Placental microphysiological systems: new advances on promising platforms that mimic the microenvironment of the human placenta.

One of the most complex human physiological processes to study is pregnancy. Standard animal models, as well as two-dimensional models, lack the complexity and biological relevance required to accurately study such a physiological process. Recent studies have focused on the development of three-dimensional models based on microfluidic systems, designated as placental microphysiological systems (PMPSs). PMPS devices provide a model of the placental barrier through culturing relevant cell types in specific arrangements and media to mimic the in vivo environment of the maternal-fetal circulation. Here, recent developments of PMPS models for embryo uterine implantation, preeclampsia evaluation, and toxicological screening are presented. Studies that use bioprinting techniques are also discussed. Lastly, recent developments in endometrium microphysiological systems are reviewed. All these presented models showed their superiority compared to standard models in recapitulating the biological environment seen in vivo. However, several limitations regarding the types of cells and materials used for these systems were also widely reported. Despite the need for further improvements, PMPS models contribute to a better understanding of the biological mechanisms surrounding pregnancy and the respective pathologies.

Therapeutic approaches targeting aging and cellular senescence in Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disease that is manifested by a gradual loss of physical, cognitive, and mental abilities. As the disease advances, age has a major impact on the pathogenic signature of mutant huntingtin (mHTT) protein aggregation. This review aims to explore the intricate relationship between aging, mHTT toxicity, and cellular senescence in HD. Scientific data on the interplay between aging, mHTT, and cellular senescence in HD were collected from several academic databases, including PubMed, Google Scholar, Google, and ScienceDirect. The search terms employed were "AGING," "HUNTINGTON'S DISEASE," "MUTANT HUNTINGTIN," and "CELLULAR SENESCENCE." Additionally, to gather information on the molecular mechanisms and potential therapeutic targets, the search was extended to include relevant terms such as "DNA DAMAGE," "OXIDATIVE STRESS," and "AUTOPHAGY." According to research, aging leads to worsening HD pathophysiology through some processes. As a result of the mHTT accumulation, cellular senescence is promoted, which causes DNA damage, oxidative stress, decreased autophagy, and increased inflammatory responses. Pro-inflammatory cytokines and other substances are released by senescent cells, which may worsen the neuronal damage and the course of the disease. It has been shown that treatments directed at these pathways reduce some of the HD symptoms and enhance longevity in experimental animals, pointing to a new possibility of treating the condition. Through their amplification of the harmful effects of mHTT, aging and cellular senescence play crucial roles in the development of HD. Comprehending these interplays creates novel opportunities for therapeutic measures targeted at alleviating cellular aging and enhancing HD patients' quality of life.

Protective activity of hirsutidin in high-fat intake and streptozotocin-induced diabetic rats: In silico and in vivo study.

Background: Type 2 diabetes mellitus (T2DM) is defined by a wide variety of metabolic abnormalities, persistent hyperglycemia, and a slew of other complications. Catharanthus roseus L. (apocyanaceae), remarkably notable as Vinca Rosea, appears to be the source of the active component hirsutidin, which is reported in various diseases. Objective: The study intended to appraise the antidiabetic capability of hirsutidin in a high-fat diet (HFD) and streptozotocin (STZ) induced diabetes in experimental rats. Materials and methods: An experimental rodent T2DM model was elicited by consuming an HFD regimen with STZ 50 mg/kg, i.p. dose formulated in a 0.1 M cold citrate buffer (pH 4.5). The test drug hirsutidin (10 and 20 mg/kg) and the standard drug glimeclamide (5 mg/kg) were administered daily for six weeks. The efficacy of hirsutidin was observed on several diabetes parameters. The average body weight and an array of biochemical markers were determined, including blood glucose, insulin, dyslipidemia (lipid profile), total protein (TP), liver injury [aspartate aminotransferase (AST), alanine aminotransferase (ALT)], inflammation [IL-6, IL-1ß, tumor necrosis factor-α (TNF-α)], oxidative stress [malondialdehyde (MDA)] and antioxidant status [catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD)]. In addition, the concentrations of leptin, adiponectin, and resistin were also assessed. Also, molecular docking studies were undertaken to investigate critical targets associated with diabetes, including TNF-α, insulin, adiponectin, and leptin. Results: Diabetes induction with HFD/STZ resulted in hyperglycemia (significantly reduced blood glucose and increased insulin level), dyslipidemia (significantly reduced TC, TG and increased HDL), total protein (significantly reduced), oxidative stress and antioxidant status (significantly reduced MDA and increased CAT, SOD and GSH levels), inflammation (significantly decreased IL-6, IL-1ß, TNF-α), liver damage (significantly reduced AST, ALT), and specific hormones such as adiponectin, leptin significantly improved and resistin significantly reduced as evidenced by biochemical data in this study. Intermolecular interactions of ligands and docking score, hirsutidin proteins TNF-α (2AZ5), Insulin (4IBM), Adiponectin (6KS1), Leptin (7Z3Q) with binding energy of -6.708, -7.674, -7.2 and -7.547 Kcal/mol. Conclusion: Hirsutidin may have an evidential hypoglycemic outcome and may exhibit potent antidiabetic activity in HFD/STZ-induced T2DM in rats. Treatment with hirsutidin significantly improved glycemic control, lipid metabolism, oxidative stress, inflammation, and liver function. Additionally, it normalized dysregulated levels of adiponectin, leptin, and resistin. Molecular docking confirmed its strong binding affinity to key diabetic targets.

Radiosynthesis and Preclinical Evaluation of [99mTc]Tc-Tigecycline Radiopharmaceutical to Diagnose Bacterial Infections.

BACKGROUND/OBJECTIVES: As a primary source of mortality and disability, bacterial infections continue to develop a severe threat to humanity. Nuclear medicine imaging (NMI) is known for its promising potential to diagnose deep-seated bacterial infections. This work aims to develop a new technetium-99m (99mTc) labeled tigecycline radiopharmaceutical as an infection imaging agent. METHODS: Reduced 99mTc was used to make a coordinate complex with tigecycline at pH 7.7-7.9 at room temperature. Instantaneous thin-layer chromatography impregnated with silica gel (ITLC-SG) and ray detector equipped high-performance liquid chromatography (ray-HPLC) was performed to access the radiolabeling yield and radiochemical purity (RCP). RESULTS: More than 91% labeling efficiency was achieved after 25 min of mild shaking of the reaction mixture. The radiolabeled complex was found intact up to 4 h in saline. Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infection-induced rats were used to record the biodistribution of the radiopharmaceutical and its target specificity; 2 h' post-injection biodistribution revealed a 2.39 ± 0.29 target/non-target (T/NT) ratio in the E. coli infection-induced animal model, while a 2.9 ± 0.31 T/NT value was recorded in the S. aureus bacterial infection-induced animal model. [99mTc]Tc-tigecycline scintigraphy was performed in healthy rabbits using a single photon emission computed tomography (SPECT) camera. Scintigrams showed normal kidney perfusion and excretion into the bladder. CONCLUSION: In conclusion, the newly developed [99mTc]Tc-tigecycline radiopharmaceutical could be considered to diagnose broad-spectrum bacterial infections.

6-Shogaol Abrogates Parkinson's Disease in Rotenone-Induced Rodents: Based on In Silico Study and Inhibiting TNF-α/NF-κB/IL-1ß/MAO-B.

Background/Objectives: 6-Shogaol is a comparatively innovative anti-Parkinson's remedy with antioxidant and anti-inflammatory characteristics. This investigation intended to determine the role of 6-shogaol in the Parkinson's disease (PD) paradigm in rotenone-induced rats. Methods: Thirty male Wistar rats (10-12 weeks old; 180 ± 20 g) were divided into five groups. Animals with rotenone-induced experimental PD were subsequently treated with 6-shogaol-10 at 20 mg/kg for 28 days. After the experimental duration, behavioural investigations were performed, i.e., open field test, forced swim test, rotarod test, and catalepsy test. Biochemical assessments like AChE, GSH, CAT, SOD, MDA, nitrite, ceruloplasmin, proinflammatory markers such as IL-1ß, NF-κB, TNF-α, and catecholamines markers (DA, GABA, and MAO-B) were determined. The docking procedure was conducted using the AutoDock Vina docking protocol. Furthermore, histopathology was performed. Results: Rotenone significantly increased the level of MAO-B, oxidative, nitrative, and pro-inflammatory markers. However, there was a decline in ceruloplasmin, dopamine, and endogenous antioxidants. Treatment with 6-shogaol (10 and 20 mg/kg) considerably sustained the elevation of oxidative stress and inflammatory indicators and decreased AChE activity and dopamine levels. In the histology of the brain, 6-shogaol improved the neuronal structure and reduced the degeneration of neurons. Based on the binding energy values, compound 6-shogaol demonstrates a favourable binding affinity to AChE, MAO-B, DA, and GABA with respective binding energies of -8.214, -8.133, -7.396 and -6.189 kcal/mol. Conclusions: In this study, 6-shogaol exhibited neuroprotective properties against PD, which could be employed as a prospective medication for PD.

Potential Therapeutic Targets for the Treatment of HPV-Associated Malignancies.

This review article aims to summarize broadly recent developments in the treatment of HPV-associated cancers, including cervical cancer and head and neck squamous cell carcinoma. Relatively new treatments targeting the key HPV E6 and E7 oncoproteins, including gene editing with TALENs and CRISPR/Cas9, are discussed. Given the increased immunogenicity of HPV-related diseases, other therapies such as PRR agonists, adoptive cell transfer, and tumor vaccines are reaching the clinical trial phase. Due to the mechanism, immunogenicity, and reversibility of HPV carcinogenesis, HPV-related cancers present unique targets for current and future therapies.

The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective.

Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a key regulator of cellular processes linked to ageing and neurodegeneration. SIRT1 modulates various signalling pathways, including those involved in autophagy, oxidative stress, and mitochondrial function, which are critical in the pathogenesis of neurodegenerative diseases. This review explores the therapeutic potential of SIRT1 in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Preclinical studies have demonstrated that SIRT1 activators, such as resveratrol, SRT1720, and SRT2104, can alleviate disease symptoms by reducing oxidative stress, enhancing autophagic flux, and promoting neuronal survival. Ongoing clinical trials are evaluating the efficacy of these SIRT1 activators, providing hope for future therapeutic strategies targeting SIRT1 in neurodegenerative diseases. This review explores the role of SIRT1 in ageing and neurodegenerative diseases, with a particular focus on its molecular mechanisms, therapeutic potential, and clinical applications.

Fustin, a Potent Phytochemical, Attenuates Scopolamine-induced Memory Impairment and Neurodegeneration by Modulating Neuroinflammation and Neurotransmitters.

INTRODUCTION: Fustin, a photogenic flavanol found in the plant Rhus verniciflua Stokes, has been involved in multiple disease ailments and has a beneficial pharmacological effect and a history of use in traditional medicine. The present research aimed to study the impact of fustin on scopolamine (SCOP)-induced memory impairment and neurodegeneration by modulating neuroinflammation and neurotransmitters in rats. METHODS: A total of 30 healthy Wistar rats were allocated into five groups (n=6). Group I- served as control and received saline solution (1mL/kg i.p.), group -II- fustin (100 mg/kg, orally), group -III -SCOP (1 mg/kg, i.p.), and group -IV and V were given fustin (50 and 100 mg/kg/p.o.) with SCOP (1 mg/kg, i.p.) for 14-days. After 14 days, 2 hours after SCOP injection, the Y-maze and Morris water maze (MWM) tests were performed. After behavioral tests rats were subsequently euthanized, and brain supernatants were used to estimate choline-acetyltransferase (ChAT), acetylcholinesterase (AChE), antioxidant [superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)], and total protein, oxidative stress markers [nitrate and malondialdehyde (MDA)], pro-inflammatory markers [tumor necrosis factor (TNF-α), and Interleukins-1ß (IL-1ß) and IL-6]. Also, neurotransmitters such as serotonin (5-HT), dopamine (DA), ϒ-amino butyric acid (GABA), acetylcholine (Ach), and noradrenaline (NA) contents were performed. RESULTS: Fustin exhibited substantial behavioral improvement in the Y-maze measures spontaneous alterations percentage (SA%) and decreased latency time following the acquisition and prolonged time spent in the probe trial in the MWM test. Moreover, fustin inhibits enhanced neuroinflammatory cytokines and oxidative stress markers and improves the neurotransmitters. CONCLUSION: The findings of this study suggest that fustin inhibits SCOP impact on cognitive abilities in rats. The present investigation demonstrates that fustin, a potent phytochemical, effectively mitigated the behavioral and physiological changes induced by SCOP in rats. This was primarily achieved by modulating the levels of inflammatory response and neurotransmitters.

Role of nanofertilization in plant nutrition under abiotic stress conditions.

Plants require nutrients for growth, which they obtain from the soil via the root system. Fertilizers offer the essential nutrients (nitrogen, phosphorus, and potassium, as well as critical secondary elements) required by plants. Soil productivity falls with each crop until nutrients are provided. A wide range of so-called fertilizer products, such as organic fertilizers, argon mineral fertilizers, and mineral fertilizers, can assist farmers in adjusting fertilization methods based on the environment and agricultural conditions (inhibitors, restricted materials, growth mediums, plant bio-stimulants, etc.). Agricultural land is reduced by erosion, pollution, careless irrigation, and fertilization. On the other hand, more agricultural production is needed to meet the demands of expanding industries and the nutritional needs of a growing population. Nano fertilizers have recently started to be manufactured to obtain the highest yield and its quality per unit area. Previous researchers found that nano fertilizers could improve plant nutrient uptake efficiency, lower soil toxicity, mitigate the potential negative effects of excessive chemical fertilizer use, and reduce the frequency of fertilization. To maximize crop yields and optimize nutrient use while reducing the overuse of chemical fertilizers, nano fertilizersNFs are crucial in agriculture. The key component of these fertilizers is that they contain one or more macro- and micronutrients that can be applied regularly in minute doses while not damaging the environment. However, they have a minimal effect on plant growth and agricultural yields when employed in high numbers, like synthetic fertilizers. This article explains the features, relevance and classification of nano-fertilizers, their use in plant development, their advantages and disadvantages, and the results achieved in this field.

Design of in-situ implant for the brain-targeted drug delivery using cross-linked gellan gum polymer through response surface methodology.

The analysis aimed to prepare an in-situ implant (ISFI) formulation holding dimethyl fumarate as (a model drug) using cross-linked gellan gum by homogenization method. Cross-linking of gellan gum was done with L-cysteine to improve its gelation properties. Fourier transform infrared spectroscopy (FTIR) and (DSC) Differential scanning calorimetry were used to test the compatibility of the drug-polymer. The diverse formulations were prepared and tested using Design Expert® ver 8.0.1 software to optimize the experiment technique and employ the response surface. The tissue compatibility of the test verified the existence of non-irritants in the established formulation. All preparations contained the drug content from approximately 97.98 to 99.88%. Viscosities are ideal for injection in the optimized formulation (1,55 percent w/w in water). The optimized formula was monitored, and up to 156hours, it was found to be 95.7%. The result was that ISFI can effectively monitor and control the delivery of several powerful drug products.

Pyroptosis in lung cancer: The emerging role of non-coding RNAs.

Lung cancer remains an intractable malignancy worldwide, prompting novel therapeutic modalities. Pyroptosis, a lethal form of programmed cell death featured by inflammation, has been involved in cancer progression and treatment response. Simultaneously, non-coding RNA has been shown to have important roles in coordinating pattern formation and oncogenic pathways, including long non-coding RNA (lncRNAs), microRNA (miRNAs), circular RNA (circRNAs), and small interfering RNA (siRNAs). Recent studies have revealed that ncRNAs can promote or inhibit pyroptosis by interacting with key molecular players such as NLRP3, GSDMD, and various transcription factors. This dual role of ncRNAs offers a unique therapeutic potential to manipulate pyroptosis pathways, providing opportunities for innovative cancer treatments. In this review, we integrate current research findings to propose novel strategies for leveraging ncRNA-mediated pyroptosis as a therapeutic intervention in lung cancer. We explore the potential of ncRNAs as biomarkers for predicting patient response to treatment and as targets for overcoming resistance to conventional therapies.

Transformer-based active learning for multi-class text annotation and classification.

Objective: Data-driven methodologies in healthcare necessitate labeled data for effective decision-making. However, medical data, particularly in unstructured formats, such as clinical notes, often lack explicit labels, making manual annotation challenging and tedious. Methods: This paper introduces a novel deep active learning framework designed to facilitate the annotation process for multiclass text classification, specifically using the SOAP (subjective, objective, assessment, plan) framework, a widely recognized medical protocol. Our methodology leverages transformer-based deep learning techniques to automatically annotate clinical notes, significantly easing the manual labor involved and enhancing classification performance. Transformer-based deep learning models, with their ability to capture complex patterns in large datasets, represent a cutting-edge approach for advancing natural language processing tasks. Results: We validate our approach through experiments on a diverse set of clinical notes from publicly available datasets, comprising over 426 documents. Our model demonstrates superior classification accuracy, with an F1 score improvement of 4.8% over existing methods but also provides a practical tool for healthcare professionals, potentially improving clinical documentation practices and patient care. Conclusions: The research underscores the synergy between active learning and advanced deep learning, paving the way for future exploration of automatic text annotation and its implications for clinical informatics. Future studies will aim to integrate multimodal data and large language models to enhance the richness and accuracy of clinical text analysis, opening new pathways for comprehensive healthcare insights.

Nrf2 pathways in neuroprotection: Alleviating mitochondrial dysfunction and cognitive impairment in aging.

Mitochondrial dysfunction and cognitive impairment are widespread phenomena among the elderly, being crucial factors that contribute to neurodegenerative diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular defense systems, including that against oxidative stress. As such, increased Nrf2 activity may serve as a strategy to avert mitochondrial dysfunction and cognitive decline. Scientific data on Nrf2-mediated neuroprotection was collected from PubMed, Google Scholar, and Science Direct, specifically addressing mitochondrial dysfunction and cognitive impairment in older people. Search terms included "Nrf2", "mitochondrial dysfunction," "cognitive impairment," and "neuroprotection." Studies focusing on in vitro and in vivo models and clinical investigations were included to review Nrf2's therapeutic potential comprehensively. The relative studies have demonstrated that increased Nrf2 activity could improve mitochondrial performance, decrease oxidative pressure, and mitigate cognitive impairment. To a large extent, this is achieved through the modulation of critical cellular signalling pathways such as the Keap1/Nrf2 pathway, mitochondrial biogenesis, and neuroinflammatory responses. The present review summarizes the recent progress in comprehending the molecular mechanisms regarding the neuroprotective benefits mediated by Nrf2 through its substantial role against mitochondrial dysfunction and cognitive impairment. This review also emphasizes Nrf2-target pathways and their contribution to cognitive function improvement and rescue from mitochondria-related abnormalities as treatment strategies for neurodegenerative diseases that often affect elderly individuals.

Microbial-assistance and chelation-support techniques promoting phytoremediation under abiotic stresses.

Phytoremediation, the use of plants to remove heavy metals from polluted environments, has been extensively studied. However, abiotic stresses such as drought, salt, and high temperatures can limit plant growth and metal uptake, reducing phytoremediation efficiency. High levels of HMs are also toxic to plants, further decreasing phytoremediation efficacy. This manuscript explores the potential of microbial-assisted and chelation-supported approaches to improve phytoremediation under abiotic stress conditions. Microbial assistance involves the use of specific microbes, including fungi that can produce siderophores. Siderophores bind essential metal ions, increasing their solubility and bioavailability for plant uptake. Chelation-supported methods employ organic acids and amino acids to enhance soil absorption and supply of essential metal ions. These chelating agents bind HMs ions, reducing their toxicity to plants and enabling plants to better withstand abiotic stresses like drought and salinity. Managed microbial-assisted and chelation-supported approaches offer more efficient and sustainable phytoremediation by promoting plant growth, metal uptake, and mitigating the effects of heavy metal and abiotic stresses. Managed microbial-assisted and chelation-supported approaches offer more efficient and sustainable phytoremediation by promoting plant growth, metal uptake, and mitigating the effects of HMs and abiotic stresses.These strategies represent a significant advancement in phytoremediation technology, potentially expanding its applicability to more challenging environmental conditions. In this review, we examined how microbial-assisted and chelation-supported techniques can enhance phytoremediation a method that uses plants to remove heavy metals from contaminated sites. These approaches not only boost plant growth and metal uptake but also alleviate the toxic effects of HMs and abiotic stresses like drought and salinity. By doing so, they make phytoremediation a more viable and effective solution for environmental remediation.

Boosting efficiency in a clinical literature surveillance system with LightGBM.

Given the suboptimal performance of Boolean searching to identify methodologically sound and clinically relevant studies in large bibliographic databases, exploring machine learning (ML) to efficiently classify studies is warranted. To boost the efficiency of a literature surveillance program, we used a large internationally recognized dataset of articles tagged for methodological rigor and applied an automated ML approach to train and test binary classification models to predict the probability of clinical research articles being of high methodologic quality. We trained over 12,000 models on a dataset of titles and abstracts of 97,805 articles indexed in PubMed from 2012-2018 which were manually appraised for rigor by highly trained research associates and rated for clinical relevancy by practicing clinicians. As the dataset is unbalanced, with more articles that do not meet the criteria for rigor, we used the unbalanced dataset and over- and under-sampled datasets. Models that maintained sensitivity for high rigor at 99% and maximized specificity were selected and tested in a retrospective set of 30,424 articles from 2020 and validated prospectively in a blinded study of 5253 articles. The final selected algorithm, combining a LightGBM (gradient boosting machine) model trained in each dataset, maintained high sensitivity and achieved 57% specificity in the retrospective validation test and 53% in the prospective study. The number of articles needed to read to find one that met appraisal criteria was 3.68 (95% CI 3.52 to 3.85) in the prospective study, compared with 4.63 (95% CI 4.50 to 4.77) when relying only on Boolean searching. Gradient-boosting ML models reduced the work required to classify high quality clinical research studies by 45%, improving the efficiency of literature surveillance and subsequent dissemination to clinicians and other evidence users.

The effect of intrathecal pethidine on post-spinal anesthesia shivering after cesarean section: a systematic review and meta-analysis.

Background: Spinal anesthesia is the most preferred method for cesarean section (C-section). This meta-analysis was performed to determine the effect of low and high intrathecal doses of pethidine on the maternal outcomes after C-section. Methods: A systematic search of PubMed, Scopus, Cochrane Library, and Google Scholar was performed. Random-effects meta-analysis was performed to derive odds ratios (ORs) from dichotomous data. Results: Seventeen randomized controlled trials with 1304 C-section patients were included. Patients who had received intrathecal pethidine experienced decreased shivering and intensity of shivering (OR 0.13; P<0.001) and (OR 0.21; P<0.001), respectively. Moreover, vomiting (OR 2.47; P=0.002) and pruritus (OR 5.92; P<0.001) were significantly higher in the pethidine group. There was no statistically significant difference in the incidence of nausea (OR 2.55; P=0.06) and hypotension (OR 0.91; P=0.67). Conclusions: Intrathecal pethidine can effectively decrease shivering, although it increases the risk of vomiting and pruritus. No significant difference was found both in the maternal hypotension and nausea.

Imitation-inhibition training can reduce the observation-inflation effect in face-to-face scenarios.

Observing others performing an action can lead to false memories of self-performance-the observation-inflation effect. Previous research has indicated that this phenomenon might impact the memory of actions in real-world interactions. However, whether direct observation without interaction can lead to observation inflation remains unclear. In Experiment 1, participants passively observed the experimenter performing actions live. In subsequent memory tests, they indeed reported false memories regarding their performances. Building on this, Experiment 2 investigated the causes of the observation-inflation effect induced by "real" actions. Participants underwent imitation-inhibition training with the individuals they observed previously. The results revealed that participants who completed imitation-inhibition training reported fewer false memories in memory tests than those who completed imitation training. These findings suggest that even passive observation of "real" actions can lead to observation inflation, and the simulation of others' actions by individuals may be a potential underlying cause of their occurrence in real-life situations.

In vivo and computational investigation of butin against alloxan-induced diabetes via biochemical, histopathological, and molecular interactions.

Herbs have been used as medicines since antiquity, and it has been discovered that the human body responds well to herbal remedies. Research on the effect of butin was conducted in the current study in the alloxan-induced diabetic rat paradigm. A total of 30 Wistar rats were randomly assigned into the following groups (n = 6): I-Normal; II-Alloxan-induced (50 mg/kg); III-Alloxan + butin 25 mg/kg; IV-Alloxan + butin 50 mg/kg; V-Butin per se 50 mg/kg. Various diabetic parameters (blood glucose, insulin, HbA1c), lipid profile, inflammatory (TNF-α, IL-1ß, IL-6 and NF-κB), antioxidant enzymes (CAT, SOD and GSH), oxidative stress indicators (MDA), apoptosis marker (caspase-3), hepatic markers (ALT and AST), and histopathological changes were assessed. Additionally, molecular docking and dynamics were performed to evaluate the interaction of butin with target proteins. Butin treatment, at both doses, significantly restored biochemical parameters and preserved pancreatic histopathology in diabetic rats. It effectively modulated blood parameters, lipid profiles, inflammatory markers, apoptosis, antioxidant enzyme activity, oxidative stress, and hepatic markers. Molecular docking revealed that butin binds to proteins such as caspase-3 (1NME), NF-κB (1SVC), and serum insulin (4IBM) with binding affinities of - 7.4, - 6.5, and - 8.2 kcal/mol, respectively. Molecular dynamics simulations further suggested that butin induces significant conformational changes in these proteins. Butin exhibits potential effects against alloxan-induced diabetic rats by restoring biochemical balance, reducing inflammation, and protecting pancreatic tissue. Its binding to key proteins involved in apoptosis and inflammation highlights its therapeutic potential in diabetes management.

Gut microbiota metabolites and risk of major adverse cardiovascular events and death: A systematic review and meta-analysis.

BACKGROUND: Gut microbial metabolites such as trimethylamine N-oxide (TMAO) and its precursors, namely betaine, L-carnitine, and choline, have been implicated as risk factors for cardiovascular events and mortality development. Therefore, we aim to perform a systematic review and meta-analysis to assess the validity of these associations. METHODS: MEDLINE and Scopus were queried from their inception to August 2023 to identify studies that quantified estimates of the associations of TMAO with the development of major adverse cardiovascular events (MACE) or death. A random-effects meta-analysis was conducted to pool unadjusted or multivariable-adjusted hazard ratios (HR) and their 95% confidence intervals. The primary endpoint was the risk of MACE and all-cause death. RESULTS: 30 prospective observational studies (n = 48 968) were included in the analysis. Elevated TMAO levels were associated with a significantly greater risk of MACE and all-cause death compared to low TMAO levels (HR: 1.41, 95% CI 1.2-1.54, P < .00001, I2 = 43%) and (HR: 1.55, 95% CI 1.37-1.75, P < .00001, I2 = 46%), respectively. Furthermore, high levels of either L-carnitine or choline were found to significantly increase the risk of MACE. However, no significant difference was seen in MACE in either high or low levels of betaine. CONCLUSION: Elevated concentrations of TMAO were associated with increased risks of MACE and all-cause mortality. High levels of L-carnitine/choline were also significantly associated with an increased risk of MACE. However, no significant difference was found between high or low levels of betaine for the outcome of MACE.