophages suppress tumor growth, while their M2 counterparts exert pro-tumoral effects by promoting tumor growth, angiogenesis, metastasis, and resistance to current therapies. Several subsets of the M2 phenotype have been observed, often denoted as M2a, M2b, M2c, and M2d. These are induced by different stimuli and differ in phenotypes as well as functions. In this review, we discuss the key features of each M2 subset, their implications in cancers, and highlight the strategies that are being developed to harness TAMs for cancer treatment.

Despite the undisputed development of medicine, antibiotics still serve as first-choice drugs for patients with infectious disorders. The widespread use of antibiotics results from a wide spectrum of their actions encompassing mechanisms responsible for: the inhibition of bacterial cell wall biosynthesis, the disruption of cell membrane integrity, the suppression of nucleic acids and/or proteins synthesis, as well as disturbances of metabolic processes. However, the widespread availability of antibiotics, accompanied by their overprescription, acts as a double-edged sword, since the overuse and/or misuse of antibiotics leads to a growing number of multidrug-resistant microbes. This, in turn, has recently emerged as a global public health challenge facing both clinicians and their patients. In addition to intrinsic resistance, bacteria can acquire resistance to particular antimicrobial agents through the transfer of genetic material conferring resistance. Amongst the most common bacterial resistance strategies are: drug target site changes, increased cell wall permeability to…

In recent years, research on silver nanoparticles (AgNPs) has attracted considerable interest among scientists because of, among other things, their alternative application to well-known medical agents with antibacterial properties. The size of the silver nanoparticles ranges from 1 to 100 nm. In this paper, we review the progress of research on AgNPs with respect to the synthesis, applications, and toxicological safety of AgNPs, and the issue of in vivo and in vitro research on silver nanoparticles. AgNPs' synthesis methods include physical, chemical, and biological routes, as well as "green synthesis". The content of this article covers issues related to the disadvantages of physical and chemical methods, which are expensive and can also have toxicity. This review pays special attention to AgNP biosafety concerns, such as potential toxicity to cells, tissues, and organs.

To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.

Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.

Wounds are considered to be a serious problem that affects the healthcare sector in many countries, primarily due to diabetes and obesity. Wounds become worse because of unhealthy lifestyles and habits. Wound healing is a complicated physiological process that is essential for restoring the epithelial barrier after an injury. Numerous studies have reported that flavonoids possess wound-healing properties due to their well-acclaimed anti-inflammatory, angiogenesis, re-epithelialization, and antioxidant effects. They have been shown to be able to act on the wound-healing process via expression of biomarkers respective to the pathways that mainly include Wnt/β-catenin, Hippo, Transforming Growth Factor-beta (TGF-β), Hedgehog, c-Jun N-Terminal Kinase (JNK), NF-E2-related factor 2/antioxidant responsive element (Nrf2/ARE), Nuclear Factor Kappa B (NF-κB), MAPK/ERK, Ras/Raf/MEK/ERK, phosphatidylinositol 3-kinase (PI3K)/Akt, Nitric oxide (NO) pathways, etc. Hence, we have compiled existing evidence on the manipulation of flavonoids towards achieving skin wound healing, together with current…

Burns and their treatment are a significant medical problem. The loss of the physical barrier function of the skin opens the door to microbial invasion and can lead to infection. The repair process of the damage caused by the burn is impaired due to the enhanced loss of fluids and minerals through the burn wound, the onset of hypermetabolism with the concomitant disruption of nutrient supply, and derangements in the endocrine system. In addition, the initiated inflammatory and free radical processes drive the progression of oxidative stress, the inhibition of which largely depends on an adequate supply of antioxidants and minerals. Clinical experience and research provide more and more data to make the treatment of patients with thermal injury increasingly effective. The publication discusses disorders occurring in patients after thermal injury and the methods used at various stages of treatment.

Saponins are a diverse group of naturally occurring plant secondary metabolites present in a wide range of foods ranging from grains, pulses, and green leaves to sea creatures. They consist of a hydrophilic sugar moiety linked to a lipophilic aglycone, resulting in an amphiphilic nature and unique functional properties. Their amphiphilic structures enable saponins to exhibit surface-active properties, resulting in stable foams and complexes with various molecules. In the context of food applications, saponins are utilized as natural emulsifiers, foaming agents, and stabilizers. They contribute to texture and stability in food products and have potential health benefits, including cholesterol-lowering and anticancer effects. Saponins possess additional bioactivities that make them valuable in the pharmaceutical industry as anti-inflammatory, antimicrobial, antiviral, and antiparasitic agents to name a few. Saponins can demonstrate cytotoxic activity against cancer cell lines and can also act as adjuvants, enhancing the immune response to vaccines. Their ability to form stable…

Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related…

Hyaluronic acid (HA) is a glycosaminoglycan widely distributed in the human body, especially in body fluids and the extracellular matrix of tissues. It plays a crucial role not only in maintaining tissue hydration but also in cellular processes such as proliferation, differentiation, and the inflammatory response. HA has demonstrated its efficacy as a powerful bioactive molecule not only for skin antiaging but also in atherosclerosis, cancer, and other pathological conditions. Due to its biocompatibility, biodegradability, non-toxicity, and non-immunogenicity, several HA-based biomedical products have been developed. There is an increasing focus on optimizing HA production processes to achieve high-quality, efficient, and cost-effective products. This review discusses HA's structure, properties, and production through microbial fermentation. Furthermore, it highlights the bioactive applications of HA in emerging sectors of biomedicine.

Since their first discovery in the 1960s by Alec Bangham, liposomes have been shown to be effective drug delivery systems for treating various cancers. Several liposome-based formulations received approval by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), with many others in clinical trials. Liposomes have several advantages, including improved pharmacokinetic properties of the encapsulated drug, reduced systemic toxicity, extended circulation time, and targeted disposition in tumor sites due to the enhanced permeability and retention (EPR) mechanism. However, it is worth noting that despite their efficacy in treating various cancers, liposomes still have some potential toxicity and lack specific targeting and disposition. This explains, in part, why their translation into the clinic has progressed only incrementally, which poses the need for more research to focus on addressing such translational limitations. This review summarizes the main properties of liposomes, their current status in cancer therapy, and their limitations and challenges to…

The trace element zinc (Zn) displays a wide range of biological functions. Zn ions control intercellular communication and intracellular events that maintain normal physiological processes. These effects are achieved through the modulation of several Zn-dependent proteins, including transcription factors and enzymes of key cell signaling pathways, namely those involved in proliferation, apoptosis, and antioxidant defenses. Efficient homeostatic systems carefully regulate intracellular Zn concentrations. However, perturbed Zn homeostasis has been implicated in the pathogenesis of several chronic human diseases, such as cancer, diabetes, depression, Wilson's disease, Alzheimer's disease, and other age-related diseases. This review focuses on Zn's roles in cell proliferation, survival/death, and DNA repair mechanisms, outlines some biological Zn targets, and addresses the therapeutic potential of Zn supplementation in some human diseases.

Gastric cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. Helicobacter pylori (H. pylori) is one of the main risk factors for this type of neoplasia. Carcinogenetic mechanisms associated with H. pylori are based, on the one hand, on the onset of chronic inflammation and, on the other hand, on bacterial-specific virulence factors that can damage the DNA of gastric epithelial cells and promote genomic instability. Here, we review and discuss the major pathogenetic mechanisms by which H. pylori infection contributes to the onset and development of gastric cancer.

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein that is secreted mostly by immune cells such as neutrophils, macrophages, and dendritic cells. Its production is stimulated in response to inflammation. The concentrations of NGAL can be measured in plasma, urine, and biological fluids such as peritoneal effluent. NGAL is known mainly as a biomarker of acute kidney injury and is released after tubular damage and during renal regeneration processes. NGAL is also elevated in chronic kidney disease and dialysis patients. It may play a role as a predictor of the progression of renal function decreases with complications and mortality due to kidney failure. NGAL is also useful in the diagnostic processes of cardiovascular diseases. It is highly expressed in injured heart tissue and atherosclerostic plaque; its serum concentrations correlate with the severity of heart failure and coronary artery disease. NGAL increases inflammatory states and its levels rise in arterial hypertension, obesity, diabetes, and metabolic complications such as insulin resistance, and is also…

Endocrine-disrupting chemicals (EDCs) have significant impacts on biological systems, and have been shown to interfere with physiological systems, especially by disrupting the hormone balance. During the last few decades, EDCs have been shown to affect reproductive, neurological, and metabolic development and function and even stimulate tumor growth. EDC exposure during development can disrupt normal development patterns and alter susceptibility to disease. Many chemicals have endocrine-disrupting properties, including bisphenol A, organochlorines, polybrominated flame retardants, alkylphenols, and phthalates. These compounds have gradually been elucidated as risk factors for many diseases, such as reproductive, neural, and metabolic diseases and cancers. Endocrine disruption has been spread to wildlife and species that are connected to the food chains. Dietary uptake represents an important source of EDC exposure. Although EDCs represent a significant public health concern, the relationship and specific mechanism between EDCs and diseases remain unclear. This review focuses on the…

Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal tract, the incidence of which has rapidly increased worldwide, especially in developing and Western countries. Recent research has suggested that genetic factors, the environment, microbiota, and immune responses are involved in the pathogenesis; however, the underlying causes of IBD are unclear. Recently, gut microbiota dysbiosis, especially a decrease in the abundance and diversity of specific genera, has been suggested as a trigger for IBD-initiating events. Improving the gut microbiota and identifying the specific bacterial species in IBD are essential for understanding the pathogenesis and treatment of IBD and autoimmune diseases. Here, we review the different aspects of the role played by gut microbiota in the pathogenesis of IBD and provide a theoretical basis for modulating gut microbiota through probiotics, fecal microbiota transplantation, and microbial metabolites.

Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn's disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota dysbiosis and the disruption of the intestinal barrier, resulting in increased bacterial exposure. In response to signals from microorganisms and damaged tissue, innate immune cells produce inflammatory cytokines and factors that stimulate T and B cells of the adaptive immune system, and a prominent characteristic of IBD patients is the accumulation of inflammatory T-cells and their proinflammatory-associated cytokines in intestinal tissue. Upon antigen recognition and activation, CD4 T-cells differentiate towards a range of distinct phenotypes: T helper(h)1, Th2, Th9, Th17, Th22, T follicular helper (Tfh), and several types of T-regulatory cells (Treg). T-cells are generated according to and adapt to microenvironmental conditions and participate in a complex network of…

Epidermal growth factor receptors (EGFRs) are a class of receptor tyrosine kinase that are also called ErbB1 and HER1. EGFR tyrosine kinase activity inhibition is considered a promising therapeutic strategy for the treatment of cancer. Many small-molecule inhibitors of EGFR tyrosine kinase (EGFR-TK), from medicinally privileged molecules to commercial drugs, have been overviewed. Particular attention has been paid to the structure of the molecule and its mechanism of action if reported. Subsequent classification of the molecules under discussion has been carried out. Both natural and synthetic and reversible and irreversible EGFR-tyrosine kinase inhibitors have been discussed. Various types of cancers that are caused by overexpression of the EGFR gene, their possible molecular origins, and their natures have also been counted in this article. Because the EGFR signaling pathway controls the proliferation, growth, survival, and differentiation of cells, and the mutated EGFR gene overproduces EGFR protein, which ultimately causes several types of cancer, proper understanding of the…

Autism spectrum disorder (ASD) is a heterogeneous, behaviorally defined neurodevelopmental disorder. Over the past two decades, the prevalence of autism spectrum disorders has progressively increased, however, no clear diagnostic markers and specifically targeted medications for autism have emerged. As a result, neurobehavioral abnormalities, neurobiological alterations in ASD, and the development of novel ASD pharmacological therapy necessitate multidisciplinary collaboration. In this review, we discuss the development of multiple animal models of ASD to contribute to the disease mechanisms of ASD, as well as new studies from multiple disciplines to assess the behavioral pathology of ASD. In addition, we summarize and highlight the mechanistic advances regarding gene transcription, RNA and non-coding RNA translation, abnormal synaptic signaling pathways, epigenetic post-translational modifications, brain-gut axis, immune inflammation and neural loop abnormalities in autism to provide a theoretical basis for the next step of precision therapy. Furthermore, we review existing autism…

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication, repetitive behaviors, restricted interests, and hyperesthesia/hypesthesia caused by genetic and/or environmental factors. In recent years, inflammation and oxidative stress have been implicated in the pathogenesis of ASD. In this review, we discuss the inflammation and oxidative stress in the pathophysiology of ASD, particularly focusing on maternal immune activation (MIA). MIA is a one of the common environmental risk factors for the onset of ASD during pregnancy. It induces an immune reaction in the pregnant mother's body, resulting in further inflammation and oxidative stress in the placenta and fetal brain. These negative factors cause neurodevelopmental impairments in the developing fetal brain and subsequently cause behavioral symptoms in the offspring. In addition, we also discuss the effects of anti-inflammatory drugs and antioxidants in basic studies on animals and clinical studies of ASD. Our review provides the latest findings and new insights into…

Baicalin is one of the most abundant flavonoids found in the dried roots of Scutellaria baicalensis Georgi (SBG) belonging to the genus Scutellaria. While baicalin is demonstrated to have anti-inflammatory, antiviral, antitumor, antibacterial, anticonvulsant, antioxidant, hepatoprotective, and neuroprotective effects, its low hydrophilicity and lipophilicity limit the bioavailability and pharmacological functions. Therefore, an in-depth study of baicalin’s bioavailability and pharmacokinetics contributes to laying the theoretical foundation for applied research in disease treatment. In this view, the physicochemical properties and anti-inflammatory activity of baicalin are summarized in terms of bioavailability, drug interaction, and inflammatory conditions.

Despite the physiological role of oxidant molecules, oxidative stress (OS) could underlie several human diseases. When the levels of antioxidants are too low or too high, OS occurs, leading to damage at the molecular, tissue and cellular levels. Therefore, antioxidant compounds could represent a way to modulate OS and/or to maintain proper redox balance. This review provides an overview of the methods available to assess total antioxidant capacity (TAC) in biological systems to elucidate the correct terminology and the pathophysiological roles. The clinical context is fundamental to obtain a correct interpretation of TAC. Hence, we discuss metabolic syndrome and infertility, two clinical conditions that involve OS, including the potential prognostic role of TAC evaluation in monitoring antioxidant supplementation. This approach would provide more personalised and precise therapy.

Although historically, the traditional bidimensional in vitro cell system has been widely used in research, providing much fundamental information regarding cellular functions and signaling pathways as well as nuclear activities, the simplicity of this system does not fully reflect the heterogeneity and complexity of the in vivo systems. From this arises the need to use animals for experimental research and in vivo testing. Nevertheless, animal use in experimentation presents various aspects of complexity, such as ethical issues, which led Russell and Burch in 1959 to formulate the 3R (Replacement, Reduction, and Refinement) principle, underlying the urgent need to introduce non-animal-based methods in research. Considering this, three-dimensional (3D) models emerged in the scientific community as a bridge between in vitro and in vivo models, allowing for the achievement of cell differentiation and complexity while avoiding the use of animals in experimental research. The purpose of this review is to provide a general overview of the most common methods to establish 3D cell culture…

Neuroinflammation is a critical factor in developing and progressing numerous brain diseases, including neurodegenerative diseases. Chronic or excessive neuroinflammation can lead to neurotoxicity, causing brain damage and contributing to the onset and progression of various brain diseases. Therefore, understanding neuroinflammation mechanisms and developing strategies to control them is crucial for treating brain diseases. Studies have shown that neuroinflammation plays a vital role in the progression of neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD), and stroke. Additionally, the effects of PM2.5 pollution on the brain, including neuroinflammation and neurotoxicity, are well-documented. Quercetin is a flavonoid, a plant pigment in many fruits, vegetables, and grains. Quercetin has been studied for its potential health benefits, including its anti-inflammatory, antioxidant, and anti-cancer properties. Quercetin may also have a positive impact on immune function and allergy symptoms. In addition, quercetin has been shown to have anti-inflammatory and…

As the greatest defense organ of the body, the skin is exposed to endogenous and external stressors that produce reactive oxygen species (ROS). When the antioxidant system of the body fails to eliminate ROS, oxidative stress is initiated, which results in skin cellular senescence, inflammation, and cancer. Two main possible mechanisms underlie oxidative stress-induced skin cellular senescence, inflammation, and cancer. One mechanism is that ROS directly degrade biological macromolecules, including proteins, DNA, and lipids, that are essential for cell metabolism, survival, and genetics. Another one is that ROS mediate signaling pathways, such as MAPK, JAK/STAT, PI3K/AKT/mTOR, NF-κB, Nrf2, and SIRT1/FOXO, affecting cytokine release and enzyme expression. As natural antioxidants, plant polyphenols are safe and exhibit a therapeutic potential. We here discuss in detail the therapeutic potential of selected polyphenolic compounds and outline relevant molecular targets. Polyphenols selected here for study according to their structural classification include curcumin, catechins,…

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2 or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex,…

Diabetic neuropathy (DN) is one of the main microvascular complications of both type 1 and type 2 diabetes mellitus. Sometimes, this could already be present at the time of diagnosis for type 2 diabetes mellitus (T2DM), while it appears in subjects with type 1 diabetes mellitus (T1DM) almost 10 years after the onset of the disease. The impairment can involve both somatic fibers of the peripheral nervous system, with sensory-motor manifestations, as well as the autonomic system, with neurovegetative multiorgan manifestations through an impairment of sympathetic/parasympathetic conduction. It seems that, both indirectly and directly, the hyperglycemic state and oxygen delivery reduction through the vasa nervorum can determine inflammatory damage, which in turn is responsible for the alteration of the activity of the nerves. The symptoms and signs are therefore various, although symmetrical painful somatic neuropathy at the level of the lower limbs seems the most frequent manifestation. The pathophysiological aspects underlying the onset and progression of DN are not entirely clear.…

Availability of artificial light and light-emitting devices have altered human temporal life, allowing 24-hour healthcare, commerce and production, and expanding social life around the clock. However, physiology and behavior that evolved in the context of 24 h solar days are frequently perturbed by exposure to artificial light at night. This is particularly salient in the context of circadian rhythms, the result of endogenous biological clocks with a rhythm of ~24 h. Circadian rhythms govern the temporal features of physiology and behavior, and are set to precisely 24 h primarily by exposure to light during the solar day, though other factors, such as the timing of meals, can also affect circadian rhythms. Circadian rhythms are significantly affected by night shift work because of exposure to nocturnal light, electronic devices, and shifts in the timing of meals. Night shift workers are at increased risk for metabolic disorder, as well as several types of cancer. Others who are exposed to artificial light at night or late mealtimes also show disrupted circadian rhythms and increased…

Around 40-50% of all triple-negative breast cancer (TNBC) patients achieve a pathological complete response (pCR) after treatment with neoadjuvant chemotherapy (NAC). The identification of biomarkers predicting the response to NAC could be helpful for personalized treatment. This systematic review provides an overview of putative biomarkers at baseline that are predictive for a pCR following NAC. Embase, Medline and Web of Science were searched for articles published between January 2010 and August 2022. The articles had to meet the following criteria: patients with primary invasive TNBC without distant metastases and patients must have received NAC. In total, 2045 articles were screened by two reviewers resulting in the inclusion of 92 articles. Overall, the most frequently reported biomarkers associated with a pCR were a high expression of Ki-67, an expression of PD-L1 and the abundance of tumor-infiltrating lymphocytes, particularly CD8+ T cells, and corresponding immune gene signatures. In addition, our review reveals proteomic, genomic and transcriptomic markers that relate to…

Nanomaterials have been the focus of intensive development and research in the medical and industrial sectors over the past several decades. Some studies have found that these compounds can have a detrimental impact on living organisms, including their cellular components. Despite the obvious advantages of using nanomaterials in a wide range of applications, there is sometimes skepticism caused by the lack of substantial proof that evaluates potential toxicities. The interactions of nanoparticles (NPs) with cells of the immune system and their biomolecule pathways are an area of interest for researchers. It is possible to modify NPs so that they are not recognized by the immune system or so that they suppress or stimulate the immune system in a targeted manner. In this review, we look at the literature on nanomaterials for immunostimulation and immunosuppression and their impact on how changing the physicochemical features of the particles could alter their interactions with immune cells for the better or for the worse (immunotoxicity). We also look into whether the NPs have a…

Bacterial biofilms can cause widespread infection. In addition to causing urinary tract infections and pulmonary infections in patients with cystic fibrosis, biofilms can help microorganisms adhere to the surfaces of various medical devices, causing biofilm-associated infections on the surfaces of biomaterials such as venous ducts, joint prostheses, mechanical heart valves, and catheters. Biofilms provide a protective barrier for bacteria and provide resistance to antimicrobial agents, which increases the morbidity and mortality of patients. This review summarizes biofilm formation processes and resistance mechanisms, as well as the main features of clinically persistent infections caused by biofilms. Considering the various infections caused by clinical medical devices, we introduce two main methods to prevent and treat biomaterial-related biofilm infection: antibacterial coatings and the surface modification of biomaterials. Antibacterial coatings depend on the covalent immobilization of antimicrobial agents on the coating surface and drug release to prevent and combat infection,…

The phospholipase A2 (PLA2) superfamily of phospholipase enzymes hydrolyzes the ester bond at the sn-2 position of the phospholipids, generating a free fatty acid and a lysophospholipid. The PLA2s are amphiphilic in nature and work only at the water/lipid interface, acting on phospholipid assemblies rather than on isolated single phospholipids. The superfamily of PLA2 comprises at least six big families of isoenzymes, based on their structure, location, substrate specificity and physiologic roles. We are reviewing the secreted PLA2 (sPLA2), cytosolic PLA2 (cPLA2), Ca2+-independent PLA2 (iPLA2), lipoprotein-associated PLA2 (LpPLA2), lysosomal PLA2 (LPLA2) and adipose-tissue-specific PLA2 (AdPLA2), focusing on the differences in their structure, mechanism of action, substrate specificity, interfacial kinetics and tissue distribution. The PLA2s play important roles both physiologically and pathologically, with their expression increasing significantly in diseases such as sepsis, inflammation, different cancers, glaucoma, obesity and Alzheimer’s disease, which are also detailed in this…

Polysaccharides are one of the most abundant natural polymers and their molecular structure influences many crucial characteristics-inter alia hydrophobicity, mechanical, and physicochemical properties. Vibrational spectroscopic techniques, such as infrared (IR) and Raman spectroscopies are excellent tools to study their arrangement during polymerization and cross-linking processes. This review paper summarizes the application of the above-mentioned analytical methods to track the structure of natural polysaccharides, such as cellulose, hemicellulose, glucan, starch, chitosan, dextran, and their derivatives, which affects their industrial and medical use.

Several studies in recent years have demonstrated that gut microbiota-host interactions play an important role in human health and disease, including inflammatory and cardiovascular diseases. Dysbiosis has been linked to not only well-known inflammatory diseases, such as inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematous, but also to cardiovascular risk factors, such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. The ways the microbiota is involved in modulating cardiovascular risk are multiple and not only related to inflammatory mechanisms. Indeed, human and the gut microbiome cooperate as a metabolically active superorganism, and this affects host physiology through metabolic pathways. In turn, congestion of the splanchnic circulation associated with heart failure, edema of the intestinal wall, and altered function and permeability of the intestinal barrier result in the translocation of bacteria and their products into the systemic circulation, further enhancing the pro-inflammatory…

The blood-brain barrier (BBB) is a unique and selective feature of the central nervous system's vasculature. BBB dysfunction has been observed as an early sign of Alzheimer's Disease (AD) before the onset of dementia or neurodegeneration. The intricate relationship between the BBB and the pathogenesis of AD, especially in the context of neurovascular coupling and the overlap of pathophysiology in neurodegenerative and cerebrovascular diseases, underscores the urgency to understand the BBB's role more deeply. Preserving or restoring the BBB function emerges as a potentially promising strategy for mitigating the progression and severity of AD. Molecular and genetic changes, such as the isoform ε4 of apolipoprotein E (ApoEε4), a significant genetic risk factor and a promoter of the BBB dysfunction, have been shown to mediate the BBB disruption. Additionally, receptors and transporters like the low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein (P-gp), and the receptor for advanced glycation end products (RAGEs) have been implicated in AD's pathogenesis. In this…

In the last decade, an increasing awareness was directed to the role of Vitamin D in non-skeletal and preventive roles for chronic diseases. Vitamin D is an essential hormone in regulating calcium/phosphorous balance and in the pathogenesis of inflammation, insulin resistance, and obesity. The main forms of vitamin D, Cholecalciferol (Vitamin D3) and Ergocalciferol (Vitamin D2) are converted into the active form (1,25-dihydroxyvitamin D) thanks to two hydroxylations in the liver, kidney, pancreas, and immune cells. Some anti-inflammatory cytokines are produced at higher levels by vitamin D, while some pro-inflammatory cytokines are released at lower levels. Toll-Like Receptor (TLR) expression is increased, and a pro-inflammatory state is also linked to low levels of vitamin D. Regardless of how it affects inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body may change the ratio of pro- to anti-inflammatory cytokines, which would impact insulin action, lipid metabolism, and the development and…

Diabetes mellitus (DM) is a serious chronic metabolic disease that is associated with hyperglycemia and several complications including cardiovascular disease and chronic kidney disease. DM is caused by high levels of blood sugar in the body associated with the disruption of insulin metabolism and homeostasis. Over time, DM can induce life-threatening health problems such as blindness, heart disease, kidney damage, and stroke. Although the cure of DM has improved over the past decades, its morbidity and mortality rates remain high. Hence, new therapeutic strategies are needed to overcome the burden of this disease. One such prevention and treatment strategy that is easily accessible to diabetic patients at low cost is the use of medicinal plants, vitamins, and essential elements. The research objective of this review article is to study DM and explore its treatment modalities based on medicinal plants and vitamins. To achieve our objective, we searched scientific databases of ongoing trials in PubMed Central, Medline databases, and Google Scholar websites. We also searched databases…

Gene therapy is a technique involving the modification of an individual's genes for treating a particular disease. The key to effective gene therapy is an efficient carrier delivery system. Viral vectors that have been artificially modified to lose their pathogenicity are used widely as a delivery system, with the key advantages of their natural high transduction efficiency and stable expression. With decades of development, viral vector-based gene therapies have achieved promising clinical outcomes. Currently, the three key vector strategies are based on adeno-associated viruses, adenoviruses, and lentiviruses. However, certain challenges, such as immunotoxicity and "off-target", continue to exist. In the present review, the above three viral vectors are discussed along with their respective therapeutic applications. In addition, the major translational challenges encountered in viral vector-based gene therapies are summarized, and the possible strategies to address these challenges are also discussed.

Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of stroke and its sequelae. The acute treatment for stroke is restricted to causative recanalization and restoration of cerebral blood flow, including both intravenous thrombolysis and mechanical thrombectomy. Still, only a limited number of patients are eligible for these time-sensitive treatments. Hence, new neuroprotective approaches are urgently needed. Neuroprotection is thus defined as an intervention resulting in the preservation, recovery, and/or regeneration of the nervous system by interfering with the ischemic-triggered stroke cascade. Despite numerous preclinical studies generating promising data for several neuroprotective agents, successful bench-to-bedside translations are still lacking. The present study provides an overview of current approaches in the research field of neuroprotective stroke treatment. Aside from "traditional" neuroprotective drugs focusing on inflammation, cell death, and excitotoxicity,…

Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages' responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid β-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of…

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications,…

Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal…

Natural ingredients have been used for centuries for skin treatment and care. Interest in the health effects of plants has recently increased due to their safety and applicability in the formulation of pharmaceuticals and cosmetics. Long-known plant materials as well as newly discovered ones are increasingly being used in natural products of plant origin. This review highlights the beneficial effects of plants and plant constituents on the skin, including moisturizing (e.g., Cannabis sativa, Hydrangea serrata, Pradosia mutisii and Carthamus tinctorius), anti-aging (e.g., Aegopodium podagraria, Euphorbia characias, Premna odorata and Warburgia salutaris), antimicrobial (e.g., Betula pendula and Epilobium angustifolium), antioxidant (e.g., Kadsura coccinea, Rosmarinus officinalis, Rubus idaeus and Spatholobus suberectus), anti-inflammatory (e.g., Antidesma thwaitesianum, Helianthus annuus, Oenanthe javanica, Penthorum chinense, Ranunculus bulumei and Zanthoxylum bungeanum), regenerative (e.g., Aloe vera, Angelica polymorpha, Digitaria ciliaris, Glycyrrihza glabra and Marantodes…

Antibacterial chitosan films, versatile and eco-friendly materials, have garnered significant attention in both the food industry and medicine due to their unique properties, including biodegradability, biocompatibility, and antimicrobial activity. This review delves into the various types of chitosan films and their distinct applications. The categories of films discussed span from pure chitosan films to those enhanced with additives such as metal nanoparticles, metal oxide nanoparticles, graphene, fullerene and its derivatives, and plant extracts. Each type of film is examined in terms of its synthesis methods and unique properties, establishing a clear understanding of its potential utility. In the food industry, these films have shown promise in extending shelf life and maintaining food quality. In the medical field, they have been utilized for wound dressings, drug delivery systems, and as antibacterial coatings for medical devices. The review further suggests that the incorporation of different additives can significantly enhance the antibacterial properties of chitosan films.…

Biological membranes, primarily composed of lipids, envelop each living cell. The intricate composition and organization of membrane lipids, including the variety of fatty acids they encompass, serve a dynamic role in sustaining cellular structural integrity and functionality. Typically, modifications in lipid composition coincide with consequential alterations in universally significant signaling pathways. Exploring the various fatty acids, which serve as the foundational building blocks of membrane lipids, provides crucial insights into the underlying mechanisms governing a myriad of cellular processes, such as membrane fluidity, protein trafficking, signal transduction, intercellular communication, and the etiology of certain metabolic disorders. Furthermore, comprehending how alterations in the lipid composition, especially concerning the fatty acid profile, either contribute to or prevent the onset of pathological conditions stands as a compelling area of research. Hence, this review aims to meticulously introduce the intricacies of membrane lipids and their constituent fatty…

Sex hormones are key determinants of gender-related differences and regulate growth and development during puberty. They also exert a broad range modulation of immune cell functions, and a dichotomy exists in the immune response between the sexes. Both clinical and animal models have demonstrated that androgens, estrogens, and progestogens mediate many of the gender-specific differences in immune responses, from the susceptibility to infectious diseases to the prevalence of autoimmune disorders. Androgens and progestogens mainly promote immunosuppressive or immunomodulatory effects, whereas estrogens enhance humoral immunity both in men and in women. This study summarizes the available evidence regarding the physiological effects of sex hormones on human immune cell function and the underlying biological mechanisms, focusing on gender differences triggered by different amounts of androgens between males and females.

In this review, we delve into the realm of photodynamic therapy (PDT), an established method for combating cancer. The foundation of PDT lies in the activation of a photosensitizing agent using specific wavelengths of light, resulting in the generation of reactive oxygen species (ROS), notably singlet oxygen (1O2). We explore PDT’s intricacies, emphasizing its precise targeting of cancer cells while sparing healthy tissue. We examine the pivotal role of singlet oxygen in initiating apoptosis and other cell death pathways, highlighting its potential for minimally invasive cancer treatment. Additionally, we delve into the complex interplay of cellular components, including catalase and NOX1, in defending cancer cells against PDT-induced oxidative and nitrative stress. We unveil an intriguing auto-amplifying mechanism involving secondary singlet oxygen production and catalase inactivation, offering promising avenues for enhancing PDT’s effectiveness. In conclusion, our review unravels PDT’s inner workings and underscores the importance of selective illumination and photosensitizer…

Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory immune-mediated disease characterized by musculoskeletal inflammation (arthritis, enthesitis, spondylitis, and dactylitis), generally occurs in patients with psoriasis. PsA is also associated with uveitis and inflammatory bowel disease (Crohn's disease and ulcerative colitis). To capture these manifestations as well as the associated comorbidities, and to recognize their underlining common pathogenesis, the name of psoriatic disease was coined. The pathogenesis of PsA is complex and multifaceted, with an interplay of genetic predisposition, triggering environmental factors, and activation of the innate and adaptive immune system, although autoinflammation has also been implicated. Research has identified several immune-inflammatory pathways defined by cytokines (IL-23/IL-17, TNF), leading to the development of efficacious therapeutic targets. However, heterogeneous responses to these drugs occur in different patients and in the different tissues involved, resulting in a challenge to the global management of the disease.…

Nano-range bioactive colloidal carrier systems are envisaged to overcome the challenges associated with treatments of numerous diseases. Lipid nanoparticles (LNPs), one of the extensively investigated drug delivery systems, not only improve pharmacokinetic parameters, transportation, and chemical stability of encapsulated compounds but also provide efficient targeting and reduce the risk of toxicity. Over the last decades, nature-derived polyphenols, vitamins, antioxidants, dietary supplements, and herbs have received more attention due to their remarkable biological and pharmacological health and medical benefits. However, their poor aqueous solubility, compromised stability, insufficient absorption, and accelerated elimination impede research in the nutraceutical sector. Owing to the possibilities offered by various LNPs, their ability to accommodate both hydrophilic and hydrophobic molecules and the availability of various preparation methods suitable for sensitive molecules, loading natural fragile molecules into LNPs offers a promising solution. The primary objective of this…

Biopolymeric nanoparticles are gaining importance as nanocarriers for various biomedical applications, enabling long-term and controlled release at the target site. Since they are promising delivery systems for various therapeutic agents and offer advantageous properties such as biodegradability, biocompatibility, non-toxicity, and stability compared to various toxic metal nanoparticles, we decided to provide an overview on this topic. Therefore, the review focuses on the use of biopolymeric nanoparticles of animal, plant, algal, fungal, and bacterial origin as a sustainable material for potential use as drug delivery systems. A particular focus is on the encapsulation of many different therapeutic agents categorized as bioactive compounds, drugs, antibiotics, and other antimicrobial agents, extracts, and essential oils into protein- and polysaccharide-based nanocarriers. These show promising benefits for human health, especially for successful antimicrobial and anticancer activity. The review article, divided into protein-based and polysaccharide-based biopolymeric nanoparticles…

It is generally accepted that diet-derived polyphenols are bioactive compounds with several potentially beneficial effects on human health. In general, polyphenols have several chemical structures, and the most representative are flavonoids, phenolic acids, and stilbenes. It should be noted that the beneficial effects of polyphenols are closely related to their bioavailability and bioaccessibility, as many of them are rapidly metabolized after administration. Polyphenols—with a protective effect on the gastrointestinal tract—promote the maintenance of the eubiosis of the intestinal microbiota with protective effects against gastric and colon cancers. Thus, the benefits obtained from dietary supplementation of polyphenols would seem to be mediated by the gut microbiota. Taken at certain concentrations, polyphenols have been shown to positively modulate the bacterial component, increasing Lactiplantibacillus spp. and Bifidobacterium spp. involved in the protection of the intestinal barrier and decreasing Clostridium and Fusobacterium, which are negatively associated with human…

Antibiotic therapy through short-term or repeated long-term prescriptions can have several damaging effects on the normal microbiota of the gastrointestinal tract. Changes in microbiota could be multiple including decreased diversity of species in gut microbiota, changed metabolic activity, and the occurrence of antibiotic-resistant strains. Antibiotic-induced gut dysbiosis in turn can induce antibiotic-associated diarrhoea and recurrent infections caused by Clostridioides difficile. There is also evidence that the use of different chemical classes of antibiotics for the treatment of a variety of ailments can lead to several health issues including gastrointestinal, immunologic, and neurocognitive conditions. This review discusses gut dysbiosis, its symptoms and one important cause, which is antibiotic therapy for the induction of gut dysbiosis. Since the maintenance of good gut health is important for the well-being and functioning of physiological and cognitive activities through the normal gut-microbiota–brain relationship, the condition of dysbiosis is not desirable. Specific…

Our skin is the largest organ of the body, serving as an important barrier against the harsh extrinsic environment. Alongside preventing desiccation, chemical damage and hypothermia, this barrier protects the body from invading pathogens through a sophisticated innate immune response and co-adapted consortium of commensal microorganisms, collectively termed the microbiota. These microorganisms inhabit distinct biogeographical regions dictated by skin physiology. Thus, it follows that perturbations to normal skin homeostasis, as occurs with ageing, diabetes and skin disease, can cause microbial dysbiosis and increase infection risk. In this review, we discuss emerging concepts in skin microbiome research, highlighting pertinent links between skin ageing, the microbiome and cutaneous repair. Moreover, we address gaps in current knowledge and highlight key areas requiring further exploration. Future advances in this field could revolutionise the way we treat microbial dysbiosis associated with skin ageing and other pathologies.

Copper is a metal historically used to prevent infections. One of the most relevant challenges in modern society are infectious disease outbreaks, where copper-based technologies can play a significant role. Currently, copper nanoparticles and surfaces are the most common antimicrobial copper-based technologies. Despite the widespread use of copper on nanoparticles and surfaces, the toxicity mechanism(s) explaining their unique antimicrobial properties are not entirely known. In general, toxicity effects described in bacteria and fungi involve the rupture of membranes, accumulation of ions inside the cell, protein inactivation, and DNA damage. A few studies have associated Cu-toxicity with ROS production and genetic material degradation in viruses. Therefore, understanding the mechanisms of the toxicity of copper nanoparticles and surfaces will contribute to developing and implementing efficient antimicrobial technologies to combat old and new infectious agents that can lead to disease outbreaks such as COVID-19. This review summarizes the current knowledge regarding the microbial…

Nano-hydroxyapatite (n-HAp) is similar to human bone mineral in structure and biochemistry and is, therefore, widely used as bone biomaterial and a drug carrier. Further, n-HAp composite scaffolds have a great potential role in bone regeneration. Loading bioactive factors and drugs onto n-HAp composites has emerged as a promising strategy for bone defect repair in bone tissue engineering. With local delivery of bioactive agents and drugs, biological materials may be provided with the biological activity they lack to improve bone regeneration. This review summarizes classification of n-HAp composites, application of n-HAp composite scaffolds loaded with bioactive factors and drugs in bone tissue engineering and the drug loading methods of n-HAp composite scaffolds, and the research direction of n-HAp composite scaffolds in the future is prospected.

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR), and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptors (INSRs). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay…

Mitochondria, the membrane-bound cell organelles that supply most of the energy needed for cell function, are highly regulated, dynamic organelles bearing the ability to alter both form and functionality rapidly to maintain normal physiological events and challenge stress to the cell. This amazingly vibrant movement and distribution of mitochondria within cells is controlled by the highly coordinated interplay between mitochondrial dynamic processes and fission and fusion events, as well as mitochondrial quality-control processes, mainly mitochondrial autophagy (also known as mitophagy). Fusion connects and unites neighboring depolarized mitochondria to derive a healthy and distinct mitochondrion. In contrast, fission segregates damaged mitochondria from intact and healthy counterparts and is followed by selective clearance of the damaged mitochondria via mitochondrial specific autophagy, i.e., mitophagy. Hence, the mitochondrial processes encompass all coordinated events of fusion, fission, mitophagy, and biogenesis for sustaining mitochondrial homeostasis. Accumulated evidence…

Neurological disorders have been linked to a defective blood-brain barrier (BBB), with dysfunctions triggered by stage-specific disease mechanisms, some of these being generated through interactions in the neurovascular unit (NVU). Advanced knowledge of molecular and signaling mechanisms in the NVU and the emergence of improved experimental models allow BBB permeability prediction and the development of new brain-targeted therapies. As NVU constituents, astrocytes are the most numerous glial cells, characterized by a heterogeneity that occurs as a result of developmental and context-based gene expression profiles and the differential expression of non-coding ribonucleic acids (RNAs). Due to their heterogeneity and dynamic responses to different signals, astrocytes may have a beneficial or detrimental role in the BBB's barrier function, with deep effects on the pathophysiology of (and on the progression of) central nervous system diseases. The implication of astrocytic-derived extracellular vesicles in pathological mechanisms, due to their ability to pass the BBB, must also be…

The transition from normal to chronic pain is believed to involve alterations in several brain areas that participate in the perception of pain. These plastic changes are then responsible for aberrant pain perception and comorbidities. The insular cortex is consistently found activated in pain studies of normal and chronic pain patients. Functional changes in the insula contribute to chronic pain; however, the complex mechanisms by which the insula is involved in pain perception under normal and pathological conditions are still not clear. In this review, an overview of the insular function is provided and findings on its role in pain from human studies are summarized. Recent progress on the role of the insula in pain from preclinical experimental models is reviewed, and the connectivity of the insula with other brain regions is examined to shed new light on the neuronal mechanisms of the insular cortex's contribution to normal and pathological pain sensation. This review underlines the need for further studies on the mechanisms underlying the involvement of the insula in the…

Heavy metals are defined as metals with relatively high density and atomic weight, and their various applications have raised serious concerns about the environmental impacts and potential human health effects. Chromium is an important heavy metal that is involved in biological metabolism, but Cr exposure can induce a severe impact on occupational workers or public health. In this study, we explore the toxic effects of Cr exposure through three exposure routes: dermal contact, inhalation, and ingestion. We propose the underlying toxicity mechanisms of Cr exposure based on transcriptomic data and various bioinformatic tools. Our study provides a comprehensive understanding of the toxicity mechanisms of different Cr exposure routes by diverse bioinformatics analyses.

Organ-on-A-chip (OoAC) devices are miniaturized, functional, in vitro constructs that aim to recapitulate the in vivo physiology of an organ using different cell types and extracellular matrix, while maintaining the chemical and mechanical properties of the surrounding microenvironments. From an end-point perspective, the success of a microfluidic OoAC relies mainly on the type of biomaterial and the fabrication strategy employed. Certain biomaterials, such as PDMS (polydimethylsiloxane), are preferred over others due to their ease of fabrication and proven success in modelling complex organ systems. However, the inherent nature of human microtissues to respond differently to surrounding stimulations has led to the combination of biomaterials ranging from simple PDMS chips to 3D-printed polymers coated with natural and synthetic materials, including hydrogels. In addition, recent advances in 3D printing and bioprinting techniques have led to the powerful combination of utilizing these materials to develop microfluidic OoAC devices. In this narrative review, we evaluate the different…

Inflammation has been described for two millennia, but cellular aspects and the paradigm involving different mediators have been identified in the recent century. Two main groups of molecules, the prostaglandins (PG) and the cytokines, have been discovered and play a major role in inflammatory processes. The activation of prostaglandins PGE2, PGD2 and PGI2 results in prominent symptoms during cardiovascular and rheumatoid diseases. The balance between pro- and anti-inflammatory compounds is nowadays a challenge for more targeted therapeutic approaches. The first cytokine was described more than a century ago and is now a part of different families of cytokines (38 interleukins), including the IL-1 and IL-6 families and TNF and TGFβ families. Cytokines can perform a dual role, being growth promotors or inhibitors and having pro- and anti-inflammatory properties. The complex interactions between cytokines, vascular cells and immune cells are responsible for dramatic conditions and lead to the concept of cytokine storm observed during sepsis, multi-organ failure and, recently, in some…

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and…

Manganese (Mn) is an essential trace element with unique functions in the body; it acts as a cofactor for many enzymes involved in energy metabolism, the endogenous antioxidant enzyme systems, neurotransmitter production, and the regulation of reproductive hormones. However, overexposure to Mn is toxic, particularly to the central nervous system (CNS) due to it causing the progressive destruction of nerve cells. Exposure to manganese is widespread and occurs by inhalation, ingestion, or dermal contact. Associations have been observed between Mn accumulation and neurodegenerative diseases such as manganism, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. People with genetic diseases associated with a mutation in the gene associated with impaired Mn excretion, kidney disease, iron deficiency, or a vegetarian diet are at particular risk of excessive exposure to Mn. This review has collected data on the current knowledge of the source of Mn exposure, the experimental data supporting the dispersive accumulation of Mn in the brain, the…

Cardiovascular disease, particularly coronary artery disease (CAD), remains a predominant cause of mortality globally. Factors such as atherosclerosis and inflammation play significant roles in the pathogenesis of CAD. The nexus between inflammation and CAD is underscored by the role of immune cells, such as neutrophils, lymphocytes, monocytes, and macrophages. These cells orchestrate the inflammatory process, a core component in the initiation and progression of atherosclerosis. The activation of these pathways and the subsequent lipid, fibrous element, and calcification accumulation can result in vessel narrowing. Hematological parameters derived from routine blood tests offer insights into the underlying inflammatory state. Recent studies have highlighted the potential of inflammatory hematological ratios, such as the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, monocyte/lymphocyte ratio and lymphocyte/monocyte ratio. These parameters are not only accessible and cost-effective but also mirror the degree of systemic inflammation. Several studies have indicated a…

Secondary metabolism plays an important role in the adaptation of plants to their environments, particularly by mediating bio-interactions and protecting plants from herbivores, insects, and pathogens. Terpenoids form the largest group of plant secondary metabolites, and their biosynthesis and regulation are extremely complicated. Terpenoids are key players in the interactions and defense reactions between plants, microorganisms, and animals. Terpene compounds are of great significance both to plants themselves and the ecological environment. On the one hand, while protecting plants themselves, they can also have an impact on the environment, thereby affecting the evolution of plant communities and even ecosystems. On the other hand, their economic value is gradually becoming clear in various aspects of human life; their potential is enormous, and they have broad application prospects. Therefore, research on terpenoids is crucial for plants, especially crops. This review paper is mainly focused on the following six aspects: plant terpenes (especially terpene volatiles and plant…

Millions of people are affected by pain-related conditions worldwide. Literature has consistently shown that each individual experiences and perceives pain in a unique manner due to biological, environmental, and cultural factors in which they have been raised. It has been established that biological males and females perceive pain differently and that it may be partially explained by their distinct hormonal profiles since birth, which are only further magnified during puberty. For biological males, high levels of testosterone have shown to increase their pain threshold; and for biological females, estrogen fluctuations have shown to increase pain intensity and perception. However, sex hormones have not been studied in the context of pain treatment or their impact on biochemical pathways involved in pain perception. For this purpose, the transgender community serves as a unique population to investigate the impact of hormone replacement therapy on molecular pathways involved in the perception of pain. The purpose of this review is to explore the biochemistry of hormone replacement…

CRISPR/Cas9-mediated cleavage of DNA, which depends on the endonuclease activity of Cas9, has been widely used for gene editing due to its excellent programmability and specificity. However, the changes to the DNA sequence that are mediated by CRISPR/Cas9 affect the structures and stability of the genome, which may affect the accuracy of results. Mutations in the RuvC and HNH regions of the Cas9 protein lead to the inactivation of Cas9 into dCas9 with no endonuclease activity. Despite the loss of endonuclease activity, dCas9 can still bind the DNA strand using guide RNA. Recently, proteins with active/inhibitory effects have been linked to the end of the dCas9 protein to form fusion proteins with transcriptional active/inhibitory effects, named CRISPRa and CRISPRi, respectively. These CRISPR tools mediate the transcription activity of protein-coding and non-coding genes by regulating the chromosomal modification states of target gene promoters, enhancers, and other functional elements. Here, we highlight the epigenetic mechanisms and applications of the common CRISPR/dCas9 tools, by…

Piperidines are among the most important synthetic fragments for designing drugs and play a significant role in the pharmaceutical industry. Their derivatives are present in more than twenty classes of pharmaceuticals, as well as alkaloids. The current review summarizes recent scientific literature on intra- and intermolecular reactions leading to the formation of various piperidine derivatives: substituted piperidines, spiropiperidines, condensed piperidines, and piperidinones. Moreover, the pharmaceutical applications of synthetic and natural piperidines were covered, as well as the latest scientific advances in the discovery and biological evaluation of potential drugs containing piperidine moiety. This review is designed to help both novice researchers taking their first steps in this field and experienced scientists looking for suitable substrates for the synthesis of biologically active piperidines.