Acute liver injury (ALI) is a globally important public health issue that, when severe, rapidly progresses to acute liver failure, seriously compromising the life safety of patients. The pathogenesis of ALI is defined by massive cell death in the liver, which triggers a cascade of immune responses. Studies have shown that the aberrant activation of the nod-like receptor protein 3 (NLRP3) inflammasome plays an important role in various types of ALI and that the activation of the NLRP3 inflammasome causes various types of programmed cell death (PCD), and these cell death effectors can in turn regulate NLRP3 inflammasome activation. This indicates that NLRP3 inflammasome activation is inextricably linked to PCD. In this review, we summarize the role of NLRP3 inflammasome activation and PCD in various types of ALI (APAP, liver ischemia reperfusion, CCl₄, alcohol, Con A, and LPS/D-GalN induced ALI) and analyze the underlying mechanisms to provide references for future relevant studies. Full article

Intranasal (IN) drug delivery is a non-invasive and effective route for the administration of drugs to the brain at pharmacologically relevant concentrations, bypassing the blood–brain barrier (BBB) and minimizing adverse side effects. IN drug delivery can be particularly promising for the treatment of neurodegenerative diseases. The drug delivery mechanism involves the initial drug penetration through the nasal epithelial barrier, followed by drug diffusion in the perivascular or perineural spaces along the olfactory or trigeminal nerves, and final extracellular diffusion throughout the brain. A part of the drug may be lost by drainage through the lymphatic system, while a part may even enter the systemic circulation and reach the brain by crossing the BBB. Alternatively, drugs can be directly transported to the brain by axons of the olfactory nerve. To improve the effectiveness of drug delivery to the brain by the IN route, various types of nanocarriers and hydrogels and their combinations have been proposed. This review paper analyzes the main biomaterials-based strategies to enhance IN drug delivery to the brain, outlining unsolved challenges and proposing ways to address them. Full article

Plastic pollution is a significant problem worldwide because of the risks it poses to the equilibrium and health of the environment as well as to human beings. Discarded plastic released into the environment can degrade into microplastics (MPs) due to various factors, such as sunlight, seawater flow, and temperature. MP surfaces can act as solid scaffolds for microorganisms, viruses, and various biomolecules (such as LPS, allergens, and antibiotics), depending on the MP characteristics of size/surface area, chemical composition, and surface charge. The immune system has efficient recognition and elimination mechanisms for pathogens, foreign agents, and anomalous molecules, including pattern recognition receptors and phagocytosis. However, associations with MPs can modify the physical, structural, and functional characteristics of microbes and biomolecules, thereby changing their interactions with the host immune system (in particular with innate immune cells) and, most likely, the features of the subsequent innate/inflammatory response. Thus, exploring differences in the immune response to microbial agents that have been modified by interactions with MPs is meaningful in terms of identifying new possible risks to human health posed by anomalous stimulation of immune reactivities. Full article

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death globally. Tumor cells recruit and remodel various types of stromal and inflammatory cells to form a tumor microenvironment (TME), which encompasses cellular and molecular entities, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), immune cells, myeloid-derived suppressor cells (MDSCs), immune checkpoint molecules and cytokines that promote cancer cell growth, as well as their drug resistance. HCC usually arises in the context of cirrhosis, which is always associated with an enrichment of activated fibroblasts that are owed to chronic inflammation. CAFs are a major component of the TME, providing physical support in it and secreting various proteins, such as extracellular matrices (ECMs), hepatocyte growth factor (HGF), insulin-like growth factor 1/2 (ILGF1/2) and cytokines that can modulate tumor growth and survival. As such, CAF-derived signaling may increase the pool of resistant cells, thus reducing the duration of clinical responses and increasing the degree of heterogeneity within tumors. Although CAFs are often implicated to be associated with tumor growth, metastasis and drug resistance, several studies have reported that CAFs have significant phenotypic and functional heterogeneity, and some CAFs display antitumor and drug-sensitizing properties. Multiple studies have highlighted the relevance of crosstalk between HCC cells, CAFs and other stromal cells in influence of HCC progression. Although basic and clinical studies partially revealed the emerging roles of CAFs in immunotherapy resistance and immune evasion, a better understanding of the unique functions of CAFs in HCC progression will contribute to development of more effective molecular-targeted drugs. In this review article, molecular mechanisms involved in crosstalk between CAFs, HCC cells and other stromal cells, as well as the effects of CAFs on HCC-cell growth, metastasis, drug resistance and clinical outcomes, are comprehensively discussed. Full article

Dysbiosis has been identified in many dermatological conditions (e.g., psoriasis, atopic dermatitis, systemic lupus erythematosus). One of the ways by which the microbiota affect homeostasis is through microbiota-derived molecules (metabolites). There are three main groups of metabolites: short-chain fatty acids (SCFAs), tryptophan metabolites, and amine derivatives including trimethylamine N-oxide (TMAO). Each group has its own uptake and specific receptors through which these metabolites can exert their systemic function. This review provides up-to-date knowledge about the impact that these groups of gut microbiota metabolites may have in dermatological conditions. Special attention is paid to the effect of microbial metabolites on the immune system, including changes in the profile of the immune cells and cytokine disbalance, which are characteristic of several dermatological diseases, especially psoriasis and atopic dermatitis. Targeting the production of microbiota metabolites may serve as a novel therapeutic approach in several immune-mediated dermatological diseases. Full article

Vascular remodeling is a common pathological hallmark of many cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant cell type lining the tunica media and play a crucial role in maintaining aortic morphology, integrity, contraction and elasticity. Their abnormal proliferation, migration, apoptosis and other activities are tightly associated with a spectrum of structural and functional alterations in blood vessels. Emerging evidence suggests that mitochondria, the energy center of VSMCs, participate in vascular remodeling through multiple mechanisms. For example, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis prevents VSMCs from proliferation and senescence. The imbalance between mitochondrial fusion and fission controls the abnormal proliferation, migration and phenotypic transformation of VSMCs. Guanosine triphosphate-hydrolyzing enzymes, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy protein 1 (OPA1) and dynamin-related protein 1 (DRP1), are crucial for mitochondrial fusion and fission. In addition, abnormal mitophagy accelerates the senescence and apoptosis of VSMCs. PINK/Parkin and NIX/BINP3 pathways alleviate vascular remodeling by awakening mitophagy in VSMCs. Mitochondrial DNA (mtDNA) damage destroys the respiratory chain of VSMCs, resulting in excessive ROS production and decreased ATP levels, which are related to the proliferation, migration and apoptosis of VSMCs. Thus, maintaining mitochondrial homeostasis in VSMCs is a possible way to relieve pathologic vascular remodeling. This review aims to provide an overview of the role of mitochondria homeostasis in VSMCs during vascular remodeling and potential mitochondria-targeted therapies. Full article

Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ET_A) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ET_A receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment. Full article

Orchidaceae is one of the largest families of angiosperms. Considering the large number of species in this family and its symbiotic relationship with fungi, Orchidaceae provide an ideal model to study the evolution of plant mitogenomes. However, to date, there is only one draft mitochondrial genome of this family available. Here, we present a fully assembled and annotated sequence of the mitochondrial genome (mitogenome) of Paphiopedilum micranthum, a species with high economic and ornamental value. The mitogenome of P. micranthum was 447,368 bp in length and comprised 26 circular subgenomes ranging in size from 5973 bp to 32,281 bp. The genome encoded for 39 mitochondrial-origin, protein-coding genes; 16 tRNAs (three of plastome origin); three rRNAs; and 16 ORFs, while rpl10 and sdh3 were lost from the mitogenome. Moreover, interorganellar DNA transfer was identified in 14 of the 26 chromosomes. These plastid-derived DNA fragments represented 28.32% (46,273 bp) of the P. micranthum plastome, including 12 intact plastome origin genes. Remarkably, the mitogenome of P. micranthum and Gastrodia elata shared 18% (about 81 kb) of their mitochondrial DNA sequences. Additionally, we found a positive correlation between repeat length and recombination frequency. The mitogenome of P. micranthum had more compact and fragmented chromosomes compared to other species with multichromosomal structures. We suggest that repeat-mediated homologous recombination enables the dynamic structure of mitochondrial genomes in Orchidaceae. Full article

Biopolymers are an emerging class of novel materials with diverse applications and properties such as superior sustainability and tunability. Here, applications of biopolymers are described in the context of energy storage devices, namely lithium-based batteries, zinc-based batteries, and capacitors. Current demand for energy storage technologies calls for improved energy density, preserved performance overtime, and more sustainable end-of-life behavior. Lithium-based and zinc-based batteries often face anode corrosion from processes such as dendrite formation. Capacitors typically struggle with achieving functional energy density caused by an inability to efficiently charge and discharge. Both classes of energy storage need to be packaged with sustainable materials due to their potential leakages of toxic metals. In this review paper, recent progress in energy applications is described for biocompatible polymers such as silk, keratin, collagen, chitosan, cellulose, and agarose. Fabrication techniques are described for various components of the battery/capacitors including the electrode, electrolyte, and separators with biopolymers. Of these methods, incorporating the porosity found within various biopolymers is commonly used to maximize ion transport in the electrolyte and prevent dendrite formations in lithium-based, zinc-based batteries, and capacitors. Overall, integrating biopolymers in energy storage solutions poses a promising alternative that can theoretically match traditional energy sources while eliminating harmful consequences to the environment. Full article

Cellular growth and the preparation of cells for division between two successive cell divisions is called the cell cycle. The cell cycle is divided into several phases; the length of these particular cell cycle phases is an important characteristic of cell life. The progression of cells through these phases is a highly orchestrated process governed by endogenous and exogenous factors. For the elucidation of the role of these factors, including pathological aspects, various methods have been developed. Among these methods, those focused on the analysis of the duration of distinct cell cycle phases play important role. The main aim of this review is to guide the readers through the basic methods of the determination of cell cycle phases and estimation of their length, with a focus on the effectiveness and reproducibility of the described methods. Full article

This paper reviews recent studies investigating chitosan nanoparticles as drug delivery systems for quercetin. The therapeutic properties of quercetin include antioxidant, antibacterial and anti-cancer potential, but its therapeutic value is limited by its hydrophobic nature, low bioavailability and fast metabolism. Quercetin may also act synergistically with other stronger drugs for specific disease states. The encapsulation of quercetin in nanoparticles may increase its therapeutic value. Chitosan nanoparticles are a popular candidate in preliminary research, but the complex nature of chitosan makes standardisation difficult. Recent studies have used in-vitro, and in-vivo experiments to study the delivery of quercetin alone or in combination with another active pharmaceutical ingredient encapsulated in chitosan nanoparticles. These studies were compared with the administration of non-encapsulated quercetin formulation. Results suggest that encapsulated nanoparticle formulations are better. In-vivo or animal models simulated the type of disease required to be treated. The types of diseases were breast, lung, liver and colon cancers, mechanical and UVB-induced skin damage, cataracts and general oxidative stress. The reviewed studies included various routes of administration: oral, intravenous and transdermal routes. Although toxicity tests were often included, it is believed that the toxicity of loaded nanoparticles needs to be further researched, especially when not orally administered. Full article

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. Its heterogeneous clinical presentation is characterized by hyperandrogenemia, reproductive changes, polycystic ovary morphology, and insulin resistance (IR). The primary pathophysiological process in its multifactorial etiology has not yet been identified. However, the two most proposed core etiologies are the disruption of insulin metabolism and hyperandrogenemia, both of which begin to intertwine and propagate each other in the later stages of the disease. Insulin metabolism can be viewed as the interconnectedness of beta cell function, IR or insulin sensitivity, and insulin clearance. Previous studies of insulin metabolism in PCOS patients have yielded conflicting results, and literature reviews have focused mainly on the molecular mechanisms and clinical implications of IR. In this narrative review, we comprehensively explored the role of insulin secretion, clearance, and decreased sensitivity in target cells as a potential primary insult in PCOS pathogenesis, along with the molecular mechanism behind IR in PCOS. Full article

The role of dysbiosis in the development and progression of oral potentially malignant disorders (OPMDs) remains largely unknown. Here, we aim to characterize and compare the oral microbiome of homogeneous leucoplakia (HL), proliferative verrucous leukoplakia (PVL), oral squamous cell carcinoma (OSCC), and OSCC preceded by PVL (PVL-OSCC). Fifty oral biopsies from HL (n = 9), PVL (n = 12), OSCC (n = 10), PVL-OSCC (n = 8), and healthy (n = 11) donors were obtained. The sequence of the V3–V4 region of the 16S rRNA gene was used to analyze the composition and diversity of bacterial populations. In the cancer patients, the number of observed amplicon sequence variants (ASVs) was lower and Fusobacteriota constituted more than 30% of the microbiome. PVL and PVL-OSCC patients had a higher abundance of Campilobacterota and lower Proteobacteria than any other group analyzed. A penalized regression was performed to determine which species were able to distinguish groups. HL is enriched in Streptococcus parasanguinis, Streptococcus salivarius, Fusobacterium periodonticum, Prevotella histicola, Porphyromonas pasteri, and Megasphaera micronuciformis; PVL is enriched in Prevotella salivae, Campylobacter concisus, Dialister pneumosintes, and Schaalia odontolytica; OSCC is enriched in Capnocytophaga leadbetteri, Capnocytophaga sputigena, Capnocytophaga gingivalis, Campylobacter showae, Metamycoplasma salivarium, and Prevotella nanceiensis; and PVL-OSCC is enriched in Lachnospiraceae bacterium, Selenomonas sputigena, and Prevotella shahii. There is differential dysbiosis in patients suffering from OPMDs and cancer. To the best of our knowledge, this is the first study comparing the oral microbiome alterations in these groups; thus, additional studies are needed. Full article

The oxytocin receptor (OXTR), encoded by the OXTR gene, is responsible for the signal transduction after binding its ligand, oxytocin. Although this signaling is primarily involved in controlling maternal behavior, it was demonstrated that OXTR also plays a role in the development of the nervous system. Therefore, it is not a surprise that both the ligand and the receptor are involved in the modulation of behaviors, especially those related to sexual, social, and stress-induced activities. As in the case of every regulatory system, any disturbances in the structures or functions of oxytocin and OXTR may lead to the development or modulation of various diseases related to the regulated functions, which in this case include either mental problems (autism, depression, schizophrenia, obsessive-compulsive disorders) or those related to the functioning of reproductive organs (endometriosis, uterine adenomyosis, premature birth). Nevertheless, OXTR abnormalities are also connected to other diseases, including cancer, cardiac disorders, osteoporosis, and obesity. Recent reports indicated that the changes in the levels of OXTR and the formation of its aggregates may influence the course of some inherited metabolic diseases, such as mucopolysaccharidoses. In this review, the involvement of OXTR dysfunctions and OXTR polymorphisms in the development of different diseases is summarized and discussed. The analysis of published results led us to suggest that changes in OXTR expression and OXTR abundance and activity are not specific to individual diseases, but rather they influence processes (mostly related to behavioral changes) that might modulate the course of various disorders. Moreover, a possible explanation of the discrepancies in the published results of effects of the OXTR gene polymorphisms and methylation on different diseases is proposed. Full article

Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas. Full article