Search

Hyperlipidemia contributes significantly in the manifestation and development of atherosclerosis and coronary heart disease (CHD). Although synthetic lipid-lowering drugs are useful in treating hyperlipidemia, there are number of adverse effects. So the current interest has stimulated the search for new lipid-lowering agents with minimal side effects from natural sources. The present study was designed to investigate the antihyperlipidemic and antiatherogenic potentiality of ethanolic extract of Terminalia pallida fruits in high fat diet-induced hyperlipidemic rats. T. pallida fruits ethanolic extract (TPEt) was prepared using Soxhlet apparatus. Sprague-Dawley male rats were made hyperlipidemic by giving high fat diet, supplied by NIN (National Institute of Nutrition), Hyderabad, India. TPEt was administered in a dose of 100 mg/kg.b.w./day for 30 days in high fat diet-induced hyperlipidemic rats. The body weights, plasma lipid, and lipoprotein levels were measured before and after the treatment. TPEt showed significant antihyperlipidemic and antiatherogenic activities as evidenced by significant decrease in plasma total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels coupled together with elevation of high-density lipoprotein cholesterol levels and diminution of atherogenic index in high fat diet-induced hyperlipidemic rats. There was a significantly reduced body weight gain in TPEt-treated hyperlipidemic rats than in the control group. The present study demonstrates that TPEt possesses significant antihyperlipidemic and antiatherogenic properties, thus suggesting its beneficial effect in the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The paralogues Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) control cell proliferation and cell fate determination from embryogenesis to ageing. In the skin epidermis, these proteins are involved in both homeostatic cell renewal and injury-induced regeneration and also drive carcinogenesis and other pathologies. YAP and TAZ are usually considered downstream of the Hippo pathway. However, they are the central integrating link for the signalling microenvironment since they are involved in the interplay with signalling cascades induced by growth factors, cytokines, and physical parameters of the extracellular matrix. In this review, we summarise the evidence on how YAP and TAZ are activated in epidermal keratinocytes; how YAP/TAZ-mediated signalling cooperates with other signalling molecules at the plasma membrane, cytoplasmic, and nuclear levels; and how YAP/TAZ ultimately controls transcription programmes, defining epidermal cell fate. [ABSTRACT FROM AUTHOR]

The mechanical properties of sclera play an important role in ocular functions, protection, and disease. Modulating the sclera's properties by exogenous crosslinking offers a way to expand the tissue's range of properties for study of the possible influences on the eye's behavior and diseases such as glaucoma and myopia. The focus of this work was to evaluate the effects of genipin crosslinking targeting the porcine perilimbal sclera (PLS) since the stiffness of this tissue was previously found in a number of studies to influence the eye's intraocular pressure (IOP). The work includes experiments on tensile test specimens and whole globes. The specimen tests showed decreased strain-rate dependence and increased relaxation stress due to the cross-linker. Whole globe perfusion experiments demonstrated that eyes treated with genipin in the perilimbal region had increased IOPs compared to the control globes. Migration of the cross-linker from the target tissue to other tissues is a confounding factor in whole globe, biomechanical measurements, with crosslinking. A novel quantitative genipin assay of the trabecular meshwork (TM) was developed to exclude globes where the TM was inadvertently crosslinked. The perfusion study, therefore, suggests that elevated stiffness of the PLS can significantly increase IOP apart from effects of the TM in the porcine eye. These results demonstrate the importance of PLS biomechanics in aqueous outflow regulation and support additional investigations into the distal outflow pathways as a key source of outflow resistance. [ABSTRACT FROM AUTHOR]

Positioned at the head of the nephron, the renal corpuscle generates a plasma ultrafiltrate to initiate urine formation. Three major cell types within the renal corpuscle, the glomerular mesangial cells, podocytes, and glomerular capillary endothelial cells, communicate via endocrine- and paracrine-signaling mechanisms to maintain the structure and function of the glomerular capillary network and filtration barrier. Ca2+ signaling mediated by several distinct plasma membrane Ca2+ channels impacts the functions of all three cell types. The past two decades have witnessed pivotal advances in understanding of non-voltage-gated Ca2+ channel function and regulation in the renal corpuscle in health and renal disease. This review summarizes the current knowledge of the physiological and pathological impact of non-voltage-gated Ca2+ channel signaling in mesangial cells, podocytes and glomerular capillary endothelium. The main focus is on transient receptor potential and store-operated Ca2+ channels, but ionotropic N-methyl- d -aspartate receptors and purinergic receptors also are discussed. This update of Ca2+ channel functions and their cellular signaling cascades in the renal corpuscle is intended to inform the development of therapeutic strategies targeting these channels to treat kidney diseases, particularly diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high‐density lipoprotein (rHDL) ameliorated renal injury in eNOS−/−dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non‐diabetes), eNOS−/−dbdb (diabetes), and eNOS−/−dbdb treated with rHDL (diabetes+rHDL) with both males and females were used. The rHDL nanoparticles were administered to eNOS−/−dbdb mice at Week 16 at 5 μg/g body weight in ~100 μL of saline solution twice per week for 4 weeks via retroorbital injection. We found that rHDL treatment significantly blunted progression of albuminuria and GFR decline observed in DKD mice. Histological examinations showed that the rHDLs significantly alleviated glomerular injury and renal fibrosis, and inhibited podocyte loss. Western blots and immunohistochemical examinations showed that increased protein abundances of fibronectin and collagen IV in the renal cortex of eNOS−/−dbdb mice were significantly reduced by the rHDLs. Taken together, the present study suggests a renoprotective effect of rHDLs on DKD. [ABSTRACT FROM AUTHOR]

Age and elevated intraocular pressure (IOP) are the two primary risk factors for glaucoma, an optic neuropathy that is the leading cause of irreversible blindness. In most people, IOP is tightly regulated over a lifetime by the conventional outflow tissues. However, the mechanistic contributions of age to conventional outflow dysregulation, elevated IOP and glaucoma are unknown. To address this gap in knowledge, we studied how age affects the morphology, biomechanical properties and function of conventional outflow tissues in C57BL/6 mice, which have an outflow system similar to humans. As reported in humans, we observed that IOP in mice was maintained within a tight range over their lifespan. Remarkably, despite a constellation of age‐related changes to the conventional outflow tissues that would be expected to hinder aqueous drainage and impair homeostatic function (decreased cellularity, increased pigment accumulation, increased cellular senescence and increased stiffness), outflow facility, a measure of conventional outflow tissue fluid conductivity, was stable with age. We conclude that the murine conventional outflow system has significant functional reserve in healthy eyes. However, these age‐related changes, when combined with other underlying factors, such as genetic susceptibility, are expected to increase risk for ocular hypertension and glaucoma. [ABSTRACT FROM AUTHOR]

Chronic nonhealing wounds significantly reduce patients' quality of life and are a major burden on healthcare systems. Over the past few decades, tissue engineering materials have emerged as a viable option for wound healing, with cell-derived extracellular matrix (CDM) showing remarkable results. The CDM's compatibility and resemblance to the natural tissue microenvironment confer distinct advantages to tissue-engineered scaffolds in wound repair. This review summarizes the current processes for CDM preparation, various cell decellularization protocols, and common characterization methods. Furthermore, it discusses the applications of CDM in wound healing, including skin defect and wound repair, angiogenesis, and engineered vessels, and offers perspectives on future developments. [ABSTRACT FROM AUTHOR]

Global warming, water scarcity, population growth, rising food prices, urbanization, and other socio-economic factors pose significant threats to agriculture and food security in the 21st century. This situation is particularly grave for low-income individuals in the Asia-Pacific region. To tackle this challenge and eradicate hunger and poverty, it is imperative for scientists to explore alternative food sources, covering all stages from production through processing to consumption. Cereal grains serve as a crucial food source and hold substantial importance in human diets. Therefore, revamping the food system becomes crucial to achieve food and nutritional security. A pragmatic approach toward reaching this goal involves ensuring universal access to affordable, wholesome, and nourishing food through the utilization of millets—nutrient-dense grains (often referred to as Nutri-cereals) that offer a rich array of vital macronutrients, micronutrients, carbohydrates, protein, dietary fiber, lipids, and phytochemicals. Leveraging these grains holds the potential to significantly alleviate the challenges of food insecurity and malnutrition. Millet, a drought-resistant grain, constitutes a primary source of carbohydrates and proteins for populations residing in semi-arid regions of Africa and Asia. Given its crucial contribution to national food security and potential health advantages, there is a growing focus among food scientists. Additionally, the United Nations designated 2023 as the International Year of Millet, underscoring its importance. This article delves into various methods of production and processing, highlighting opportunities to enhance the production and nutritional qualities of millet. We attribute millets to inadequate rainfall distribution, poor crop management high prices of farm inputs such as fertilizer and pesticides and low adoption of improved varieties by the farmers. It also outlines the constraints, challenges, and future prospects associated with promoting millet as a viable food source for the burgeoning population. Despite the promise that millets hold, they have not received adequate research attention. Therefore, increased research efforts on integrating genomics in genome-wide marker-trait association are imperative, encompassing germplasm collection, protection, evaluation, consumption patterns, development of high-yielding cultivars, processing techniques, and policy interventions. Such initiatives are necessary to bolster the cultivation of millets and harness their potential to address the escalating global food challenge. [ABSTRACT FROM AUTHOR]

This study investigated the hypoglycemic and anti-diabetic potentials of Leptadenia hastata crude ethanol root extracts in normal and diabetic albino rats. The hypoglycemic study consisted of twenty-five (25) rats assigned to five (5) groups of five (5) rats each. Group A (control), Groups B to E were administered 200, 400, 600 and 800 mg/kg of the extract respectively, orally. Blood-glucose levels were monitored on Days 0, 7, 14, 21, and 28. The anti-diabetic study consisted of Thirty-five (35) albino rats assigned to seven (7) groups of five (5) rats each. Diabetes was induced using a single intra-peritoneal administration of alloxan monohydrate at a dose of 160 mg/kg. Group A was administered distilled water, while Group B was administered Insulin at 0.1µg/kg, Groups C, D and E were administered 200, 400, 600, and 800 mg/kg of the extract (orally), respectively. Diabetes was induced in rats in group F while Group G comprised normal control rats. Blood glucose levels were monitored at 0, 1, 3, 6, 12, and 18 hours post treatment. Phytochemical analysis identified flavonoids, tannins, alkaloids, terpenoids, and varying quantities of micro and macro elements in the LHERE. The extract exhibited a dose-dependent effect on blood glucose levels in diabetic rats, with the highest dose (800 mg/kg) showed a consistent reduction in blood glucose levels compared to the standard drug (insulin). Furthermore, the extract had a hypoglycemic effect on normocemic rats, significantly reducing blood glucose over time. In conclusion, the crude ethanol root extract of Leptadenia hastata demonstrated significant anti-diabetic and hypoglycemic effects in rat models. The results obtained in the present study support the traditional use of Leptadenia hastata extracts, and its therapeutic potential for developing novel anti-diabetic agents. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic nephropathy (DN), distinguished by detrimental changes in the renal glomeruli, is regarded as the leading cause of death from end-stage renal disease among diabetics. Cellular senescence plays a paramount role, profoundly affecting the onset and progression of chronic kidney disease (CKD) and acute kidney injuries. This study was designed to delve deeply into the pathological mechanisms between glomerulus-associated DN and cellular senescence. Methods: Glomerulus-associated DN datasets and cellular senescence-related genes were acquired from the Gene Expression Omnibus (GEO) and CellAge database respectively. By integrating bioinformatics and machine learning methodologies including the LASSO regression analysis and Random Forest, we screened out four signature genes. The receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic performance of the selected genes. Rigorous experimental validations were subsequently conducted in the mouse model to corroborate the identification of three signature genes, namely LOX, FOXD1 and GJA1. Molecular docking with chlorogenic acids (CGA) was further established not only to validate LOX, FOXD1 and GJA1 as diagnostic markers but also reveal their potential therapeutic effects. Results and discussion: In conclusion, our findings pinpointed three diagnostic markers of glomerulus-associated DN on the basis of cellular senescence. These markers could not only predict an increased risk of DN progression but also present promising therapeutic targets, potentially ushering in innovative treatments for DN in the elderly population. [ABSTRACT FROM AUTHOR]

Glucocorticoid (GC) therapy is indicated in many diseases, including ocular diseases. An important side-effect of GC therapy is GC-induced ocular hypertension (GIOHT), which may cause irreversible blindness known as GC-induced glaucoma (GIG). Here, we reviewed the pathological changes that contribute to GIOHT including in the trabecular meshwork and Schlemm's canal at cellular and molecular levels. We also discussed the clinical aspects of GIOHT/GIG including disease prevalence, risk factors, the type of GCs, the route of GC administration, and management strategies. [ABSTRACT FROM AUTHOR]

Background: Cardiolipin (CL) plays a critical role in maintaining mitochondrial membrane integrity and overall mitochondrial homeostasis. Recent studies have suggested that mitochondrial damage resulting from abnormal cardiolipin remodelling is associated with the pathogenesis of diabetic kidney disease (DKD). Acyl-coenzyme A:lyso-cardiolipin acyltransferase-1 (ALCAT1) was confirmed to be involved in the progression of Parkinson's disease, diet-induced obesity and other ageing-related diseases by regulating pathological cardiolipin remodelling. Thus, the purpose of this investigation was to determine the role of ALCAT1-mediated CL remodelling in DKD and to explore the potential underlying mechanism. Methods: In vivo study, the mitochondrial structure was examined by transmission electron microscopy (TEM). The colocalization of ALCAT1 and synaptopodin was evaluated by double immunolabelling. Western blotting (WB) was performed to assess ALCAT1 expression in glomeruli. Lipidomics analysis was conducted to evaluate the composition of reconstructed cardiolipins. In vitro study, the lipidomics, TEM and WB analyses were similar to those in vivo. Mitochondrial function was evaluated by measuring the mitochondrial membrane potential (MMP) and the production of ATP and ROS. Results: Here, we showed that increased oxidized cardiolipin (ox-CL) and significant mitochondrial damage were accompanied by increased ALCAT1 expression in the glomeruli of patients with DKD. Similar results were found in db/db mouse kidneys and in cultured podocytes stimulated with high glucose (HG). ALCAT1 deficiency effectively prevented HG-induced ox-CL production and mitochondrial damage in podocytes. In contrast, ALCAT1 upregulation enhanced ox-CL levels and podocyte mitochondrial dysfunction. Moreover, treatment with the cardiolipin antioxidant SS-31 markedly inhibited mitochondrial dysfunction and cell injury, and SS-31 treatment partly reversed the damage mediated by ALCAT1 overexpression. We further found that ALCAT1 could mediate the key regulators of mitochondrial dynamics and mitophagy through the AMPK pathway. Conclusions: Collectively, our studies demonstrated that ALCAT1-mediated cardiolipin remodelling played a crucial role in DKD, which might provide new insights for DKD treatment. 8W-yWNeRvGfBjkPoWDJZJ2 Video Abstract [ABSTRACT FROM AUTHOR]

Aim: Methanol, which is a type of toxic alcohol, can cause poisoning through voluntary or involuntary exposure. It is known that the frequency of methanol poisoning has increased especially recently. The aim of this research is bibliometric analysis of scientific studies conducted on methanol poisoning in Web of Sciences (WoS) database. Material and Method: Studies in Web of Science database including the words "methanol" or "methyl alcohol" in their title and the words "poisoning" or "poison" or "toxicity" or "toxic" or "overdose" as the topic were reviewed as of 21.08.2023. "Web of Science Categories", "Web of Science Index" and "Document Types" categories were used as filtering options. Language of article, year of publication, the journal in which it was published, the publishing company to which the journal is affiliated, authors of the article, institutions of authors, the country where the research was conducted, whether financial support was received and citation status of the research were analysed and evaluated. Results: A total of 548 articles were included in the research. It was found that language of most of the studies were English (n=536; 97.8%) and they were published in journals that were in Science Citation Index-Expanded (SCI-E) (n=451; 82.3%) indices. It was found that the highest number of articles were published in 2020 and the country in which the highest number of articles was published was the United States of America (n=143; 22.7%). Conclusion: The present research performs a bibliometric analysis of articles on methanol poisoning in WoS database. The data found in this research can be a valuable source for other researchers and a guide future studies. [ABSTRACT FROM AUTHOR]

Cooling causes cutaneous dilatation to restrain cold‐induced constriction and prevent tissue injury. Cooling increases communication through myoendothelial gap junctions (MEGJs), thereby increasing endothelium‐derived hyperpolarization (EDH)‐type dilatation. EDH is initiated by calcium‐activated potassium channels (KCa) activated by endothelial stimuli or muscle‐derived mediators traversing MEGJs (myoendothelial feedback). The goal of this study was to determine the individual roles of KCa with small (SK3) and intermediate (IK1) conductance in cooling‐induced dilatation. Vasomotor responses of mice isolated cutaneous tail arteries were analyzed by pressure myography at 37°C and 28°C. Cooling increased acetylcholine‐induced EDH‐type dilatation during inhibition of NO and prostacyclin production. IK1 inhibition did not affect dilatations to acetylcholine, whereas SK3 inhibition inhibited dilatation at both temperatures. Cooling uncovered myoendothelial feedback to inhibit constrictions in U46619. IK1 inhibition did not affect U46619 constrictions, whereas SK3 inhibition abolished the inhibitory effect of cooling without affecting U46619 constriction at 37°C. Immunoblots confirmed SK3 expression, which was localized (immunofluorescence) to holes in the internal elastic lamina consistent with myoendothelial projections. Immunoblots and Immunofluorescence did not detect IK1. Studies in non‐cutaneous arteries have highlighted the predominant role of IK1 in EDH‐type dilatation. Cutaneous arteries are distinctly reliant on SK3, which may enable EDH‐type dilation to be amplified by cooling. [ABSTRACT FROM AUTHOR]

Background and Purpose: High‐fat diet (HFD) induces dysregulated pathways in coronary artery endothelial cells (CAECs), which leads to altered regulation of vascular tone, tissue perfusion and increases the risk of coronary artery diseases. Ca2+‐activated K+ (KCa) channels are known to be associated with transient receptor potential (TRP) channels, which are important for regulating endothelial function. But how TRPV4 channels interacts with KCa channels in regulating coronary vascular tone in HFD mice requires further exploration. Experimental Approach: TRPV4 channel activity was assessed by fluorescent Ca2+ imaging. Interactions between TRPV4 and KCa3.1 channels were verified by co‐immunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site‐directed mutagenesis. Endothelium‐specific TRPV4 knockout (TRPV4EC−/−) mice were used to study the effect of the interactions between TRPV4‐KCa3.1 channels on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device. Key Results: TRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca2+‐sensitive K+ channel (KCa3.1) in CAECs, affecting vasodilation and coronary blood flow. In mice fed a HFD diet, the coupling was damaged by a high concentration of plasma 1‐heptadecanoyl‐2‐hydroxy‐sn‐glycero‐3‐phosphocholine. Using a bridging approach, we then identified folic acid as an effective drug to repair the uncoupled TRPV4‐KCa3.1 channels and to improve coronary arterial function. Conclusion and Implications: Our data highlight the importance of coupling between TRPV4 and KCa3.1 channels in the regulation of coronary vascular tone and provide a novel strategy for developing new drugs to reduce the incidence of cardiovascular events. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), cardio-cerebrovascular diseases (CCVDs), hyperuricemia and gout, and metabolic-related sexual dysfunction are metabolic diseases that affect human health in modern society. Scientists have made great efforts to investigate metabolic diseases using cell models in vitro or animal models in the past. However, the findings from cells or animals are difficult to translate into clinical applications due to factors such as the in vitro and in vivo differences; the differences in anatomy, physiology, and genetics between humans and animals; and the differences in microbiome--host interaction. The Chinese have extensively used the medicated diet of traditional Chinese medicine (TCM) (also named as Yao-Shan of TCM, Chinese Yao-Shan et al.) to maintain or improve cardiometabolic health for more than 2,200 years. These ancient classic diets of TCM are essential summaries of long-term life and clinical practices. Over the past 5 years, our group has made every effort to collect and sort out the classic Yao-Shan of TCM from the ancient TCM literature since Spring and Autumn and Warring States Period, especially these are involved in the prevention and treatment of metabolic diseases, such as diabetes, NAFLD, CCVDs, hyperuricemia and gout, and sexual dysfunction. Here, we summarized and discussed the classic Yao-Shan of TCM for metabolic diseases according to the time recorded in the ancient literature, and revised the Latin names of the raw materials in these Yao- Shan of TCM. Moreover, the modern medicine evidences of some Yao-Shan of TCM onmetabolic diseases have also been summarized and emphasized in here. However, the exact composition (in terms of ratios), preparation process, and dosage of many Yao-Shan are not standardized, and their main active ingredients are vague. Uncovering the mystery of Yao-Shan of TCM through modern biological and chemical strategies will help us open a door, which is ancient but now looks new, to modulate metabolic homeostasis and diseases. [ABSTRACT FROM AUTHOR]

Glaucoma, an age-related neurodegenerative disease, is characterized by the death of retinal ganglion cells (RGCs) and the corresponding loss of visual fields. This disease is the leading cause of irreversible blindness worldwide, making early diagnosis and effective treatment paramount. The pathophysiology of primary open-angle glaucoma (POAG), the most common form of the disease, remains poorly understood. Current available treatments, which target elevated intraocular pressure (IOP), are not effective at slowing disease progression in approximately 30% of patients. There is a great need to identify and study treatment options that target other disease mechanisms and aid in neuroprotection for POAG. Increasingly, the role of mitochondrial injury in the development of POAG has become an emphasized area of research interest. Disruption in the function of mitochondria has been linked to problems with neurodevelopment and systemic diseases. Recent studies have shown an association between RGC death and damage to the cells' mitochondria. In particular, oxidative stress and disrupted oxidative phosphorylation dynamics have been linked to increased susceptibility of RGC mitochondria to secondary mechanical injury. Several mitochondriatargeted treatments for POAG have been suggested, including physical exercise, diet and nutrition, antioxidant supplementation, stem cell therapy, hypoxia exposure, gene therapy, mitochondrial transplantation, and light therapy. Studies have shown that mitochondrial therapeutics may have the potential to slow the progression of POAG by protecting against mitochondrial decline associated with age, genetic susceptibility, and other pathology. Further, these therapeutics may potentially target already present neuronal damage and symptom manifestations. In this review, the authors outline potential mitochondria-targeted treatment strategies and discuss their utility for use in POAG. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a noncellular structure that plays an indispensable role in a series of cell life activities. Accumulating studies have demonstrated that ECM stiffness, a type of mechanical forces, exerts a pivotal influence on regulating organogenesis, tissue homeostasis, and the occurrence and development of miscellaneous diseases. Nevertheless, the role of ECM stiffness in ophthalmology is rarely discussed. In this review, we focus on describing the important role of ECM stiffness and its composition in multiple ocular structures (including cornea, retina, optic nerve, trabecular reticulum, and vitreous) from a new perspective. The abnormal changes in ECM can trigger physiological and pathological activities of the eye, suggesting that compared with different biochemical factors, the transmission and transduction of force signals triggered by mechanical cues such as ECM stiffness are also universal in different ocular cells. We expect that targeting ECM as a therapeutic approach or designing advanced ECM-based technologies will have a broader application prospect in ophthalmology. [ABSTRACT FROM AUTHOR]

Rising concerns with the use of synthetic antidiabetic drugs have promoted a shift towards the use of natural products. This study therefore investigated the antidiabetic activity of peptide hydrolysate of Telfairia occidentalis (T. occidentalis) seed protein (PHTOSP) in streptozotocin-induced diabetic rats. Thirty-six (36) experimental animals were randomly distributed into six groups (A–F) of six rats each (n = 6). Group A served as normal control while groups B, C, D, E, and F were treated with streptozotocin (STZ, 50 mg/kg body weight, b.w, i.p) dissolved in cold citrate buffer (0.1 M, pH 4.5) to induce type 2 diabetes. Groups C, D, and E were administered 50, 100, and 150 mg/kg b.w PHTOSP, respectively, while groups B and F were diabetic untreated and 5 mg/kg b.w glibenclamide-treated controls, respectively, in the experiment that lasted for 21 days. Subsequently, the analysis of biochemical parameters demonstrated a significant (p < 0.05) increase in serum insulin, hepatic glycogen, hexokinase, and glucose-6-phosphate dehydrogenase activities, accompanied by a significant (p < 0.05) reduction in fasting serum glucose, glucose-6-phosphatase, and fructose-1,6-bisphosphatase, along with an enhancement in relative body weight. Similarly, PHTOSP demonstrated a significant (p < 0.05) improvement on high-density (HDL) and low-density (LDL) lipoproteins, triglyceride (TG), total cholesterol (TC), and atherogenic index (AI) significantly (p < 0.05). In addition, histoarchitectural analysis revealed a reversal of congestion and proliferation of inflammatory cells in the pancreatic tissue following treatment with PHTOSP. Therefore, PHTOSP might possess potential antidiabetic properties such that it improves glycolytic pathway and promotes cell survival that are helpful in the management of diabetes mellitus (DM). [ABSTRACT FROM AUTHOR]

Hyperglycemia and increased activity of the renal angiotensin II (ANG II) system are two primary pathogenic stimuli for the onset and progression of podocyte injury in diabetic nephropathy. However, the underlying mechanisms are not fully understood. Store-operated Ca2+ entry (SOCE) is an important mechanism that helps maintain cell Ca2+ homeostasis in both excitable and nonexcitable cells. Our previous study demonstrated that high glucose (HG) enhanced podocyte SOCE (1). It is also known that ANG II activates SOCE by releasing endoplasmic reticulum Ca2+. However, the role of SOCE in stress-induced podocyte apoptosis and mitochondrial dysfunction remains unclear. The present study was aimed to determine whether enhanced SOCE mediated HG- and ANG II-induced podocyte apoptosis and mitochondrial damage. In kidneys of mice with diabetic nephropathy, the number of podocytes was significantly reduced. In cultured human podocytes, both HG and ANG II treatment induced podocyte apoptosis, which was significantly blunted by an SOCE inhibitor, BTP2. Seahorse analysis showed that podocyte oxidative phosphorylation in response to HG and ANG II was impaired. This impairment was significantly alleviated by BTP2. The SOCE inhibitor, but not a transient receptor potential cation channel subfamily C member 6 inhibitor, significantly blunted the damage of podocyte mitochondrial respiration induced by ANG II treatment. Furthermore, BTP2 reversed impaired mitochondrial membrane potential and ATP production and enhanced mitochondrial superoxide generation induced by HG treatment. Finally, BTP2 prevented the overwhelming Ca2+ uptake in HG-treated podocytes. Taken together, our results suggest that enhanced SOCE mediated HG- and ANG II-induced podocyte apoptosis and mitochondrial injury. [ABSTRACT FROM AUTHOR]

Type 2 diabetes has become one of the major health concerns of the 21st century, marked by hyperglycemia or glycosuria, and is associated with the development of several secondary health complications. Due to the fact that chemically synthesized drugs lead to several inevitable side effects, new antidiabetic medications from plants have gained substantial attention. Thus, the current study aims to evaluate the antidiabetic capacity of the Ageratina adenophora hydroalcoholic (AAHY) extract in streptozotocin–nicotinamide (STZ–NA)- induced diabetic Wistar albino rats. The rats were segregated randomly into five groups with six rats each. Group I was normal control, and the other four groups were STZ–NA-induced. Group II was designated diabetic control, and group III, IV, and V received metformin (150 mg/kg b.w.) and AAHY extract (200 and 400 mg/kg b.w.) for 28 days. Fasting blood glucose, serum biochemicals, liver and kidney antioxidant parameters, and pancreatic histopathology were observed after the experimental design. The study concludes that the AAHY extract has a significant blood glucose lowering capacity on normoglycemic (87.01 ± 0.54 to 57.21 ± 0.31), diabetic (324 ± 2.94 to 93 ± 2.04), and oral glucose-loaded (117.75 ± 3.35 to 92.75 ± 2.09) Wistar albino rats. The in vitro studies show that the AAHY extract has αglucosidase and α-amylase inhibitory activities which can restore the altered blood glucose level, glycated hemoglobin, body weight, and serum enzymes such as serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, serum alkaline phosphatase, total protein, urea, and creatinine levels close to the normal range in the treated STZ–NA-induced diabetic rats. The evaluation of these serum biochemicals is crucial for monitoring the diabetic condition. The AAHY extract has significantly enhanced tissue antioxidant parameters, such as superoxide dismutase, glutathione, and lipid peroxidation, close to normal levels. The presence of high-quantity chlorogenic (6.47% w/w) and caffeic (3.28% w/w) acids as some of the major phytoconstituents may contribute to the improvement of insulin resistance and oxidative stress. The study provides scientific support for the utilization of A. adenophora to treat type 2 diabetes in the STZ–NA-induced diabetic rat model. Although the preventive role of the AAHY extract in treating Wistar albino rat models against type 2 diabetes mellitus is undeniable, further elaborative research is required for efficacy and safety assessment in human beings. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (DM2) is a widespread metabolic disorder that results in podocyte damage and diabetic nephropathy. Previous studies demonstrated that TRPC6 channels play a pivotal role in podocyte function and their dysregulation is associated with development of different kidney diseases including nephropathy. Here, using single channel patch clamp technique, we demonstrated that non-selective cationic TRPC6 channels are sensitive to the Ca2+ store depletion in human podocyte cell line Ab8/13 and in freshly isolated rat glomerular podocytes. Ca2+ imaging indicated the involvement of ORAI and sodium–calcium exchanger in Ca2+ entry induced upon store depletion. In male rats fed a high-fat diet combined with a low-dose streptozotocin injection, which leads to DM2 development, we observed the reduction of a store-operated Ca2+ entry (SOCE) in rat glomerular podocytes. This was accompanied by a reorganization of store-operated Ca2+ influx such that TRPC6 channels lost their sensitivity to Ca2+ store depletion and ORAI-mediated Ca2+ entry was suppressed in TRPC6-independent manner. Altogether our data provide new insights into the mechanism of SOCE organization in podocytes in the norm and in pathology, which should be taken into account when developing pharmacological treatment of the early stages of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Emerging evidence on molecular biology related to tumors, inflammation, and immunity, highlights their architectural commonality shifting cancer treatment paradigms toward more economical prevention than treatment. Statistical surveys reveal exponentially growing herbal drug supplementation in cancer worldwide as vast pre‐clinical and clinical data unravel their multi‐mechanistic pharmacology. The integrative oncological approach calls for more "holistic" principles to be amalgamated into cancer care. New cancer drug development from herbs need not be limited by the archetypal 'RCT‐Standardization' bottlenecks. Based on comprehensive literature scoping as per Prisma‐ScR guidelines, we herein concurrently reviewed evidence‐based research reports of selected Indian Traditional Medicine (ITM) herbs of anticancer repute in parallel with their holistic therapeutics; a rationalistic exploration of ITM's scientific genre. Their synergy effect on cancer revisited using a trans‐pharmacological approach validates ITM's seemingly simplistic health/disease equation model, showing a fresh new avenue for re‐purposing whole herbal drug complexes in cancer management. Herbal drugs as per ITM are natural matrices whose dynamics of interaction in the etiopathology of cancer are conceptually and mechanistically integrative. Lateral perspective to the same as laid out in this review holds the key to their effectual development as more tangible cancer chemopreventives/new drug targets/leads if not as new pharmacological tools. [ABSTRACT FROM AUTHOR]

The present study was to examine sex and strain differences in glomerular filtration rate (GFR) and renal blood flow (RBF) in C57BL6, 129/Sv, and C57BLKS/J mice, three commonly used mouse strains in renal research. GFR was measured by transdermal measurement of FITC‐sinitrin clearance in conscious mice. RBF was measured by a flow probe placed in the renal artery under an anesthetic state. In C57BL6 mice, there were no sex differences in both GFR and RBF. In 129/Sv mice, females had significantly greater GFR than males at age of 24 weeks, but not at 8 weeks. However, males had higher RBF and lower renal vascular resistance (RVR). Similar to 129/Sv, female C57BLKS/J had significantly greater GFR at both 8 and 24 weeks, lower RBF, and higher RVR than males. Across strains, male 129/Sv had lower GFR and higher RBF than male C57BL6, but no significant difference in GFR and greater RBF than male C57BLKS/J. No significant difference in GFR or RBF was observed between C57BL6 and C57BLKS/J mice. Deletion of eNOS in C57BLKS/J mice reduced GFR in both sexes, but decreased RBF in males. Furthermore, there were no sex differences in the severity of renal injury in eNOS−/−dbdb mice. Taken together, our study suggests that sex differences in renal hemodynamics in mice are strain and age dependent. eNOS was not involved in the sex differences in GFR, but in RBF. Furthermore, the sexual dimorphism did not impact the severity of renal injury in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Devdarvadyarishta is a honey based medicated alcoholic formulation that has been documented to elicit hypoglycemic activity in Ayurvedic lexicon. The aim of this present study was to evaluate the anti-diabetic and anti-oxidant effect of Devdarvadyarishta in STZ induced type II diabetic rats. 24 Wistar albino rats were distributed into four groups with six animals in each group viz., Group I (Normal Control Group), Group II (Diabetic control group), group III (Standard drug Glibenclamide at 10 mg/kg of body weight), group IV (Devdarvadyarishta at 2000 mg/kg of body weight). Diabetes was induced by intraperitoneal injection of STZ at dose level of 35 mg/kg. The whole study was conducted for 30 days. Changes in parameters like body weight, blood glucose, blood urea, serum cholesterol, triglycerides, creatinine, insulin, alkaline phosphatase, oral glucose tolerance test and liver anti-oxidant parameters viz., superoxide dismutase and reduced glutathione were recorded. Histopathology of liver and pancreas was also done. Result showed significant improvement in parameters like body weight, lipid profile, blood glucose, serum creatinine, insulin and alkaline phosphatase which were almost analogous to potent antidiabetic drug glibenclamide. Histopathological studies reinforce the healing of pancreas by increase in pancreatic islet numbers and size, amelioration in atrophy, well-rejuvenated normal cellular arrangement and reduced necrosis with normal blood vessels in liver by test drug as a possible mechanism of its antidiabetic and anti-oxidant activity our study suggests that Devdarvadyarishta suppresses the symptoms of diabetes and diabetes related oxidative stress in animal study. [ABSTRACT FROM AUTHOR]

Introduction: Glaucoma, a disease of retinal ganglion cell (RGC) injury and potentially devastating vision loss, is associated with both ocular hypertension (OHT) and reduced ocular blood flow. However, the relationship between OHT and retinal capillary architecture is not well understood. In this project, we studied microvasculature damage in mice exposed to mild levels of induced OHT. Methods: Mild OHT was induced with the microbead model for 2 weeks. At this time point, some retinas were immunostained with CD31 (endothelium), Collagen IV (basement membrane), and RBPMS (RGCs) for z-stack confocal microscopy. We processed these confocal images to distinguish the three retinal capillary plexi (superficial, intermediate, and deep). We manually counted RGC density, analyzed vascular complexity, and identified topographical and spatial vascular features of the retinal capillaries using a combination of novel manual and automated workflows. Other retinas were dissociated and immunopanned to isolate RGCs and amacrine cells (ACs) for hypoxia gene array analysis. Results: RGC counts were normal but there was decreased overall retinal capillary complexity. This reduced complexity could be explained by abnormalities in the intermediate retinal capillary plexus (IRCP) that spared the other plexi. Capillary junction density, vessel length, and vascular area were all significantly reduced, and the number of acellular capillaries was dramatically increased. ACs, which share a neurovascular unit (NVU) with the IRCP, displayed a marked increase in the relative expression of many hypoxiarelated genes compared to RGCs from the same preparations. Frontiers Discussion: We have discovered a rapidly occurring, IRCP-specific, OHTinduced vascular phenotype that precedes RGC loss. AC/IRCP NVU dysfunction may be a mechanistic link for early vascular remodeling in glaucoma. [ABSTRACT FROM AUTHOR]

Using allelopathic plants, particularly those with growth inhibitory action, has gained significant consideration worldwide because such plants do not have detrimental effects on the environment. Piper longum L. (Piperaceae) is a medicinal plant that has already been documented for its diverse ethnomedicinal uses but not for its phytotoxic action. Therefore, aqueous methanol extracts of P. longum were evaluated for their allelopathic activity at plant biochemistry laboratory, Kagawa University, Kagawa, Japan. The allelopathic efficacy of different concentrations of P. longum leaf extract was investigated against six plant species (alfalfa, cress, lettuce, Italian ryegrass, barnyard grass, and foxtail fescue), and their growth was recorded after 48 h of treatment. The results showed significant inhibition of seedling growth at 0.03 g dry weight (DW) equivalent P. longum extract, and this inhibition was further increased with increasing extract concentration. The maximum inhibitory effect was noted at 0.3 g DW equivalent P. longum extract per mL. The concentrations required for 50% inhibition of shoot and root growth were 0.003-0.070 and 0.003-0.028 g DW equivalent P. longum leaf extract per mL, respectively. The shoot growth of cress, alfalfa, and lettuce, and the root growth of cress, foxtail fescue, and alfalfa were inhibited the most by the P. longum extracts. Thus, these results indicate the potent allelopathic activity of P. longum, which also implies the presence of allelopathic compounds in the P. longum leaf extract. [ABSTRACT FROM AUTHOR]

Piper longum (family Piperaceae), commonly known as "long‐pepper" or "Pippali" grows as a perennial shrub or as an herbaceous vine. It is native to the Indo‐Malaya region and widely distributed in the tropical and subtropical world including the Indian subcontinent, Sri Lanka, Middle‐East, and America. The fruits are mostly used as culinary spice and preservatives and are also a potent remedy in various traditional medicinal systems against bronchitis, cough, cold, snakebite, and scorpion‐sting and are also used as a contraceptive. Various bioactive‐phytochemicals including alkaloids, flavonoids, esters, and steroids were identified from the plant extracts and essential oils from the roots and fruits were reported as antimicrobial, antiparasitic, anthelminthic, mosquito‐larvicidal, antiinflammatory, analgesic, antioxidant, anticancer, neuro‐pharmacological, antihyperglycaemic, hepato‐protective, antihyperlipidaemic, antiangiogenic, immunomodulatory, antiarthritic, antiulcer, antiasthmatic, cardioprotective, and anti‐snake‐venom agents. Many of its pharmacological properties were attributed to its antioxidative and antiinflammatory effects and its ability to modulate a number of signalling pathways and enzymes. This review comprehensively encompasses information on habit, distribution, ethnobotany, phytochemistry, and pharmacology of P. longum in relation to its medicinal importance and health benefits to validate the traditional claims supported by specific scientific experiments. In addition, it also discusses the safety and toxicity studies, application of green synthesis and nanotechnology as well as clinical trials performed with the plant also elucidating research gaps and future perspectives of its multifaceted uses. [ABSTRACT FROM AUTHOR]

Transforming growth factor beta induced (TGFBI) gene mutations have been reported as the cause of a group of genetically inherited, visually debilitating, corneal dystrophies (CD). A scoping literature review to identify and categorize compounds that inhibit corneal TGFBI expression and/or promote TGFBIp degradation was performed. Emphasis was given to their potential to be used as a cost-effective approach via drug repurposing. We performed a thorough search of original peer-reviewed literature using electronic bibliographic databases and selected articles according to a set of criteria. The total number of articles retrieved from the search terms applied to the databases was 2344. The number of relevant full-text articles included added up to 19. We identified 16 compounds that can theoretically reduce the levels of mutant TGFBIp in human corneal cells. Currently, the only temporary treatments available for this condition are lubricant drops and surgery. Here, we explored the crosstalk between cascades that regulate TGFBI expression and identified compounds that target these pathways. Compounds that inhibit DNA synthesis and function, increase elimination of TGFBIp or bind to mutant TGFBIp were also explored with the aim of highlighting promising compounds that can be used in future cost-effective drug-repurposing studies. [ABSTRACT FROM AUTHOR]

This is a spectacular moment for genetics to evolve in genome editing, which encompasses the precise alteration of the cellular DNA sequences within various species. One of the most fascinating genome-editing technologies currently available is Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and its associated protein 9 (CRISPR-Cas9), which have integrated deeply into the research field within a short period due to its effectiveness. It became a standard tool utilized in a broad spectrum of biological and therapeutic applications. Furthermore, reliable disease models are required to improve the quality of healthcare. CRISPR-Cas9 has the potential to diversify our knowledge in genetics by generating cellular models, which can mimic various human diseases to better understand the disease consequences and develop new treatments. Precision in genome editing offered by CRISPR-Cas9 is now paving the way for gene therapy to expand in clinical trials to treat several genetic diseases in a wide range of species. This review article will discuss genome-editing tools: CRISPR-Cas9, Zinc Finger Nucleases (ZFNs), and Transcription Activator-Like Effector Nucleases (TALENs). It will also encompass the importance of CRISPR-Cas9 technology in generating cellular disease models for novel therapeutics, its applications in gene therapy, and challenges with novel strategies to enhance its specificity. [ABSTRACT FROM AUTHOR]

Gene editing and gene regulatory fields are continuously developing new and safer tools that move beyond the initial CRISPR/Cas9 technology. As more advanced applications are emerging, it becomes crucial to understand and establish more complex gene regulatory and editing tools for efficient gene therapy applications. Ophthalmology is one of the leading fields in gene therapy applications with more than 90 clinical trials and numerous proof-ofconcept studies. The majority of clinical trials are gene replacement therapies that are ideal for monogenic diseases. Despite Luxturna's clinical success, there are still several limitations to gene replacement therapies including the size of the target gene, the choice of the promoter as well as the pathogenic alleles. Therefore, further attempts to employ novel gene regulatory and gene editing applications are crucial to targeting retinal diseases that have not been possible with the existing approaches. CRISPR-Cas9 technology opened up the door for corrective gene therapies with its gene editing properties. Advancements in CRISPR-Cas9-associated tools including base modifiers and prime editing already improved the efficiency and safety profile of base editing approaches. While base editing is a highly promising effort, gene regulatory approaches that do not interfere with genomic changes are also becoming available as safer alternatives. Antisense oligonucleotides are one of the most commonly used approaches for correcting splicing defects or eliminating mutant mRNA. More complex gene regulatory methodologies like artificial transcription factors are also another developing field that allows targeting haploinsufficiency conditions, functionally equivalent genes, and multiplex gene regulation. In this review, we summarized the novel gene editing and gene regulatory technologies and highlighted recent translational progress, potential applications, and limitations with a focus on retinal diseases. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is the most widely recognized endocrine disorder which is influencing a bigger populace on the planet. There are various causes of diabetes, such as physical inactivity, obesity, family history, race, and age. Diabetes mellitus is associated with some life-threatening complications, such as neuropathy, nephropathy, various eye diseases or retinopathy, and cardiovascular disorders. Many synthetic antihyperglycemic agents are available in the market for the treatment of diabetes and its complications. But, due to some serious side effects of these synthetic agents, people are opting for herbal remedies and, therefore, they are now becoming popular. Herbal remedies have lesser side effects and higher affordability and therefore can be preferably used over synthetic agents for a long-term disorder like diabetes mellitus. In the present study, scientific research and review studies on the topic were collected from Science Direct, Scopus, PubMed, Google Scholar, and other relevant sources. The references of all the articles were screened manually for any additional information on popular polyherbal formulations in traditional Ayurvedic, Chinese, and Unani medicinal systems. It is found that these polyherbal formulations are studied for anti-diabetic potential. Furthermore, some are also investigated for mechanism of action of anti-diabetic effects. This review highlights various Ayurvedic, Chinese, and Unani polyherbal formulations commonly utilized in the management of diabetes mellitus along with their pre-clinical and clinical investigations, which will enhance the existing knowledge of the researchers. [ABSTRACT FROM AUTHOR]

MYOC is a common pathogenic gene for primary open-angle glaucoma and encodes the protein named myocilin. Multiple MYOC variations have been found, with different clinical significance. However, the pathogenesis of glaucoma induced by MYOC mutations has not been fully clarified. Here, we analyze the molecular and cellular biological differences caused by multiple variant myocilins, including protein secretion characteristics, structural changes, subcellular localization, cellular autophagic activity and oxidative stress. Denaturing and nondenaturing electrophoresis showed myocilin to be a secreted protein with the tendency to self-oligomerize. The full-length myocilin and its C-terminal cleavage fragment are secreted. Secretion analysis of 23 variant myocilins indicated that secretion defects are closely related to the pathogenicity of MYOC variants. Structural analysis showed that the alteration of steric clash is associated with the secretion characteristics and pathogenicity of myocilin variants. Immunocytochemistry results demonstrated that mutated myocilins are retained in the endoplasmic reticulum and disrupt autophagy. MTT assay, MitoTracker staining, and DCFH-DA staining showed increased oxidative injury in cells expressing MYOC mutants. Taken together, MYOC mutations are able to induce cell dysfunction via secretion defects and intracellular accumulation resulting from steric clash alterations. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) has been considered an accelerator of Alzheimer's disease (AD), but the cellular and molecular mechanisms underlying this effect are not fully understood. Here, we attempted to determine the role and regulatory mechanism of calpain in the AD-like cognitive decline and pathological changes in rats caused by DM. In the initial stages, our results verified that DM model rats showed cognitive impairment, as well as a loss of neurons, decreased pericyte marker (PDGFR-β and α-SMA), and calpain-2 expression and amyloid-β (Aβ) deposition in the hippocampal tissues. In high glucose–induced primary pericytes, the cell apoptotic rate was increased, and cell proliferation was inhibited in a time-dependent manner. The protein level of calpain-2 was also upregulated by HG induction, but the level of calpain-1 did not change with HG treatment, which was also observed in DM model rats. Subsequently, some DM model rats were administered calpeptin, an inhibitor of calpain. Our data revealed that calpeptin treatment significantly suppressed calpain-1 and calpain-2 expression in the hippocampal tissues and effectively improved the cognitive impairments of DM model rats. Neuronal loss, Aβ accumulation, pericyte loss, inflammation, and oxidative stress injury in the hippocampal tissues of DM model rats were also partly rescued by calpeptin administration. Our work demonstrated that the calpain inhibitor calpeptin could alleviate DM-induced AD-like cognitive impairments and pathological changes in rats, and this effect may be associated with pericytes. Calpeptin may become a promising drug to treat the AD-like complications of DM. [ABSTRACT FROM AUTHOR]

CRISPR-based targeted genome editing is bringing revolutionary changes in the research arena of biological sciences. CRISPR/Cas9 has been explored as an efficient therapeutic tool for the treatment of genetic diseases. It has been widely used in ophthalmology research by using mouse models to correct pathogenic mutations in the eye stem cells. In recent studies, CRISPR/Cas9 has been used to correct a large number of mutations related to inherited retinal disorders. In vivo therapeutic advantages for retinal diseases have been successfully achieved in some rodents. Current advances in the CRISPR-based gene-editing domain, such as modified Cas variants and delivery approaches have optimized its application to treat blindness. In this review, recent progress and challenges of the CRISPR-Cas system have been discussed to cure blindness and its prospects. [ABSTRACT FROM AUTHOR]

Intraocular pressure (IOP) is considered an important modifiable risk factor for glaucoma, which is known as the second leading cause of blindness worldwide. However, lowering the IOP is not always sufficient to preserve vision due to other non-IOP-dependent mechanisms being involved. To improve outcomes, adjunctive therapies with IOP-independent targets are required. To date, no studies have shown the effect of citicoline on the trabecular meshwork (TM), even though it is known to possess neuroprotective/enhancement properties and multifactorial mechanisms of action. Given that reactive oxygen species seem to be involved in glaucomatous cascade, in this present study, an advanced millifluidic in vitro model was used to evaluate if citicoline could exert a valid TM protection against oxidative stress. To this end, the cellular behavior, in terms of viability, apoptosis, mitochondrial state, senescence and pro-inflammatory cytokines, on 3D human TM cells, treated either with H2O2 alone or cotreated with citicoline, was analyzed. Our preliminary in vitro results suggest a counteracting effect of citicoline eye drops against oxidative stress on TM cells, though further studies are necessary to explore citicoline's potential as a TM-target therapy. [ABSTRACT FROM AUTHOR]

The study was designed to evaluate the geraniol's effect on the kidney and liver damage triggered by a high‐fat diet (HFD)/streptozotocin (STZ)‐induced type 2 diabetes mellitus in rats. Firstly, in vitro inhibitory geraniol's effect against α‐amylase and α‐glucosidase activities was confirmed by in‐silico molecular docking, which revealed higher binding affinity toward α‐amylase than for α‐glucosidase. The protective effect of geraniol with two separate doses (100 and 200 mg/kg b.wt) against diabetes' kidney and liver dysfunctions in Wistar rats was then evaluated. Results indicate that geraniol treatment for 6 weeks instigated a remarkable retrieval of the lipid profile, liver, and kidney function. Geraniol noticeably reinforced the antioxidant enzymes, parameters of oxidative stress of the kidney and liver in this type of diabetes. Also, geraniol treatment prompted a significant reduction in the expression levels of caspase‐3 (Casp3) and Bax mRNA. In conclusion, geraniol ameliorates the progress of HFD/STZ‐induced type 2 diabetes mellitus in rats via dependently upregulating the expression of Bcl‐2 and downregulating Casp3 and Bax expression. Practical applications: Geraniol is a naturally occurring substantial acyclic monoterpenoid compound that has numerous pharmacological activities. The positive effect of geraniol in inhibiting in vitro diabetic markers by a silico molecular docking study was evidenced by illustrating the binding sites of geraniol with both α‐amylase and α‐glucosidase. This study also focused on the therapeutic impact of geraniol against the damage caused by high fat‐diet/streptozotocin‐induced type 2 diabetic complications in Wistar rats. Geraniol limits the oxidative stress of liver and kidney tissue, and it might be used as an antiapoptotic agent in type 2 diabetes. [ABSTRACT FROM AUTHOR]

This study provides comprehensive mechanistic evidence for the role of clusterin, a stress‐response secretory chaperone protein, in the modulation of intraocular pressure (IOP) by regulating the trabecular meshwork (TM) actin cytoskeleton and the extracellular matrix (ECM). The pathological stressors on TM known to elevate IOP significantly lowered clusterin protein levels indicating stress‐related clusterin function loss. Small interfering RNA‐mediated clusterin loss in human TM cells in vitro induced actin polymerization and stabilization via protein kinase D1, serine/threonine‐protein kinase N2 (PRK2), and LIM kinase 1 (LIMK1), and the recruitment and activation of adhesome proteins including paxillin, vinculin, and integrin αV and β5. A complete loss of clusterin as seen in clusterin knockout mice (Clu‐/‐) led to significant IOP elevation at postnatal Day 70. Contrarily, constitutive clusterin expression using adenovirus (AdCLU) in HTM cells resulted in the loss of actin polymerization via decreased PRK2, and LIMK1 and negative regulation of integrin αV and β5. Furthermore, we found that AdCLU treatment in HTM cells significantly decreased the ECM protein expression and distribution by significantly increasing matrix metalloprotease 2 (MMP2) activity and lowering the levels of pro‐fibrotic proteins such as transforming growth factor‐β2 (TGFβ2), thrombospondin‐1 (TSP‐1), and plasminogen activator inhibitor‐1 (PAI‐1). Finally, we found that HTM cells supplemented with recombinant human clusterin attenuated the pro‐fibrotic effects of TGFβ2. For the first time this study demonstrates the importance of clusterin in the regulation of TM actin cytoskeleton ‐ ECM interactions and the maintenance of IOP, thus making clusterin an interesting target to reverse elevated IOP. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is a major cause of renal tissue damage and complications of diabetes. In this in‐vitro experimental study, diabetes was induced by a single injection of Streptozotocin (55 mg/kg) in rats. STZ‐diabetic rats were treated with oral doses of methanolic extract T. ammi seeds (300–400 mg/kg). After 8 weeks, serum levels of glucose, creatinine, urea, SOD, and MDA in the blood serum and protein levels in urine were measured. Also, changes in the expression of IL‐18 and TNF‐α genes in the renal tissue were examined. The results of this study showed that T. ammi seeds have anti‐hyperglycemic and anti‐hyperlipidemia effects. It can also increase SOD, decrease MDA, and inhibit IL‐18 and TNF‐α expression. T. ammi methanolic extract reduced blood glucose, oxidative stress, renal function biomarkers, and inflammatory cytokines caused by STZ in mice. Because of this, it could be used as a new treatment for diabetic nephropathy. Novelty impact statement: The effect of T. ammi seed extract on rats with nephropathy was investigated.The real‐time PCR technique was used to measure the expression of the genes IL‐18 and TNF‐a, while the ELISA technique was used to measure the level of MDA and SOD serum.T. ammi is a medicinal plant with anti‐inflammatory and anti‐nephropathy effects. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface‐localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease. Supporting this hypothesis is our recent work demonstrating direct physical and bidirectional functional interactions of TRPV4 with RhoA, which can lead to activation of RhoA and reorganization of the actin cytoskeleton. Furthermore, a confluence of evidence implicates TRPV4 and/or RhoA in pathological responses triggered by a range of acute neurological insults ranging from stroke to traumatic injury. While initiated by a variety of insults, TRPV4–RhoA signaling may represent a common pathway that disrupts axonal regeneration and blood–brain barrier integrity. These insights also suggest that TRPV4 inhibition may represent a safe, feasible, and precise therapeutic strategy for limiting pathological TRPV4–RhoA activation in a range of neurological diseases. [ABSTRACT FROM AUTHOR]

The genus Syzygium comprises 1200–1800 species that belong to the family of Myrtaceae. Moreover, plants that are belonged to this genus are being used in the traditional system of medicine in Asian countries, especially in China, India, and Bangladesh. The aim of this review is to describe the scientific works and to provide organized information on the available traditional uses, phytochemical constituents, and pharmacological activities of mostly available species of the genus Syzygium in Bangladesh. The information related to genus Syzygium was analytically composed from the scientific databases, including PubMed, Google Scholar, Science Direct, Web of Science, Wiley Online Library, Springer, Research Gate link, published books, and conference proceedings. Bioactive compounds such as flavanone derivatives, ellagic acid derivatives and other polyphenolics, and terpenoids are reported from several species of the genus Syzygium. However, many members of the species of the genus Syzygium need further comprehensive studies regarding phytochemical constituents and mechanism‐based pharmacological activities. [ABSTRACT FROM AUTHOR]

To characterize our recently established in vitro glaucomatous human trabecular meshwork (HTM) models using dexamethasone (DEX)- or TGF-β2-treated HTM cells, (1) two-dimensional (2D) cultured HTM cells were characterized by means of the real-time cellular metabolism analysis using a Seahorse analyzer, and (2) the effects of mechanical compression stresses toward the three-dimensional (3D) HTM spheroids were evaluated by analyzing the gene expression of several ECM proteins, inflammatory cytokines, and ER stress-related factors of those 3D HTM spheroid models. The results indicated that (1) the real-time cellular metabolism analysis indicated that TGF-β2 significantly induced an energy shift from mitochondrial oxidative phosphorylation (OXPHOS) into glycolysis, and DEX induced similar but lesser effects. In contrast, ROCK2 inhibition by KD025 caused a substantial reverse energy shift from glycolysis into OXPHOS. (2) Upon direct compression stresses toward the untreated control 3D HTM spheroids, a bimodal fluctuation of the mRNA expressions of ECM proteins was observed for 60 min, that is, initial significant upregulation (0–10 min) and subsequent downregulation (10–30 min) followed by another upregulation (30–60 min); those of inflammatory cytokines and ER stress-related factors were also bimodally changed. However, such compression stresses for 30 min toward TGF-β2- or DEX-treated 3D HTM spheroids induced downregulation of most of those of inflammatory cytokines and ER stress-related factors in addition to upregulation of COL1 and downregulation of FN. The findings presented herein indicate that (1) OXPHOS of the HTM cells was decreased or increased by TGF-β2 or DEX stimulation or ROCK2 inhibition, and (2) mechanical compression stresses toward 3D HTM spheroids may replicate acute, subacute, and chronic HTM models affected by elevated intraocular pressures. [ABSTRACT FROM AUTHOR]

Glaucoma is the leading cause of irreversible blindness globally; hence, relevant clinical biomarkers are necessary to enable diagnosis, early detection, and development of novel therapies. The differentially expressed genes were annotated and visualized using Gene Ontology and Kyoto Encyclopedia. In addition, a competitive endogenous ribonucleic acids network was constructed using Cytoscape, which explained the regulation of gene expression in glaucoma. The CIBERSORT algorithm was employed to analyze the immune microenvironment. We validated that the core genes could predict glaucoma occurrence and development and identified potential molecular mechanism pathways, which were associated with immune infiltration and participated in endogenous regulation networks. Our data may partially explain the pathogenesis of glaucoma and they provide potential theoretical support for targeted therapy. [ABSTRACT FROM AUTHOR]

Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Background and Purpose: Reduced NO levels and activity are signs of endothelial dysfunction, which is important in mediating BP changes. Previously, we demonstrated that transient receptor potential channel V4 (TRPV4) could form a functional complex with other proteins to mediate vasodilation in endothelial cells (ECs). But how TRPV4 interacts with the NO pathway in larger arteries requires further exploration. Experimental Approach We used single‐cell RNA‐sequencing to find the CD106+ TRPV4highNOS3high ECs. The TRPV4–eNOS interaction was verified by co‐immunoprecipitation and immuno‐FRET, and their binding site was found by site‐directed mutagenesis. Endothelium‐specific TRPV4 knockout (TRPV4EC−/−) mice were used to study the effect of the TRPV4–eNOS interaction on BP. A small molecule, JNc‐463, was designed through molecular docking technology. Key Results: We uncovered CD106+ TRPV4highNOS3high ECs in the mouse aorta, which could regulate vasodilation via a TRPV4–eNOS interaction, and were essential to regulate BP. The TRPV4–eNOS interaction markedly decreased during the process of hypertension. We further attempted to identify molecules involved in the TRPV4–eNOS interaction and developed a small‐molecule drug, JNc‐463, which could increase the TRPV4–eNOS interaction to enhance vasodilation and exert antihypertensive effects in mice. Conclusion and Implications: This is the first study integrating single‐cell RNA‐Seq, single‐cell functional study and drug screening in aorta. We identified a subpopulation of CD106+ TRPV4highNOS3high ECs, in which an impaired TRPV4–eNOS interaction was important in the progress of hypertension, and we designed a small molecule, JNc‐463, to improve the impaired TRPV4–eNOS interaction in hypertension. [ABSTRACT FROM AUTHOR]