Journal of Experimental Pharmacology最新文献

{"title":"Neuroprotective Effects of Asiatic Acid on Autophagy and Mitochondrial Integrity in a Parkinson's Disease Cellular Model.","authors":"Athinan Prommahom, Tatcha Balit, Sunisa Somkana, Satjapot Manprasong, Chonlakorn Panyasuppakun, Atipha Kijkraikul, Preawanit Thawornrungroaj, Pitchaya Thawornrungroaj, Permphan Dharmasaroja, Thanasup Gonmanee, Phisit Khemawoot, Kawinthra Khwanraj","doi":"10.2147/JEP.S536728","DOIUrl":"10.2147/JEP.S536728","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a progressive neurodegenerative disorder. PD patients mostly exhibit mitochondrial dysfunction and autophagic impairment. Asiatic acid (AA) is a triterpenoid with the highest antioxidant activity used to treat oxidative stress. It has been found to have a neuroprotective effect against mitochondrial dysfunction in cellular models of PD; however, its effect on autophagy has not been investigated.</p><p><strong>Purpose: </strong>This study aimed to investigate whether AA affects autophagy in a cellular model of PD.</p><p><strong>Methods: </strong>SH-SY5Y cells were differentiated into dopaminergic neuron-like cells via retinoic acid administration. Differentiated cells were treated with AA for 24 h and then exposed to 1-methyl-4-phenylpyridinium (MPP⁺). Cell viability was assessed using a 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. The expression of microtubule-associated protein 1 light chain 3 (LC3)-II/I, Beclin-1, sequestosome-1/ubiquitin-binding protein p62 (SQSTM1/p62), and tyrosine hydroxylase (TH) was analyzed via Western blot. Caspase-3/7 and LC3 expression was measured using immunofluorescence, as was the colocalization of LC3 and mitochondria. MitoTracker and JC-10 were used to assess the mitochondrial morphology and mitochondrial membrane potential (ΔΨ_m), respectively.</p><p><strong>Results: </strong>Pretreating cells with AA before MPP⁺ exposure resulted in significantly higher expression of LC3-II/I and Beclin-1, while the expression of SQSTM1/p62 was slightly lower compared to that in cells not pretreated with AA. Cells pretreated with AA exhibited significantly higher viability and TH expression, but significantly lower caspase-3/7 expression and numbers of apoptotic nuclei compared to cells treated with MPP⁺ alone. Notably, pretreatment with AA resulted in tubular mitochondria with considerably higher ΔΨ_m values. The colocalization of LC3 and mitochondria was also significantly higher in the cells pretreated with AA.</p><p><strong>Conclusion: </strong>AA protected dopaminergic neuron-like cells against MPP⁺-induced apoptosis via the induction of autophagy and the enhancement of mitochondrial function, suggesting that it could be developed as a therapeutic agent for PD.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"687-705"},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antihypertensive Effects of Diosmetin in Hypertension-Induced Cardiovascular Abnormalities in Rats.","authors":"Banyaphon Jan-O, Metee Iampanichakul, Prapassorn Potue, Juthamas Khamseekaew, Poungrat Pakdeechote, Piman Pocasap, Parichat Prachaney, Anuson Poasakate, Putcharawipa Maneesai","doi":"10.2147/JEP.S541405","DOIUrl":"10.2147/JEP.S541405","url":null,"abstract":"<p><strong>Introduction: </strong>Hypertension is associated with cardiovascular dysfunction and remodeling. Diosmetin, a flavonoid isolated from citrus seeds, has various biological properties. This work investigated the effects of diosmetin on cardiovascular parameters and classical and non-classical renin-angiotensin systems (RAS) in two-kidney one-clip (2K-1C) rats.</p><p><strong>Methods: </strong>2K-1C hypertension was induced by placing a silver clip on the left renal artery. Three weeks after induction, rats were orally gavage with either vehicle, diosmetin (20 or 40 mg/kg), or telmisartan (5 mg/kg) for four weeks. Blood pressure (BP) was monitored weekly while vascular function and histomorphology studies were performed at the end of the study. Oxidative stress markers and RAS parameters, including serum angiotensin-converting enzyme (ACE) activity and plasma angiotensin II and angiotensin I-7 (Ang-(1-7)) concentrations, were also measured. The expression levels of angiotensin II type 1 receptor (AT₁R), transforming growth factor-β (TGF-β), and Mas receptor protein were assessed. A molecular docking analysis was performed to analyze the potential interactions between diosmetin and the human angiotensin I converting enzyme.</p><p><strong>Results: </strong>In this in vivo study on the 2K-1C rats, diosmetin exhibited antihypertensive effects in the 2K-1C model via modulation of the RAS. Diosmetin at doses of 20 and 40 mg/kg decreased BP by 11.73% and 23.17%, respectively. Diosmetin also improved vascular function by reducing sympathetic nerve-mediated vasoconstriction and restoring endothelium-mediated vasodilation in the mesentery and aortic rings. The thickening of the left ventricle and aorta in hypertensive rats was alleviated by diosmetin treatment. RAS parameters and oxidative stress markers were improved in the diosmetin-treated group compared to the untreated group. Additionally, diosmetin treatment restored the overexpression of the AT₁R and TGF-β while reducing Mas receptor expression in cardiac and aortic tissue. The molecular docking analysis confirmed that diosmetin can bind to the active site of ACE.</p><p><strong>Conclusion: </strong>Diosmetin restored hemodynamic alterations associated with the improvement of vascular function. It also ameliorated left ventricular-aortic hypertrophy in hypertensive rats. These effects could be attributed to its capacity to modulate classical and non-classical RAS.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"667-685"},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetic Peripheral Neuropathy: Pathophysiology and New Insights into the Mechanism of Action of High-Concentration Topical Capsaicin.","authors":"David G Armstrong, Keith Bley, David M Simpson, Peter Staats, Samuel Allen, Audrey Carnevale, Lizandra Marcondes","doi":"10.2147/JEP.S526968","DOIUrl":"10.2147/JEP.S526968","url":null,"abstract":"<p><p>Diabetic peripheral neuropathy (DPN) is a chronic, progressive complication of diabetes. Pain in DPN can be severe and detrimental to the patient's quality of life. In this review, we provide an update on the mechanism of action (MOA) of high-concentration capsaicin topical system (HCCTS) for treatment of painful DPN, with an emphasis on neuroregeneration. In diabetes, hyperglycemia and other metabolic imbalances lead to oxidative stress and inflammation, which result in degeneration of the axons of afferent neurons (particularly C and Aδ fibers) within the peripheral nervous system. Dysfunction of the microvasculature supporting the nerves further exacerbates neural damage. As a result, epidermal nerve fiber density (ENFD) diminishes, and physical and chemical changes to the remaining afferent fibers render them hypersensitive to painful stimuli and hyposensitive to normal stimuli. As the longest axons are usually damaged first, DPN normally begins in the feet, then legs, and finally the hands. HCCTS incorporates a matrix technology that forcibly diffuses a high concentration of capsaicin (a TRPV1 agonist) to the dermis and epidermis, targeting TRPV1 receptors that are upregulated in DPN and play a key role in pain generation. HCCTS activates TRPV1 receptors expressed on the neuron cell membrane and endoplasmic reticulum, leading to cytoplasmic calcium ion overload, and then a cascade of cellular events resulting in reversible neurolysis of these afferent terminals. After 1-3 months, the terminals regenerate with a \"healthier\" phenotype, increasing ENFD, resulting in vasodilation, which may lead to a microenvironment conducive to improved neuroregeneration. This MOA is supported by clinical evidence demonstrating that repeated HCCTS treatment provides cumulative benefits in pain and improvements in sensory function of the feet compared with baseline. If effects on sensory function are confirmed in large-scale clinical studies, HCCTS could help slow the progression of DPN to more severe forms of diabetic foot syndrome.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"651-665"},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Psidium guajava</i> Leaves n-Hexane Fraction Antibacterial Activity and the Inhibition of Gene Expression of <i>gtfB</i> and <i>gtfC</i> in the Combination <i>Streptococcus mutans</i> ATCC 25175 and <i>Veillonella parvula</i> ATCC 10790^T.","authors":"Ame Suciati Setiawan, Anas Subarnas, Ariadna Adisatya Djais, Tiana Milanda, Solachudin Jauhari Arief Ichwan","doi":"10.2147/JEP.S531035","DOIUrl":"10.2147/JEP.S531035","url":null,"abstract":"<p><strong>Background: </strong>Oral biofilm is an extracellular polymeric matrix produced by <i>Streptococcus mutans</i> as the early colonizer in the formation of an oral biofilm. Glucosyltransferase (Gtfs) enzyme is a virulence factor for <i>S. mutans</i> in biofilm that is resistant to antibacterial agents. <i>Veillonella parvula</i> influences <i>S. mutans</i> to increased quantities of Gtfs, thereby accelerating the growth of oral biofilms. Decreasing the production of Gtfs by the use of additional materials is necessary to inhibit biofilm formation.</p><p><strong>Objective: </strong>The study was determined the inhibitory activity of the <i>Psidium guajava</i> leaves n-hexane fraction on the production of Gtfs by a single and combination of <i>S. mutans</i> and <i>V. parvula.</i></p><p><strong>Methods: </strong>Antibacterial effect of the <i>P. guajava</i> leaves n-hexane fraction against <i>S. mutans</i> and <i>V. parvula</i> was examined by the inhibition zone and, and MBC. The antibiofilm was examined on the expression of <i>gtfB</i> and <i>gtfC</i> in <i>S. mutans, V. parvula</i>, and their combination using qRT-PCR. The results were analyzed with Kruskal-Wallis test and Mann-Whitney <i>U</i>-test.</p><p><strong>Results: </strong><i>P. guajava</i> leaves inhibited the growth of <i>S. mutans</i> and <i>V. parvula</i> at the lowest concentration (3.125%), with the inhibition zones are larger than chlorhexidine (CHX). The effect on the Gtfs activity shown the gene expression of <i>gtfB</i> remained unchanged in both single <i>S. mutans</i> and combined species, while it was decreased in the single <i>V. parvula</i> at a concentration of 0.78%, but itdoes not exhibit a significant difference between single and double species. Conversely, <i>gtfC</i> gene expression in the dual-species was reduced 90.43% by the n-hexane fraction at a concentration of 0.78%.</p><p><strong>Conclusion: </strong>The <i>P. guajava</i> leaves n-hexane fraction exhibited antibacterial activity against <i>S. mutans</i> and <i>V. parvula</i>. It may exhibit antibiofilm formation, as it could reduce the expression of the <i>gtfC</i> in the double species bacteria.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"639-650"},"PeriodicalIF":0.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12428628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoglycemic and Hypolipidemic Effects of <i>Leonotis mollisima</i> Aqueous Leaf Extract in Type 2 Diabetic Rats.","authors":"Namanya Stephen, Saidi Odoma, Tijjani Shinkafi Salihu, Aruwa Ojodale Joshua, Neeza Timothy","doi":"10.2147/JEP.S532507","DOIUrl":"10.2147/JEP.S532507","url":null,"abstract":"<p><strong>Purpose: </strong>Type 2 diabetes is a global health challenge, prevalent in Uganda in about 3.6% of cases. Despite the availability of conventional treatments, there is a growing interest in natural remedies due to their potential efficacy and fewer side effects. This study evaluated <i>Leonotis mollissima</i> aqueous leaf extract for hypoglycemic and hypolipidemic effects in type 2 diabetic rats, given its traditional use and limited scientific validation.</p><p><strong>Patients and methods: </strong>Diabetes was induced in Wistar rats using a high-fat diet (60% fat; 40% carbohydrate, 15% protein, 0.5% cholesterol) and streptozotocin (35 mg/kg). Rats received <i>Leonotis mollissima</i> extract (250, 500, 1000 mg/kg) or glimepiride (5 mg/kg; sulfonylurea insulin secretagogue) for 28 days. Fasting blood glucose, oral glucose tolerance, glycated hemoglobin, lipid profiles, and pancreatic histology were assessed.</p><p><strong>Results: </strong><i>Leonotis mollissima</i> (1000 mg/kg) significantly reduced fasting blood glucose levels (<i>p</i> = 0.0172 vs negative control group), improved glucose tolerance (<i>p</i> < 0.0001), and lowered glycated haemoglobin levels in a dose-dependent manner. <i>Leonotis mollissima</i> (1000 mg/kg) also improved lipid profiles by reducing total cholesterol (<i>p</i> = 0.0016 vs negative control), and low-density lipoprotein-cholesterol levels (<i>p</i> = 0.0197 vs negative control). Histological examination revealed that higher doses of the extract restored pancreatic histoarchitecture, with intact acini cells and islets of Langerhans.</p><p><strong>Conclusion: </strong><i>Leonotis mollissima</i> aqueous leaf extract exhibits significant hypoglycemic and hypolipidemic effects in type 2 diabetic Wistar rats, supporting its traditional use. The extract's ability to improve glycemic control, lipid profiles, and pancreatic histoarchitecture suggests its potential as a therapeutic agent for managing diabetes and its complications. Further research is recommended to isolate active compounds and evaluate their efficacy in clinical trials.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"625-637"},"PeriodicalIF":0.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Intestinal Permeability for Graft-versus-Host Disease Treatment: A Therapeutic Perspective with Defibrotide.","authors":"Erika Rimondi, Elisabetta Melloni, Paola Secchiero, Stefania Braidotti, Natalia Maximova, Annalisa Marcuzzi","doi":"10.2147/JEP.S534739","DOIUrl":"10.2147/JEP.S534739","url":null,"abstract":"<p><strong>Purpose: </strong>Acute graft-versus-host disease (aGVHD) is a significant cause of death in recipients of allogeneic hematopoietic stem cell transplantation. In this type of graft, the intestine is particularly affected, with the loss of intestinal barrier integrity playing a key role in its onset. In this scenario, the aim of the present research was to evaluate defibrotide, a heparin-like compound, marked for severe veno-occlusive disease, as an innovative therapeutic approach for restoring intestinal barrier integrity using an in vitro model and analyzing aGVHD patients' sera and clinical data.</p><p><strong>Patients and methods: </strong>Using an in vitro model of colon epithelium, we evaluated the modulation of tight junction proteins after defibrotide treatment, in basal condition or in presence of an inflammatory stimulus, by immunocytochemical and Western blotting analysis. Moreover, the study involved two patients with grade IV acute multisystem GVHD with great gastrointestinal compromission. Patients' sera were collected during the acute phase and remission of intestinal aGVHD and employed for the evaluation of a panel of 27 inflammatory cytokines using a Multiplex approach.</p><p><strong>Results: </strong>Defibrotide treatment significantly increased the protein expression of Zonulin-1 and Occludin (untreated vs treated with 200 μg/mL, p<0.01). In culture conditions mimicking inflammation, defibrotide countered the reduction of Occludin and Claudin-3 while preserving Zonulin-1 levels. Serum cytokine analysis of two patients receiving defibrotide for aGVHD showed significantly higher cytokine levels (IL-7, MIP-1β, IP-10, G-CSF, Eotaxin, IL-6) during the acute phase compared to remission after defibrotide treatment.</p><p><strong>Conclusion: </strong>These findings suggest a potential therapeutic role for defibrotide in managing intestinal aGVHD by improving epithelial barrier integrity and reducing inflammation-related damage.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"613-623"},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Neuroprotective Potentials of Flavonoid Metabolites in <i>Syzygium aromaticum</i>: A Review with in-silico Insight to Therapeutic Potential.","authors":"Ekom Monday Etukudo, Ibe Michael Usman, Augustine Oviosun, Vivian Onyinye Ojiakor, Wusa Makena, Elna Owembabazi, Patrick Maduabuchi Aja, Bives Mutume Nzanzu Vivalya, Victor Bassey Archibong, Emeka Anyanwu","doi":"10.2147/JEP.S536765","DOIUrl":"10.2147/JEP.S536765","url":null,"abstract":"<p><p>The worldwide occurrence of neurodegenerative diseases in Alzheimer's and Parkinson's patients is increasing owing to multiple disease mechanisms, including oxidative stress, neuroinflammation, mitochondrial dysfunction, and excitotoxicity. <i>Syzygium aromaticum</i> (clove) flavonoid metabolites show strong neuroprotective potential because they act as antioxidants, reduce inflammation and lipid peroxidation, and prevent apoptosis. The key <i>S. aromaticum</i> flavonoid metabolites, quercetin, kaempferol, kumatakenin, myricetin, ombuin 3-O-β-d-glucopyranoside, and tamarixetin 3-O-β-d-glucopyranoside, bind to various brain receptors implicated in disease propagation pathways and induce changes that support neuronal survival and decrease cognitive impairment. In vitro, in vivo, and molecular docking studies were reviewed. The SwissADME and ADMETlab 3.0 web servers demonstrated that these metabolites have favorable drug-like properties and absorption characteristics that follow Lipinski's Rule of Five, GSK, and Pfizer rules. The metabolites showed good gastrointestinal absorption and desirable physicochemical properties, suggesting safe oral use. The toxicological profile prediction generated from the pkCSM and ADMETlab 3.0 web servers indicated minimal liver, kidney, and brain damage risks; however, ombuin 3-O-β-d-glucopyranoside exhibited weak cardiac toxicity through hERG II blocking, whereas pachypodol requires additional research on long-term toxicity effects. The data from the reviewed studies indicate that <i>S. aromaticum</i> flavonoid metabolites show great promise as therapeutic agents for neurodegenerative diseases caused by oxidative stress, inflammation, apoptosis, and lipid peroxidation. Evidence suggests that their safety and effectiveness are positive, despite minimal risks. Further studies should focus on nanocarrier utilization to improve their Blood-Brain Barrier permeability and enhance therapeutic potential. Experimenting on primates before translating them to human clinical trials will be crucial.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"587-611"},"PeriodicalIF":0.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of 8-Methyl Nonanoic Acid, a Degradation By-Product of Dihydrocapsaicin, on Energy and Glucose Homeostasis in Diet-Induced Obese Mice.","authors":"Ploychanok Keawsomnuk, Thittaya Den-Udom, Saowarose Thongin, Natsupa Wiriyakulsit, Chaiyot Mukthung, Chatchai Boonthip, Pattama Pittayakhajonwut, Pimonrat Ketsawatsomkron, Uthai Wichai, Kenjiro Muta","doi":"10.2147/JEP.S536185","DOIUrl":"10.2147/JEP.S536185","url":null,"abstract":"<p><strong>Purpose: </strong>Consumption of chili with capsaicinoids, such as dihydrocapsaicin (DHC), offers metabolic benefits to humans. However, their spiciness and rapid degradation prevent it from being used as a treatment for metabolic syndrome (MetS), including obesity, insulin resistance (IR), and hyperglycemia. During the degradation process of capsaicinoids, DHC is metabolized to non-pungent 8-methyl nonanoic acid (8-MNA), a methylated medium-chain fatty acid (MCFA). However, the metabolic functions of 8-MNA and its therapeutic potential for MetS have been unknown in animals. As other MCFAs improve metabolic status when added to obesogenic diets, we hypothesize that 8-MNA may improve energy and glucose metabolism in diet-induced obese (DIO) mice that exhibit MetS-like metabolic derangements.</p><p><strong>Methods: </strong>C57BL/6NJcl mice were fed a normal diet, or a high-fat diet (HFD) supplemented with triacylglycerols, which consisted of 8-MNAs or isocaloric soybean oil (SBO) for 18 weeks. Food intake, body weight, and blood chemicals were assessed, and glucose and insulin tolerance tests (GTT and ITT, respectively) were performed. Tissues and organs collected at the end of the experiments were used for biochemical analyses of metabolic determinants.</p><p><strong>Results: </strong>Compared with HFD + SBO-fed mice, 8-MNA feeding resulted in reduced caloric intake and body weight gain in DIO mice (p<0.05) in association with overall weight loss in several tissues and organs as well as transcriptional downregulation of orexigenic agouti-related protein in the hypothalamus. Despite no improvement in GTT and ITT, during the early experimental period, 8-MNA supplementation delayed the onset of HFD-induced IR.</p><p><strong>Conclusion: </strong>We conclude that 8-MNA slows the development of MetS in DIO mice. Furthermore, these findings suggest that 8-MNA derived from DHC accounts, in part, for the metabolic benefits of consuming chili and may represent a promising non-pungent nutraceutical for preventing MetS.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"555-570"},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Agonist of Zinc-Sensing G-Protein Coupled Receptor 39 Accelerates Skin Wound Healing and Protects Against UVB-Induced Keratinocyte Damage.","authors":"Pimngeon Chatkul, Mathusorn Wongsawat, Wilasinee Satianrapapong, Apiwan Arinno, Phachara Lamlertthon, Ungkarit Wachapatthana, Tadhi Sucharitakul, Wanapas Wachiradejkul, Dollapak Sakulpanich, Bongkod Petcharat, Wares Chancharoen, Thiansin Liamsuwan, Pawin Pongkorpsakol","doi":"10.2147/JEP.S531431","DOIUrl":"10.2147/JEP.S531431","url":null,"abstract":"<p><strong>Introduction: </strong>Keratinocytes establishes skin barrier integrity. Wound and ultraviolet B (UVB)-induced keratinocyte damage mainly contributes to the disruption of skin barrier properties. Recently, we found that pharmacological activation of zinc-sensing G-protein coupled receptor 39 (GPR39) promotes keratinocyte proliferation. Here, we further investigated the effects of TC-G 1008, a synthetic GPR39 agonist, on skin wound healing and UVB-induced keratinocyte damage.</p><p><strong>Methods: </strong>Scratch assay was used as a cell-based wound healing model. UVB exposure was performed to induce oxidative stress and cell death. BrdU incorporative assay was used to assess the rate of keratinocyte proliferation. MTT assay and Hoechst33342/ethidium homodimer-1 co-staining assay were used to evaluate cell viability and apoptosis, respectively. Western blot analysis was performed to investigate protein expression of AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK) phosphorylation. Sirtuin-1 (SIRT-1) activity assay and DCFDA assay were used to investigate SIRT-1 activity and to measure levels of intracellular reactive oxygen species (ROS).</p><p><strong>Results: </strong>We found that TC-G 1008 (up to 10 µM) dose-dependently enhanced the wound healing rate in a keratinocyte-like HaCaT cell line in a cell proliferation-independent manner. TC-G1008 reduced apoptosis and ROS production following UVB exposure. Notably, GPR39 agonism-induced wound healing and its protective effects against UVB-induced keratinocyte damage were abrogated by co-treatment with inhibitors of intracellular signaling, including protein kinase A (PKA), AMPK, sirtuin-1 (SIRT-1), and ERK. TC-G 1008 treatment induced AMPK phosphorylation via a PKA-dependent mechanism and promoted ERK phosphorylation by stimulating the AMPK/SIRT-1 pathway. In addition, TC-G 1008 treatment enzymatically activated SIRT-1 and this effect was suppressed by pretreatment with an AMPK inhibitor.</p><p><strong>Discussion and conclusion: </strong>Collectively, activation of GPR39 promoted wound healing and protected keratinocytes from UVB exposure via PKA/AMPK/SIRT-1/ERK-dependent mechanisms.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"571-585"},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicities Associated with Systemic Administration of Interleukin-6 in Wistar Albino Rats.","authors":"Patricia Nabisubi, Claire M Mugasa, Enock Matovu, Kenneth Ssekatawa, Vanessa Uwituze, Geofrey Ssentamu, Monica Namayanja, Charles D Kato","doi":"10.2147/JEP.S529995","DOIUrl":"10.2147/JEP.S529995","url":null,"abstract":"<p><strong>Background: </strong>Interleukin-6 is a pleiotropic cytokine being explored in therapy for cancer, trauma, and inflammatory infections, albeit with limited data about its safety. The main aim of this study was to investigate the toxicities associated with systemic administration of interleukin-6 in <i>Wistar albino rats.</i></p><p><strong>Methods: </strong>Four groups of rats, each containing six (6) animals received a daily intramuscular dose of 0.3mls of normal saline, 500ng/kg of recombinant interleukin-6, 1000ng/kg of Interleukin-6, and 2000ng/kg of Interleukin-6 for 21 days. On day 22 post-treatment, rats were euthanized, and blood and body organs were collected for analysis. Blood was used to determine liver and renal function, and hematology parameters, while liver and kidney tissue sections were used for histopathological analysis.</p><p><strong>Results: </strong>The results revealed that systemic administration of interleukin-6 for 21 days significantly decreased levels of serum creatinine (p<0.00) and serum urea (p<0.01). IL-6 administration had no demonstrable effects on liver function across treatment groups We observed a significant decrease in lymphocytes numbers (p<0.02) across treatment groups when compared to the negative control group. Platelets were significantly elevated in the 100ng/kg treatment groups as compared to the negative control and other treatment groups. Liver and kidney tissue sections for animals that received 500ng/kg of recombinant IL-10 were comparable to those of the negative control and at 1000 and 2000ng/kg, a dose-dependent increase in organ damage was evident.</p><p><strong>Conclusion: </strong>We demonstrate that systemic administration of recombinant IL-6 at concentrations ranging between 500-1000ng/kg is well tolerated, above this concentration, dose-dependent toxicities and adverse side effects becoming evident. It would be interesting to explore long-term toxicities associated with the systemic administration of IL-6.</p>","PeriodicalId":15846,"journal":{"name":"Journal of Experimental Pharmacology","volume":"17 ","pages":"545-554"},"PeriodicalIF":0.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}