Therapeutic Effect Research Articles

Integrated Microbiome and Metabolomic to Explore the Mechanism of Coptisine in Alleviating Ulcerative Colitis.

Coptisine (COP), a naturally occurring alkaloid, is known for its diverse pharmacological effects and its supportive role in intestinal health. Despite this, the detailed mechanisms behind its therapeutic benefits are not yet fully understood. The objective of this study is to investigate the therapeutic potential of COP for the treatment of Ulcerative Colitis (UC) and to delineate the critical pathways by which it exerts its therapeutic effects. To assess COP's therapeutic effectiveness, mice were administered COP and monitored for clinical symptoms, activity, and disease activity index (DAI) changes. Intestinal histopathology, mucosal barrier function, and gut microbiota structure were evaluated, along with metabolic profiling, focusing on Prenol lipids in the colon to identify COP-induced metabolic shifts. Mice treated with COP exhibited significant relief from diarrhea and bleeding, along with increased activity and a marked reduction in DAI scores. Histopathological evaluation revealed a reduction in intestinal inflammation, and the intestinal mucosal barrier function was notably enhanced. The gut microbiota composition in COP-treated mice showed improvements. Additionally, the levels of Prenol lipids in the colon were elevated by COP treatment, which is crucial for the recovery of intestinal function. Our study demonstrates that COP effectively ameliorates colitis symptoms by modulating colon Prenol lipids metabolism, particularly under the influence of key bacterial species. The findings of this study provide novel insights into the therapeutic mechanisms of COP in the treatment of UC.

Analysis of clinical characteristics and predictive model for effective treatment of tinnitus in patients with transient compound sound therapy

PurposeThis study explored the clinical characteristics of patients with tinnitus who responded to sound therapy and established a predictive model to evaluate the effectiveness of this therapy according to the clinical characteristics.MethodsA retrospective analysis was performed on 991 subjective tinnitus patients who received compound sound therapy in the Department of Otolaryngology of the local hospital from November 2019 to January 2022.ResultsWe found that tinnitus patients with different therapeutic effects had significant differences in the tinnitus side (p = 0.007), tone loudness distortion feedback test (FBT) (p = 0.000), residual inhibition test (RIT) (p = 0.000), tinnitus frequency (p = 0.012) and sensation level (p = 0.023). The corresponding variables were screened by univariate logistic regression, and the selected variables were analyzed using multivariate logistic regression. The results showed that FBT (p = 0.003), RIT (p = 0.000) and tinnitus frequency (p = 0.029) were independent risk factors affecting the efficacy of compound sound therapy. A predictive model and nomogram for the efficacy of compound sound therapy for tinnitus were constructed based on independent risk factors. The area under the curve (AUC) of the model constructed in this study was 0.766 (95% CI = 0.725–0.807), indicating a certain prediction ability. The calibration curve revealed that the predicted results were in good agreement with the actual results.ConclusionThe model can predict the prognosis of tinnitus in patients receiving compound sound therapy and help otolaryngologists make the best clinical decisions regarding tinnitus treatment.

Improving the Anti-Tumor Effect of Indoleamine 2,3-Dioxygenase Inhibitor CY1-4 by CY1-4 Nano-Skeleton Drug Delivery System

Background: CY1-4, 9-nitropyridine [2′,3′:4,5] pyrimido [1,2-α] indole -5,11- dione, is an indoleamine 2,3-dioxygenase (IDO) inhibitor and a poorly water-soluble substance. It is very important to increase the solubility of CY1-4 to improve its bioavailability and therapeutic effect. In this study, the mesoporous silica nano-skeleton carrier material Sylysia was selected as the carrier to load CY1-4, and then the CY1-4 nano-skeleton drug delivery system (MSNM@CY1-4) was prepared by coating the hydrophilic polymer material Hydroxypropyl methylcellulose (HPMC) and the lipid material Distearoylphosphatidyl-ethanolamine-poly(ethylene glycol)2000 (DSPE-PEG2000) to improve the anti-tumor effect of CY1-4. Methods: The solubility and dissolution of MSNM@CY1-4 were investigated, and its bioavailability, anti-tumor efficacy, IDO inhibitory ability and immune mechanism were evaluated in vivo. Results: CY1-4 was loaded in MSNM@CY1-4 in an amorphous form, and MSNM@CY1-4 could significantly improve the solubility (up to about 200 times) and dissolution rate of CY1-4. In vivo studies showed that the oral bioavailability of CY1-4 in 20 mg/kg MSNM@CY1-4 was about 23.9-fold more than that in 50 mg/kg CY1-4 suspension. In B16F10 tumor-bearing mice, MSNM@CY1-4 significantly inhibited tumor growth, prolonged survival time, significantly inhibited IDO activity in blood and tumor tissues, and reduced Tregs in tumor tissues and tumor-draining lymph nodes to improve anti-tumor efficacy. Conclusions: The nano-skeleton drug delivery system (MSNM@CY1-4) constructed in this study is a potential drug delivery platform for improving the anti-tumor effect of oral poorly water-soluble CY1-4.

Immunomodulatory Effects of Andrographis paniculata Leaf Extract in Cyclophosphamide-induced Immunosuppressed Mice

Background Cyclophosphamide is one of the most extensively used chemotherapeutic drugs and is employed to treat several malignancies. Cyclophosphamide often comes with several unpleasant side effects. The primary negative consequence of cyclophosphamide in clinical chemotherapy is immunosuppression, which can lead to life-threatening complications. Objectives: The present work was dedicated to exploring the therapeutic effects of Andrographis paniculata against cyclophosphamide-induced immunosuppression in mice. Materials and Methods The BALB/c mice were treated with 80 mg/kg of cyclophosphamide to achieve immunosuppression and treated with 250 and 500 mg/kg of A. paniculata extract. 10 mg/kg of levamisole was used as a standard drug. After the completion of the treatments, the body weights of the experimental animals were measured. The immune organs (spleen and thymus) were determined by standard methods. The levels of blood components were studied using an automated hematological analyzer. The macrophage phagocytic index, humoral response, and delayed immune response were studied by standard methods. The histopathological analysis was done on the heart, spleen, and thymus. Results The treatment with 250 and 500 mg/kg of A. paniculata extract substantially increased the body weight and elevated the immune organ index in the immunosuppressed mice. The changes in the levels of hematological parameters were successfully modulated by A. paniculata. The levels of macrophage phagocytic index and delayed and humoral immune responses were boosted by the A. paniculata extract treatment in the immunosuppressed mice. The outcomes of histopathological analysis exhibited that the A. paniculata extract attenuated the cyclophosphamide-induced damage to the heart, thymus, and spleen tissues. Conclusion The findings of the current work validate the immunomodulatory properties of A. paniculata extract in cyclophosphamide-induced immunosuppressed mice. Hence, it was clear that A. paniculata can be a talented immunomodulatory agent to treat immunological complications.

Comparison of Traditional Dressing Change Techniques and Vacuum Sealing Drainage Techniques in the Treatment of Skin and Soft Tissue Injuries

Objective: To analyze the therapeutic effects of traditional dressing change techniques and vacuum sealing drainage (VSD) techniques on skin and soft tissue injuries. Methods: 60 patients with skin and soft tissue injuries admitted to the hospital from October 2021 to October 2023 were selected. They were randomly divided into an observation group (30 cases) receiving VSD treatment and a control group (30 cases) receiving the traditional dressing change technique. The total effective rate, treatment indicators, inflammatory factors, and complication rate were compared between the two groups. Results: The total effective rate of the observation group was higher than that of the control group, and the treatment indicators were better than those of the control group (P < 0.05). Before treatment, the levels of inflammatory factors were similar between the two groups (P > 0.05). After four weeks of treatment, the levels of inflammatory factors in the observation group were lower than those in the control group (P < 0.05). The complication rate of the observation group was lower than that of the control group (P < 0.05). Conclusion: In the treatment of skin and soft tissue injuries, VSD can improve the total effective rate, shorten the treatment cycle, alleviate the degree of inflammatory reaction, and reduce the risk of complications.

Activation of cannabinoid receptor 2 by turmeric oleoresin reduces inflammation and oxidative stress in an osteoarthritis in vitro model

IntroductionOsteoarthritis (OA) is a chronic degenerative joint disease characterized by the progressive degradation of articular cartilage, resulting in pain and reduced mobility. Turmeric (Curcuma longa L.) has been widely recognized for its anti-inflammatory and antioxidant properties, but the molecular mechanisms underlying its therapeutic effects remain inadequately explored. This study investigates the potential of turmeric oleoresin (TUR) to activate Cannabinoid Receptor 2 (CBR2) and its role in mediating anti-inflammatory and antioxidant effects in an in vitro OA model.Material and methodsMolecular docking and cAMP quantification assays were used to evaluate TUR’s agonistic activity on CBR2. Human chondrosarcoma cells (SW-1353) were treated with TUR under oxidative stress induced by menadione or inflammatory conditions simulated with IL-1β and TNF-α. The effects of TUR were assessed in the presence and absence of the CBR2 antagonist SR144528. Outcomes included changes in reactive oxygen species (ROS) production, inflammatory marker expression, oxidative defense markers and endocannabinoid system components and receptors.ResultsTUR was confirmed as a CBR2 agonist and significantly reduced ROS production, downregulated pro-inflammatory cytokines (IL-6, COX-2, metalloproteases), and suppressed signaling pathways such as NFKB1, ERK 1/2, and c-Myc. These effects were reversed upon CBR2 inhibition. TUR also enhanced HMOX-1 expression and modulated endocannabinoid-related enzymes, highlighting its impact on oxidative stress and the endocannabinoid system.DiscussionThese findings suggest that CBR2 activation is central to TUR’s anti-inflammatory and antioxidant effects. By modulating key pathways and endocannabinoid system components, TUR demonstrates potential as a novel therapeutic agent for OA management. Future studies could explore its clinical applications and further validate its molecular mechanisms in vivo.

TOXICOLOGICAL IMPACT OF DICLOFENAC SODIUM: HEMATOLOGICAL, BIOCHEMICAL AND HISTOPATHOLOGICAL CHANGES IN MALE RATS

Background: Long-term administration of diclofenac sodium can lead to harmful effects on body tissues, causing cellular injuries that include changes in kidney function and contributing to the development of immune mechanisms against kidney tissues. This study aimed to evaluate the toxic effects of diclofenac sodium on hematological and biochemical parameters, as well as histopathological changes in the kidneys of experimental animals. Methods: Forty male Albino-Aster mice were divided into four groups: control and three groups administered diclofenac sodium orally at doses of 20.5, 45 and 56.25 mg/kg body weight for 20 days. Blood samples were collected for hematological and biochemical analyses and kidney tissues were examined histopathologically. Results: Diclofenac sodium administration caused a significant decrease in red blood cells, hemoglobin, packed cell volume, mean corpuscular volume and mean corpuscular hemoglobin concentration, as well as a significant increase in platelets and total white blood cells. Serum alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase were significantly elevated. Histopathological examination revealed congestion, inflammation, glomerular abnormalities, tubular necrosis and vascular changes in the kidney tissues, with the severity increasing with higher doses. Conclusion: Diclofenac sodium administration at different doses can cause significant alterations in hematological and biochemical parameters, as well as histopathological changes in the kidneys of male rats, indicating potential adverse effects on animal tissues. Caution is recommended in the clinical use of diclofenac sodium and the lowest effective dose and duration should be used to achieve the desired therapeutic effect.

Abstract A016: Targeting calpain-1 and calpain-2 for prevention of breast cancer metastasis: In vivo insights and drug discovery approaches

Abstract Calpain-1 and calpain-2 are heterodimeric calcium-dependent cysteine proteases composed of the catalytic subunits CAPN1 or CAPN2, respectively, and the common regulatory subunit CAPNS1. They are associated with cancer progression, metastasis, and treatment resistance in breast cancer. Here, we present novel insights into the therapeutic potential of calpain inhibition by combining genetic disruption and preclinical mouse tumor models and biosensor-based detection of calpain heterodimerization with ongoing efforts to discover small-molecule and peptide inhibitors. CRISPR-Cas9-mediated knockout of CAPN1, CAPN2, or CAPNS1 in MDA-MB-231 human triple-negative breast cancer (TNBC) cells revealed that disruption of both calpains, through CAPNS1 knockout, significantly reduced cell migration and inhibited spontaneous metastasis in a mouse orthotopic engraftment model by over 80%. Individual knockouts of CAPN1 or CAPN2 also reduced metastasis but to a lesser extent, highlighting the necessity of dual inhibition for optimal therapeutic effect. In parallel, we have been actively seeking small molecules and peptide inhibitors to target calpain through two approaches: inhibiting the PEF-PEF interaction that mediates heterodimerization using small molecules; and targeting the active site using a calpastatin (CAST)-based peptide. To identify small molecules capable of disrupting the PEF-PEF interaction, we conducted in silico screens of over 3.6 million compounds from several libraries. These compounds were evaluated based on their calculated binding affinity and potential to sterically hinder the conformational changes required for calpain activity. The CAST-based peptide inhibitor was designed based on the active site binding B-domain and tested on a purified calpain-2. These efforts lay the groundwork for novel therapeutic approaches targeting calpain-1 and calpain-2, which have emerged as promising targets for preventing metastasis in TNBC. We will present our progress in identifying and validating these small molecules and peptides for further development. Citation Format: Ivan Shapovalov, Pitambar Poudel, Shailesh K. Panday, Danielle Harper, Jung Yeon Min, Yan Gao, Kazem Nouri, Emil Alexov, Peter A. Greer. Targeting calpain-1 and calpain-2 for prevention of breast cancer metastasis: In vivo insights and drug discovery approaches. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A016

Serum IL-6 concentration is a useful biomarker to predict the efficacy of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

This study aims to identify biomarkers for treatment response of atezolizumab plus bevacizumab (Atezo+Bev) in patients with hepatocellular carcinoma (HCC). 96 patients who received Atezo+Bev or lenvatinib as a first-line systemic therapy were enrolled as the training group after propensity score matching (PSM), and 42 patients treated with Atezo+Bev were enrolled as the validation group. 17 serum cytokines were measured by Luminex multiplex assay at the start of treatment. For further assessment of the association between cytokine levels and the tumor microenvironment (TME), immunohistochemistry (IHC) was performed on pre-treatment liver biopsy specimens. In the derivation set, multivariate analysis identified elevated IL-6 as an independent risk factor in the Atezo+Bev group (HR 5.80: p<0.01), but not in the lenvatinib group; in a subset analysis of patients with low IL-6, PFS was longer in the Atezo+Bev training group than in the lenvatinib group (p = 0.02). A validation study also showed a significantly longer prognosis in the low IL-6 group for both PFS (p = 0.0001) and OS (p = 0.03). Serum IL-6 had a positive correlation with tumor IL-6 expression (ρ = 0.56, p < 0.0001) and an inverse correlation with the CD8/CD163-positive cell count ratio (ρ = -0.4, p < 0.01). Serum IL-6 levels are thought to be involved in the suppression of tumor immunity and are useful in predicting the therapeutic effect of Atezo+Bev treatment.

Efficacy of red algae and artichoke extracts in disrupting antioxidant/PI3K/RBP-4 pathway in high-fat diet-induced metabolic disorders in rats

BackgroundInsulin resistance (IR) leads to various metabolic abnormalities, including diabetes mellitus, obesity, nonalcoholic steatohepatitis, and neurodegenerative disorders. Natural products rich in nontoxic phytochemicals are cost-effective and widely used to manage insulin resistance, reducing drug interactions. Artichoke stems and red algae contain several phytochemical compounds that exert antioxidant and anti-inflammatory effects.AimThis study aims to explore and compare the preventive and therapeutic effects of red algae and artichoke stem extracts against high-fat diet-induced insulin resistance and then compare their impacts with those of the reference drug metformin, which is commonly used for treating type 2 diabetes.MethodsThe animals were fed a high-fat diet for eight weeks to induce insulin resistance. The plants were then treated orally with 100 mg/kg body weight red algae, artichoke extracts, or metformin per day for 14 days. The protective rat groups received the extracts at the same dose for 14 days before being fed the high-fat diet for eight weeks. Commercial kits and standardized methods were used to measure blood diabetic profiles (glucose, insulin, lipid profile, fructosamine, and retinol-binding protein-4 (RBP-4)) and liver oxidative stress parameters, nuclear factor-κβ (NF-κβ), peroxisome proliferator-activated receptor gamma (PPAR-γ), phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), retinol-binding protein-4 (RBP-4), and phosphatase and tensin homolog (PTEN).ResultsOur results showed that both extracts inhibited NF-κB and PTEN while enhancing PI3K, RPB-4, and PPAR-γ due to their potent antioxidant properties. They also increased insulin sensitivity, as reflected by reduced blood glucose and lipid profile levels and normalized fructosamine and RBP-4. Additionally, these extracts prevent oxidative stress-induced hepatic and nephric cell dysfunction, as confirmed by improved blood, liver, and kidney parameters.ConclusionTherefore, both extracts could be good antioxidant treatments for oxidative stress-related insulin resistance because they restore the balance of the PI3K/PPAR-γ/RBP-4 pathway. This pathway increases glucose uptake, stops gluconeogenesis, speeds up lipid metabolism, and stops the inflammation pathway.

Quercetin alleviates ulcerative colitis through inhibiting CXCL8-CXCR1/2 axis: a network and transcriptome analysis

IntroductionUlcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract in which mucosal healing is a crucial measure of therapeutic efficacy. Quercetin, a flavonoid prevalent in various foods and traditional Chinese medicines, exhibits notable pharmacological properties, including antioxidant and anti-inflammatory activities. Consequently, it warrants investigation to determine its potential therapeutic effects on UC. The objective of this study was to investigate the effects and underlying mechanisms of quercetin in a murine model of UC.MethodsA comprehensive approach integrating network predictions with transcriptomic analyses was employed to identify the potential targets and enriched pathways associated with quercetin in UC. Subsequently, the effects of quercetin on pathological morphology, inflammatory mediators, and mucosal barrier-associated proteins, as well as the identified potential targets and enriched pathways, were systematically investigated in a murine model of dextran sulfate sodium (DSS)-induced UC.ResultsNetwork analyses identified CXCL8 and its receptors, CXCR1 and CXCR2, as primary target genes for therapeutic intervention in UC. Further validation through transcriptomic analysis and immunofluorescence staining demonstrated significant upregulation of the CXCL8-CXCR1/2 axis in the intestinal tissues of patients with UC. Experimental investigations in animal models have shown that quercetin markedly alleviates DSS-induced symptoms in mice. This effect includes the restoration of colonic crypt architecture, normalization of goblet cell structure and density, reduction of inflammatory cell infiltration, and decreased concentrations of inflammatory mediators. Quercetin enhanced the expression of tight junction (TJ) proteins, including ZO-1, MUC2 (Mucin 2), and occludin, thereby preserving the integrity of the intestinal mucosal barrier. Additionally, it significantly diminished the levels of IL-17A, NF-κB, CXCL8, CXCR1, and CXCR2 in the colonic tissues of mice with UC.DiscussionThe ameliorative effects of quercetin on colon tissue damage in DSS-induced UC mice were significant, possibly due to its ability to inhibit the CXCL8-CXCR1/2 signaling axis. These findings provide a solid foundation for the clinical application and pharmaceutical advancement of quercetin.

Costus igneus: A Versatile Herbal Remedy for Multiple Health Conditions.

Costus igneus, commonly known as the insulin plant, is a potent medicinal herb with a wide range of pharmacological activities. Traditionally used in diabetes management, recent studies have highlighted its antidiabetic, antioxidant, antimicrobial, hepatoprotective, and kidney stone inhibitor properties. Phytochemical analyses reveal the presence of saponins, flavonoids, alkaloids, steroids, and terpenoids, which contribute to its therapeutic effects. In various in-vitro and in-vivo models, Costus igneus demonstrated significant hypoglycemic activity. The plant exhibits strong antioxidant activity, as evidenced by FRAP, DPPH, and ABTS assays, with notable radical scavenging and reducing power. Other miscellaneous pharmacological activities include anti-inflammatory, anti-arthritic, cytotoxicity and hypotensive effects. These findings support Costus igneus as a safe and cost-effective herbal remedy for managing diabetes and other ailments, highlighting its potential for future therapeutic applications and the development of herbal formulations.

Prospects for applying the chronic social conflict model in medical and biological research

Long-term studies (1987–2023) have shown that the model of chronic social conflict with the original name «sensory contact model» can be used to model various pathological conditions that develop in mice under the influence of chronic social stress, which makes it possible to study neurophysiological and neuromolecular mechanisms at different stages of disease development, in particular, increased anxiety, depression-like and psychosis-like states in mice of the C57BL/6 strain under repeated agonistic interactions. In pharmacological experiments in mice with different pathological symptoms, it becomes possible to study: the therapeutic and protective effects of drugs at different stages of disease development, the effectiveness of treatment, and methods for prevention of relapses of the disease. The model makes it possible to develop approaches to pharmacogenomic therapy, as well as search for peripheral markers of pathological conditions.

Critical review on Naga Bhasma

Rasa Shastra in Ayurveda focuses on metals and minerals categorized as Rasa, Maharasa, Uprasa, Dhatu, Ratna, Visha, etc., and is valued for its potent therapeutic effects compared to herbal drugs. Naga, a type of Putiloha in Dhatu Varga, is utilized for medicinal purposes to treat various ailments like Diabetes, Obesity, Joint issues, eye and skin conditions, and Anemia. The process of drug preparation explained in Rasa Shastra involves Samskara, which alters the characteristics of the drugs. The purification process, known as Shodhana, must be done on all medications before they are used in any mixture or undergo further processes like Jarana and Marana. In the field of Rasa Shastra, Jarana can be seen in various forms such as Parada Samskara, Gandhaka/Bali Jarana, and Putilohas Jarana. This article examines Jarana of the Putiloha. The preparation of Bhasma is a multistep and intricate process. The steps vary significantly depending on the type of herbal, metallic, or mineral media used in the Marana process. Naga (Lead) was grouped with heavy metals such as mercury, arsenic, and cadmium. It’s exposure can result in neurological disorders and issues with other body systems. Naga Bhasma is a preparation that includes Lead as its main ingredient. Lead and its compounds are harmful to human health. The presence of unique healing qualities in Naga Bhasma suggests that the Ayurvedic procedures used in its creation result in significant transformations in Naga. These processes eliminate its toxicity and add exceptional medicinal properties to Naga Bhasma.

Nanotherapy‐Engineered Stem Cells Alleviate Myocardial Reperfusion Injury by Normalizing the Pathological Microenvironment and Promoting Cardiac Repair

AbstractMyocardial infarction, the most severe manifestation of coronary artery disease, is a leading cause of mortality worldwide. Here, a novel nanotherapy engineering approach is reported for enhancing therapeutic effects of mesenchymal stem cells (MSCs) on myocardial ischemia‐reperfusion (MI/R) injury. An anti‐oxidative and anti‐inflammatory nanotherapy (TPCD NP) is first fabricated. MSCs are successfully engineered with TPCD NP by endocytosis, and TPCD NP engineering does not affect stemness of MSCs. TPCD NP‐internalized MSCs (tn‐MSCs) are resistant to oxidative stress, cytotoxicity, and apoptosis induced by reactive oxygen species (ROS). Under oxidative distress, tn‐MSCs show stronger paracrine activity compared to MSCs. Consistently, tn‐MSCs effectively enhance angiogenesis of endothelial cells under pathological conditions. Also, tn‐MSCs protect cardiomyocytes from ROS‐induced cytotoxicity and apoptosis by improving mitochondrial membrane potential and regulating the p53 signaling pathway. In mice with MI/R injury, the survival time of tn‐MSCs in the injured heart is prolonged, compared to pristine MSCs. Correspondingly, tn‐MSCs more significantly reduce the infarct size, improve cardiac function, and promote cardiac remodeling in MI/R injury mice. Mechanistically, tn‐MSCs alleviate MI/R injury by attenuating oxidative stress and inflammation, inhibiting cardiomyocyte apoptosis, and promoting cardiac repair. Consequently, tn‐MSCs are promising for treating cardiovascular diseases linked to oxidative distress and inflammation.

MicroRNAs Dependent G-ELNs Based Intervention Improves Glucose and Fatty Acid Metabolism While Protecting Pancreatic β-Cells in Type 2 Diabetic Mice.

Metabolic disorders such as Type 2 diabetes mellitus (T2DM) imposes a significant global health burden. Plant-derived exosome like nanoparticles (P-ELNs) have emerged as a promising therapeutic alternate for various diseases. Present data demonstrates that treatment with Ginger-derived exosome like nanoparticles (G-ELNs) enhance insulin dependent glucose uptake, downregulate gluconeogenesis and oxidative stress in insulin resistant HepG2 cells. Furthermore, oral administration of G-ELNs in T2DM mice decreases fasting blood glucose levels and improves glucose tolerance as effectively as metformin. These improvements are attributed to the enhanced phosphorylation of Protein kinase B (Akt-2), the phosphatidylinositol 3-kinase at serine 474 which consequently leads to increase in hepatic insulin sensitivity, improvement in glucose homeostasis and decrease in ectopic fat deposition. Oral administration of G-ELNs also exerts protective effect on Streptozotocin (STZ)-induced pancreatic β-cells damage, contributing to systemic amelioration of T2DM. Further, as per computational tools, miRNAs present in G-ELNs modulate the phosphatidylinositol 3-kinase (PI3K)/Akt-2pathway and exhibit strong interactions with various target mRNAs responsible for hepatic gluconeogenesis, ectopic fat deposition and oxidative stress. Furthermore, synthetic mimic of G-ELNs miRNA effectively downregulates its target mRNA in insulin resistant HepG2 cells. Overall, the results indicate that the miRNAs present in G-ELNs target hepatic metabolism thus, exerting therapeutic effects in T2DM.

Effects of tDCS on glutamatergic pathways in epilepsy: neuroprotective and therapeutic potential.

Epilepsy is a chronic neurological disease characterized by recurrent seizures caused by abnormal electrical activity in the brain. The aim of our study was to investigate the effect of tDCS on oxidative stress, Ca2+, glutamate, GABA, AMPAR1, and NMDAR1 levels in kindling-induced epilepsy model. Behavioral tests evaluated motor and cognitive functions, while assessing oxidative stress, Ca2+, glutamate, GABA, AMPAR1, and NMDAR1 levels in hippocampal tissue. tDCS stimulation therapy demonstrates a neuroprotective effect on motor and cognitive function postepilepsy. Our study reveals an increase in TOC, Ca2+, glutamate, GABA, AMPAR1, and NMDAR1 levels and a decline in total antioxidant capacity (TAC) following PTZ-induced seizures. However, tDCS treatment led to a significant decrease of Ca2+, total oxidant capacity (TOC), glutamate, GABA, AMPAR1, and NMDAR1 levels in the epilepsy cohorts, while simultaneously causing a spike in TAC levels. The study's results showed that tDCS treatment could have a therapeutic effect on oxidative stress, Ca2+, TOC, glutamate, GABA, AMPAR1, NMDAR1, and TAC in both acute and chronic kindling epilepsy models.

The Effect of Zeolite Zinc on Memory Performance and Hippocampal Cell Death in a Rat Model of Alzheimer's-like Disease Induced by Aβ1-42.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, characterized by the slow and progressive loss of brain structure and function, primarily affecting older individuals. Evidence has shown that disruption of zinc homeostasis in the brain contributes to synaptic dysfunction, as well as impairments in learning and memory. In this study, we evaluated the effect of zeolite zinc on memory performance and hippocampal cell death in a rat model of Alzheimer's disease (AD) induced by intracerebroventricular administration of Aβ1-42. We employed the Morris water maze, shuttle box, and open field tests to assess spatial memory, passive avoidance memory, and anxiety-like behavior, respectively. P-Tau and the amyloid precursor protein (APP) expression, along with hippocampal cell death, were also evaluated. Both Aβ1-42 and zeolite zinc were injected intracerebroventricularly. The results showed that zeolite zinc partially reversed Aβ1-42-induced impairments in memory performance and mitigated the effects of Aβ1-42 on locomotor activity, although it did not fully restore baseline levels. In addition, Aβ1-42 increased the expression of APP and P-Tau, as well as the number of dead cells, whereas zeolite zinc reduced these effects. In conclusion, our findings suggest that while zeolite zinc plays a role in modulating the pathophysiology of AD, its therapeutic effects only partially reverse the progression or symptoms of AD, indicating the need for further investigation into optimal dosing or combination therapies.

Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties.

Myeloid differentiation primary response 88 (MyD88) plays a central role in inflammatory responses and diseases. However, only a few inhibitors of MyD88 with some limits have been reported currently. Herein, we identified a lead compound (L7) through virtual screening and synthesized twenty-seven L7 derivatives. An optimal compound (A5) was determined through enzyme-linked immunosorbent assay (ELISA), 2,5-diphenyl-2H-tetrazolium bromide (MTT), and biolayer interferometry (BLI) assay. The potent isomer A5S showed a high MyD88 binding ability and exerted an anti-inflammatory effect through the NF-κB/MAPK pathway. A5S had good stability and safety, showed the highest distribution concentration in the lungs, and exhibited good therapeutic effects on LPS-induced and sepsis-induced ALI mouse models. Most importantly, A5S showed advantages in PK properties, and was identified as a promising MyD88 inhibitor with favorable drug-like properties, compared to the only approved MyD88 inhibitor, TJ-M2010-5, which is currently undergoing a Phase I study, and our previously reported MyD88 inhibitors LM8.

Therapeutic effects of Huangqi formula (Eefooton) in chronic kidney disease: clinical research and narrative literature review.

The study aimed to assess the clinical effects of employing the Huangqi formula (Eefooton; EFT) for chronic kidney disease (CKD) treatment. A narrative literature review was undertaken to elucidate the specific ingredients of EFT and their potential impact on renal health. A retrospective observational study investigated EFT treatment in outpatients with stable CKD (stages 3B to 5) from March 2019 to March 2021. Patients received 20 mL of EFT thrice daily for 6 months, along with standard treatment. Control groups were matched to the EFT cohort. Regular assessments of renal, liver functions, and lipid profiles were conducted. Serum creatinine (Cr) and eGFR levels consistently improved in stage 3B CKD patients at each follow-up visit. At 6 months, improvement in Cr and eGFR was observed for stage 4 and 5 CKD. Stage 3B CKD patients exhibited notable reductions in systolic blood pressure after 3 and 6 months of EFT treatment. Remarkably, a substantial decrease in HbA1C was noted in stage 4 CKD individuals after three months of therapy. Additionally, stage 4 CKD patients saw a significant reduction in LDL levels after both 3 and 6 months of EFT treatment. A literature review on EFT ingredients indicated that the positive effects of EFT might be associated with its anti-inflammatory, antioxidant, and anti-fibrotic properties. This research demonstrated that incorporating EFT alongside standard treatment enhanced renal function in individuals with CKD. EFT is proposed as a feasible complementary treatment for CKD patients, emphasizing the importance of early intervention.