Pharmacological Research - Reports最新文献

Pseudomonas aeruginosa infections are quickly increasing in association with a variety of illnesses, necessitating the development of novel medications. This study employed an in silico technique to find PDF inhibitors against P. aeruginosa Peptide deformylase (PaPDF). PaPDF's structure is comparable to that of other PDFs; however, binding site studies found that PaPDF has a smaller pocket than Staphylococcus aureus, covering the S1 and S2 sub pockets, and maintains a conserved hydrophobic nature. The Zn metal binding site of modified PaPDFs was examined using molecular dynamics, and the results revealed that Cys92Ala differed from His134Ala and His138Ala, respectively. Complex-based pharmacophore investigation revealed three significant pharmacophoric characteristics within the pocket: two hydrophobic and one H-bond acceptor. This allows us to perform virtual screening using the ChemBride database to uncover a variety of potential hits with specific inhibitory characteristics. Several restrictions, including docking and molecular mechanics/general born-volume integral implicit solvent (MM/GBVI), were applied, and the top-ranked ligands were tested for inhibitory characteristics against key residues in the active site. Furthermore, the bioavailability and toxicity prediction identified seven potential leads and suggested future research into the design and synthesis of a unique class of PaPDF inhibitors.

Background

The PnTx2–6 toxin is isolated from the Phoneutria nigriventer spider venom. The synthetic peptide PnPP-19 is derived from this toxin and induces antinociception. When topically applied, it is cleaved by proteases generating a 15 amino acid residues peptide, PnPP-15. PnPP-15 showed an antinociceptive effect in neuropathic pain developed by streptozotocin-induced diabetic mice. The present work aimed to investigate if PnPP-15 is also effective against the inflammatory pain induced by PGE₂. We also evaluated its cytotoxicity in vitro and studied its possible action mechanism in the pain pathway.

Methods

The nociceptive threshold was assessed using the mechanical paw pressure test. Paw tissue was collected for protein extraction and western blot analyses. The FRET enzymatic assay measured neprilysin activity. The two-electrode voltage clamp technique measured evoked electrical currents in Xenopus laevis oocytes. Cytotoxicity was measured using multiple cell lines.

Results

PnPP-15 has peripheral antinociceptive activity via µ-opioid and CB₁ cannabinoid receptors and inhibits neprilysin. In addition, it induced direct activation of mu-opioid receptors expressed in Xenopus laevis oocytes. PnPP-15 was not cytotoxic against mammalian kidney, liver, heart, nerve, or lung cells.

Conclusion

This work demonstrated the antinociceptive effect of PnPP-15 in an inflammatory pain model, suggesting its use as a possible tool for developing new analgesic drugs.

Oxidative stress, inflammation, and apoptosis are major contributors to renal ischemia/reperfusion (I/R) injury. This study aimed to investigate the effects of pretreatment with the PDE4 inhibitor roflumilast (Rof) on renal I/R and its underlying mechanisms. Sprague-Dawley rats were subjected to 30 minutes of unilateral renal ischemia followed by 45 minutes of reperfusion. Rof (1.5 and 3 mg/kg) was administered for seven days prior to I/R induction. The findings showed that Rof significantly and dose-dependently attenuated kidney damage by reducing blood urea nitrogen and creatinine levels. Rof also exhibited antioxidant and anti-inflammatory effects, as evidenced by improved glutathione and malondialdehyde levels and decreased proinflammatory cytokines (IL-6 and TNF-α). Furthermore, Rof prevented the downregulation of HO-1 and Nrf2 expression. These results suggest that Rof therapy could protect the kidneys from I/R-induced injury through its antioxidant and anti-inflammatory properties, providing a potential therapeutic approach for the management of renal I/R damage.

Aim

Non-alcoholic fatty liver disease (NAFLD) is one of the progressive and chronic disease encompass a range of conditions such as non-alcoholic steatohepatitis (NASH) and cirrhosis. The present study is aimed to elucidate the possible actions of mirabegron, a β3-adrenoreceptor agonist used in the treatment of over active bladder, against NAFLD induced by fructose.

Method

30 male Wistar rats were randomized into 5 groups (A) Veh, (B) Fru, (C) Fru + Sita, (D) Fru + Mira and (E) Fru + Mira + Resv. Rats of respective groups were treated with mirabegron (10 mg/kg, p.o.), sitagliptin (10 mg/kg, p.o.) and resveratrol (20 mg/kg, p.o.) daily for 14 days. Fructose water was given to all rats to induce NAFLD till end of the study. Simultaneously, biochemical analysis such as glucose, SGOT, SGPT, HDL, LDL, TC and TG were performed to assess the disease progression. In the end of study hepatic biochemistry, SOD, MDA, GSH, inflammatory markers such as TNF-α, IL-1β and Hematoxylin and Eosin (H&E) analysis were performed.

Key findings

The NAFLD rats exhibited a significant weight gain, substantial increase in liver enzymes, glucose, circulating and hepatic total cholesterol, triglycerides, inflammatory cytokines and histological analysis showed hepatic steatosis and inflammation in the Fru group. In contrast, mirabegron alone and in combination with antioxidant provided a promising data on ameliorative effect on hepatic inflammation and steatosis caused by fructose. As a result, mirabegron is found to be a promising therapeutic treatment strategy for NAFLD and its associated complications.

Significance

Collectively, findings in this present study revealed that mirabegron reversed NAFLD by suppressing fructose mediated inflammation, oxidative stress and steatosis.

Liver damage resulting from the administration of various allopathic drugs and their associated toxicity has become a major health problem, leading to hepatic fibrosis, cirrhosis, and metabolic disorders. This epidemic condition of liver disease represents a major global cause of death and morbidity. Although orthotopic liver transplantation remains a vital treatment option for fibrotic liver conditions, its efficacy is limited by organ scarcity and the risk of immunological rejection. Consequently, alternative therapeutic approaches are urgently needed. Cell-based therapy utilizing mesenchymal stem cells (MSCs) has garnered considerable interest as a promising treatment modality. MSCs exhibit immunomodulatory properties and can differentiate into hepatocytes, thus facilitating the regeneration of damaged hepatocytes and increasing residual hepatocyte proliferation while inhibiting activation or apoptosis of liver stellate cells. However, despite their potential benefits, transplanted cells often exhibit low survival rates due to inadequate oxidative and inflammatory stress resistance. Plants harbor a diverse array of bioactive compounds known to possess hepatoprotective and antioxidant properties. Nanomaterials play a crucial role in regenerative medicine by providing targeted delivery of therapeutic agents and scaffolds for tissue engineering. In treating fibrotic liver, nanomaterials can help mitigate fibrosis progression and promote liver regeneration through controlled release of anti-fibrotic agents and growth factors. This review highlights the synergistic potential of stem cell-based therapy, natural antioxidants, differentiation factors, and nanotechnology in combating hepatic fibrosis and advancing liver regenerative medicine. These combined approaches offer promising avenues for effectively treating fibrotic liver conditions and promoting tissue regeneration.

Targeting glucose metabolism using the glycolysis inhibitor, 2-deoxyglucose (2-DG), is a promising therapeutic strategy for cancers characterized by elevated glucose requirements. Although clinical studies have revealed that effective doses cause side effects, research on combination therapies is ongoing. 2-DG inhibits not only glycolysis but also glycosylation of newly synthesized proteins and disturbs protein folding, resulting in endoplasmic reticulum (ER) stress-mediated apoptosis. Meanwhile, bongkrekic acid (BKA) is a toxic compound, which has been reported to inhibit ADP/ATP exchange in the mitochondria and suppress apoptosis by interfering with cytochrome c release from the mitochondria. Herein, 100 µM BKA inhibited 2-DG-induced apoptosis but showed enhanced cytotoxicity in the 4T1 murine breast cancer cell line, resulting in necrotic cell death. Surprisingly, BKA did not suppress 2-DG-induced cytochrome c release from the mitochondria, but effectively inhibited caspase activation. Furthermore, BKA did not suppress the upregulation of ER stress marker C/EBP homologous protein but suppressed autophagy flux. Our findings suggest an alternative treatment for cancer using BKA in combination with 2-DG.

Introduction

Chronic plaque psoriasis is an inflammatory skin disorder that affects 2–3% of the population. The severity of the disease is influenced by the number and location of skin lesions, concomitant conditions such psoriatic arthritis, and the impact on daily life. Several comorbidities, such as depression, cardiometabolic disorders, and psoriatic arthritis, are linked to plaque psoriasis. Hence, aim of current review is to highlight the comprehensive information on the pathophysiology, mechanism of action of recent approved drugs and future prospective. Further, clinical research and lengthy prospective cohort studies have been discussed.

Materials and methods

The data were collected from the various reported literatures PubChem, scopus and other search engines which are suggesting for the management of plaque psoriasis. These literature review were selected based on the current updated treatment of chronic plaque psoriasis.

Result

Various biologics have been promoted by the National Psoriasis Foundation guidelines as a first-line treatment option for moderate to severe plaque psoriasis due to their effectiveness in treating the condition and their acceptable safety profiles. The aryl hydrocarbon receptor (AhR) modulator tapinarof, the phosphodiesterase-4 (PDE4) inhibitor roflumilast and the tyrosine kinase 2 (TYK2) inhibitor deucravacitinib are the new drugs approved by US Food and Drug Administration (FDA) for promising treatment mild-severe plaque psoriasis.

Discussions

The conventional systemic therapy for treatment of plaque psoriasis was found to be unsatisfactory due to several significant adverse effects and contraindications. It is vital to continue developing efficacious, safe, and tolerant systemic medication approach capable of being employed as first-line systemic treatments for those with moderate-to-severe psoriasis. The recent approved drugs by USFDA for the management of psoriasis offer the potential for enhanced efficacy and better disease control.

Alternative animal models have become increasingly necessary due to legal regulations aimed at reducing the use of laboratory animals. Invertebrates are gaining in importance and have been intensively researched in recent years due to their pathophysiological similarities with rodents. Among these organisms, Tenebrio molitor, also known as the yellow mealworm beetle, stands out. In this study, we investigated whether T. molitor could be an alternative for studying the toxicity of chemotherapeutic agents. For this purpose, T. molitor larvae were inoculated with irinotecan (IRI) or 5-fluorouracil (5-FU). Both chemotherapeutic agents increased the morbidity and mortality of T. molitor and led to an increase in total circulating cells. Glucose levels were decreased after treatment with 5-FU and alanine aminotransferase levels were decreased after IRI administration. Administration of IRI or 5-FU resulted in changes in the appearance, consistency and amount of T. molitor frass. Finally, both IRI and 5-FU promoted severe histologic damage in the midgut and increased melanin deposition in peripheral tissues. Finally, we succeeded in developing an alternative experimental model for evaluating the toxicity of IRI and 5-FU. This model exhibits significant features of toxicity and intestinal damage, making it suitable for translational research purposes. T. molitor proves to be a versatile model organism with numerous advantages for experimental studies and offers a viable alternative for acquiring and expanding knowledge in the field of toxicology and pharmacology.