Pharmacological Reports最新文献

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, fibrosis, and dysregulation of the immune system. The therapeutic options available for SSc have limited efficacy, and there is a clear need for new pharmacological alternatives. Thiazolidinediones (TZD) are molecules that have therapeutic potential for SSc due to their pharmacological properties. In this study, we aimed to evaluate the immunomodulatory activity of a new TZD analogue (LPSF/CR-35) in peripheral blood mononuclear cells (PBMC) from SSc patients.

Materials and methods: PBMC response to LPSF/CR-35 (100µM) was examined from SSc patients (n = 19) and healthy control subjects (n = 8) following PBMC stimulation with anti-CD3/CD28. Cytokines (IFN-γ, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17 A) and chemokines (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) levels were quantified in PBMC culture supernatants by cytometric bead array (CBA). In silico analyses were performed to evaluate the binding affinity of LPSF/CR-35 to peroxisome proliferator-activated receptor gamma (PPARγ).

Results: LPSF/CR-35 treatment significantly reduced the secretion of IL-17 A (p = 0.02), IL-10 (p = 0.001), IL-4 (p = 0.04), CCL2/MCP-1 (p = 0.003), and CXCL8/IL-8 (p = 0.03), while increasing TNF levels (p = 0.004) in PBMCs from SSc patients. Molecular docking predicted high binding affinity of both E (-9.987 kcal/mol) and Z (-9.992 kcal/mol) isomers of LPSF/CR-35 to PPARγ, supporting a possible PPARγ-dependent mechanism.

Conclusions: Our results indicate that LPSF/CR-35 modulates key cytokines and chemokines involved in SSc immunopathology, possibly through PPARγ activation. These findings support the potential of LPSF/CR-35 as an immunomodulatory agent in SSc. Further studies are needed to elucidate its effects on fibrosis and confirm its mechanism of action.

Anti-vascular endothelial growth factor (anti-VEGF), laser, and vitrectomy therapy are commonly used for the management of vision-threatening posterior eye disease (PED), but non-invasive alternatives have garnered increasing popularity as proactive preventative strategies for early retinopathy, such as targeted plant-based diets or herbal supplements. However, only some plants contain bioactive compounds that specifically target retinal degeneration and demonstrate potent pharmacological benefits that are cost-effective, safe, and accessible for at-risk individuals. This review pinpoints plant bioactive compounds, specifically polyphenols and carotenoids, that target retinopathy, with a focus on apoptotic, angiogenesis, inflammation, and oxidative pathways leading to visible, functional, and vascular macula improvements. Innovations accelerating therapeutic applications of these botanicals for ocular delivery were then explored. Finally, advancements in disease assessments and the computational methods for early retinopathy biomarker diagnosis and treatment, particularly designed to bio-prospect plant-based therapies, were also reviewed to guide future developments and address translational limitations.

Renal inflammation, oxidative stress, and fibrosis are hallmarks of kidney diseases, including diabetic nephropathy, acute kidney injury (AKI), and chronic kidney disease (CKD). The global prevalence of kidney diseases is increasing, posing a substantial public health challenge. The pathophysiology of kidney diseases is complex and multifactorial, involving a dynamic interplay of oxidative stress, inflammation, and fibrosis. Persistent inflammation in CKD is driven by elevated levels of proinflammatory mediators such as interleukin-6 (IL-6), interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α). Elevated C-reactive protein (CRP) levels are commonly associated with AKI and CKD. Moreover, oxidative stress, due to increased reactive oxygen species (ROS) and diminished antioxidant defenses, further damages renal tissues. Additionally, renal fibrosis mediated by transforming growth factor beta (TGF-β) signaling contributes to progressive structural deterioration, ultimately leading to end-stage kidney disease. Given the multifactorial nature of kidney disease, driven by the complex interplay of various mediators, there is a need for compounds with multitargeting potential. Formononetin (7-hydroxy-4'-methoxyisoflavone) is a naturally occurring isoflavone known for its broad pharmacological profile, including anti-inflammatory, antioxidant, renoprotective, cardioprotective, and antidiabetic activity. Various studies have demonstrated the significant potential of formononetin in mitigating kidney diseases through the modulation of multiple molecular mediators, including p38-mitogen-activated protein kinase (p38-MAPK), janus kinase (JNK), TGF-β, nuclear factor kappa B (NF-κB), CRP, sirtuin 1 (SIRT1), proinflammatory cytokines, nuclear factor erythroid 2-related factor 2 (Nrf-2), kelch-like ECH-associated protein 1 (Keap1), antioxidants, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Given formononetin's ability to modulate key molecular mediators involved in kidney disease, this review aims to explore the underlying mechanisms driving its renoprotective effects. By examining these complex and interconnected pathways, the review seeks to provide essential insights that will guide future research and help bridge existing knowledge gaps regarding formononetin's potential in renal disorders.

Background: Schizophrenia and related psychotic disorders represent a major cause of global disability, while patients show wide variability in their response to antipsychotic therapy. Genetic variants in one-carbon metabolism (folate and vitamin B12-dependent), catecholamine degradation, and methylation pathways may influence symptom severity and treatment outcomes. This study aimed to assess whether polymorphisms in these pathways are associated with baseline symptomatology and treatment response in a naturalistic setting.

Methods: In this prospective observational study, we examined common polymorphisms in methylenetetrahydrofolate reductase (MTHFR; rs1801133), methionine synthase (MTR; rs1805087), methionine synthase reductase (MTRR; rs1801394), catechol-O-methyltransferase (COMT; rs4680), and a variable number tandem repeat in arsenite methyltransferase (AS3MT) in relation to baseline symptoms and four-week treatment response in 163 patients with schizophrenia spectrum or other psychotic disorders. Symptoms were assessed with the Positive and Negative Syndrome Scale and the Calgary Depression Scale.

Results: The COMT rs4680 polymorphism was associated with higher baseline severity of negative symptoms in methionine homozygotes and with greater reduction in depressive symptoms. The MTR rs1805087 polymorphism was significantly associated with improvement in positive symptoms, particularly in patients with higher baseline vitamin B12 levels, whereas the AS3MT variable number tandem repeat showed a nominal association with positive symptom improvement in patients with lower B12 levels. No significant effects were observed for MTHFR rs1801133 or MTRR rs1801394.

Conclusions: Polymorphisms in one-carbon metabolism, particularly MTR rs1805087, may predict positive symptom response under adequate vitamin B12 conditions, while AS3MT variation may influence outcomes at lower B12 levels. COMT rs4680 is linked to both negative symptom severity and improvement in depressive symptoms. Although limited by modest sample size, lack of dietary and homocysteine data, and inclusion of non-drug-naïve patients, these findings support the potential of genetic and metabolic profiling for personalized antipsychotic treatment.

Clinical trial number: Not applicable.

Hepatic encephalopathy (HE) is a serious and potentially reversible neuropsychiatric syndrome resulting from severe liver insufficiency. HE is primarily considered a gliopathy in which astrocyte dysfunction is the main neuropathological hallmark, while recently microglia and neuronal alterations have been reported. It is believed that reversible factors trigger more than 80% of the cases. Several causative factors, including ammonia, inflammation, neuroinflammation, and oxidative stress, contribute to its pathogenesis, ultimately leading to abnormalities in neurotransmission and altered neuronal integrity. Current treatment strategies for managing HE include the primary use of rifaximin and lactulose, along with other pharmacological therapies that aim to reduce inflammation, neuroinflammation, and oxidative stress. However, liver transplantation remains the definitive curative treatment for end-stage liver diseases and associated encephalopathy. Recently, probiotics and fecal microbiota transplantation, as well as cell-based therapies, have shown promising results in both experimental studies and clinical trials. This review article highlights advances in understanding the complex pathophysiology of HE and assesses recent treatment strategies that aim to promote liver regeneration, target ammonia toxicity, and modulate immune responses.

Podocytopathies, driven by injury to glomerular podocytes, are a major cause of proteinuric kidney diseases like focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). The transient receptor potential canonical 6 (TRPC6) channel, expressed in podocytes, is critical for maintaining the glomerular filtration barrier. Dysregulation of TRPC6 activity-whether due to gain-of-function mutations or pathological activation-induces excessive calcium influx, leading to podocyte cytoskeletal disruption, oxidative stress, and apoptosis. While initially linked to hereditary FSGS, emerging evidence implicates TRPC6 dysfunction in diverse acquired podocytopathies, including DKD. This review explores the molecular mechanisms underlying TRPC6-mediated podocyte injury across these conditions, focusing on key calcium-dependent signaling pathways such as calcineurin/NFAT. It critically examines the role of TRPC6 as a therapeutic target, highlighting the rationale for its inhibition and the challenges involved in clinical translation. Understanding these mechanisms is crucial for developing strategies to prevent progression to end-stage renal disease.