Journal of Experimental Pharmacology最新文献

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.

Background: Oral biofilm is an extracellular polymeric matrix produced by Streptococcus mutans as the early colonizer in the formation of an oral biofilm. Glucosyltransferase (Gtfs) enzyme is a virulence factor for S. mutans in biofilm that is resistant to antibacterial agents. Veillonella parvula influences S. mutans 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.

Objective: The study was determined the inhibitory activity of the Psidium guajava leaves n-hexane fraction on the production of Gtfs by a single and combination of S. mutans and V. parvula.

Methods: Antibacterial effect of the P. guajava leaves n-hexane fraction against S. mutans and V. parvula was examined by the inhibition zone and, and MBC. The antibiofilm was examined on the expression of gtfB and gtfC in S. mutans, V. parvula, and their combination using qRT-PCR. The results were analyzed with Kruskal-Wallis test and Mann-Whitney U-test.

Results: P. guajava leaves inhibited the growth of S. mutans and V. parvula 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 gtfB remained unchanged in both single S. mutans and combined species, while it was decreased in the single V. parvula at a concentration of 0.78%, but itdoes not exhibit a significant difference between single and double species. Conversely, gtfC gene expression in the dual-species was reduced 90.43% by the n-hexane fraction at a concentration of 0.78%.

Conclusion: The P. guajava leaves n-hexane fraction exhibited antibacterial activity against S. mutans and V. parvula. It may exhibit antibiofilm formation, as it could reduce the expression of the gtfC in the double species bacteria.

Purpose: 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 Leonotis mollissima aqueous leaf extract for hypoglycemic and hypolipidemic effects in type 2 diabetic rats, given its traditional use and limited scientific validation.

Patients and methods: 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 Leonotis mollissima 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.

Results: Leonotis mollissima (1000 mg/kg) significantly reduced fasting blood glucose levels (p = 0.0172 vs negative control group), improved glucose tolerance (p < 0.0001), and lowered glycated haemoglobin levels in a dose-dependent manner. Leonotis mollissima (1000 mg/kg) also improved lipid profiles by reducing total cholesterol (p = 0.0016 vs negative control), and low-density lipoprotein-cholesterol levels (p = 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.

Conclusion: Leonotis mollissima 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.

Purpose: 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.

Patients and methods: 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.

Results: 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.

Conclusion: These findings suggest a potential therapeutic role for defibrotide in managing intestinal aGVHD by improving epithelial barrier integrity and reducing inflammation-related damage.

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. Syzygium aromaticum (clove) flavonoid metabolites show strong neuroprotective potential because they act as antioxidants, reduce inflammation and lipid peroxidation, and prevent apoptosis. The key S. aromaticum 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 S. aromaticum 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.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Introduction: 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.

Methods: 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).

Results: 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.

Discussion and conclusion: Collectively, activation of GPR39 promoted wound healing and protected keratinocytes from UVB exposure via PKA/AMPK/SIRT-1/ERK-dependent mechanisms.

Background: 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 Wistar albino rats.

Methods: 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.

Results: 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.

Conclusion: 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.

Background: N-acetyl-p-aminophenol (APAP) overdose remains a leading cause of acute liver failure worldwide. The aril extracts derived from Gac (Momordica cochinchinensis) (MC) fruit contain diverse phytonutrients that exhibit a range of pharma-nutritional properties, including antioxidant and anti-hepatic damage properties. Despite the therapeutic potential, the molecular mechanisms underlying its hepatoprotective action, particularly in preventing drug-induced toxicity, remain unelucidated.

Purpose: This study investigated the hepatoprotective potential of MC in a mouse model of APAP-induced acute liver injury and characterized its bioactive compounds.

Methods: MC was prepared using aqueous extraction. Mice were pre-treated with either 500 or 1,000 mg/kg of MC for seven consecutive days prior to intraperitoneal administration of APAP 300 mg/kg to induce hepatotoxicity. Serum and liver samples were then collected to analyze biochemical changes, histopathological changes, oxidative stress markers, and/or mRNA expression. Standard chemical tests were used to identify bioactive compounds.

Results: APAP administration caused a marked rise in liver enzymes, extensive histological necrosis, suppression of hepatocyte proliferation, infiltration of neutrophils and macrophages, and significant oxidative damage (p < 0.05). Studies revealed the constitution of MC as phenolic compounds, flavonoids, proanthocyanidins, and ascorbic acid, significantly attenuated the hepatotoxicity (p < 0.05). Mechanistically, MC ameliorated hepatic mRNA expression of CYP2E1, JNK, Ddit3, Bax, Casp3, NF-κB, and MCP-1, while increasing Bcl-2, IL-10, VEGF, Nrf2, SOD2, and GCLC mRNA (p < 0.05). Furthermore, MC prevented hyperglycemia by influencing the expression of AdipoR1, GLUT-2, and PEPCK (p < 0.05).

Conclusion: MC exhibits hepatoprotective effects against APAP-induced liver injury through multifaceted modulation of toxic metabolism (CYP2E1), cell death and ER stress (JNK, Ddit3, Bax, Casp3, and Bcl-2), antioxidant response (Nrf2 pathway), inflammation (NF-κB pathway and IL-10), tissue repair (VEGF), and glucose metabolism (AdipoR1, GLUT-2, and PEPCK).

Background: Streptococcus pneumoniae is a leading cause of respiratory infections, including pneumonia, meningitis, and otitis media. The rise in antimicrobial resistance has complicated treatment strategies, highlighting the need for alternative therapies. Plant-based remedies are increasingly being explored for their antibacterial potential, particularly in traditional medicine.

Methods: This study evaluated the antibacterial activity of ethanolic extracts from Mangifera indica bark and Callistemon citrinus leaves, individually and in combination, against S. pneumoniae. The agar well diffusion method was employed to assess zones of inhibition. A combination effect was analyzed by calculating the increase in fold area of inhibition.

Results: Both individual extracts demonstrated antibacterial activity. However, the combination of the two extracts produced larger zones of inhibition than either extract alone. The calculated increase in fold area of inhibition was 0.659, suggesting a synergistic effect.

Conclusion: The combination of Mangifera indica and Callistemon citrinus extracts shows enhanced antibacterial efficacy against S. pneumoniae, supporting their traditional use in managing respiratory infections. Further research is needed to determine the mechanism of action, in vivo efficacy, and safety profile before clinical application.