Current Research in Pharmacology and Drug Discovery最新文献

Treatment for complications associated with the hemodynamic consequences of decompensated cirrhosis remains suboptimal. Terlipressin, the latest pharmacological management of hepatorenal syndrome–acute kidney injury (HRS-AKI), targets the vasopressin system but has serious side effects. OCE-205 is a novel peptide designed to target the vasopressin receptor system as a mixed V1a agonist/antagonist, resulting in effective partial agonism without V2 agonism. We examined the in vivo pharmacokinetic/pharmacodynamic properties of OCE-205 in healthy rats and cynomolgus monkeys. OCE-205 was administered by IV or SC bolus injection; arginine vasopressin (AVP) or terlipressin were comparators. After IV OCE-205 administration in rats, mean plasma concentration decreased in a mostly linear manner to 2 mg/mL after 120 min, and for SC administration, slowly decreased to ∼50 ng/mL after 300 min. Compared with pre-test values, arterial blood pressure values significantly increased after all OCE-205 doses tested. For monkeys, the concentration after IV OCE-205 administration was mostly linear to 5 ng/mL after 180 min, and for SC administration, ∼3 ng/mL after 480 min. Subcutaneous OCE-205 administration increased mean arterial pressure (MAP) versus baseline, with ΔMAP in OCE-205–treated animals marked and long-lasting while terlipressin induced an increase from baseline in MAP, with negligible ΔMAP, on average, by 150 min after administration in all groups. AVP, but not OCE-205, significantly increased blood lactate concentrations. OCE-205 was well tolerated in adult male rats and cynomolgus monkeys following single-dose bolus administration. The preclinical results of OCE-205, with its demonstrated V1a selective partial agonist activity and potentially tolerable safety profile, suggest its potential utility for treatment of the cardiovascular complications of cirrhosis.

Institutional protocol number

Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee (IACUC) on November 27, 2006 under protocol FRI 06-011, and by the Sinclair Research Center IACUC under protocol S11177.

Introduction

In spite of the undisputed relevance of sex as critical biologic variable of the immune landscape, still limited is our understanding of the basic mechanisms implicated in sex-biased immune response thereby conditioning the therapeutic outcome in cancer patients. This hindrance delays the actual attempts to decipher the heterogeneity of cancer and its immune surveillance, further digressing the achievement of predictive biomarkers in the current immunotherapy-driven scenario. Body: The present review concisely reports on genetic, chromosomal, hormonal, and immune features underlying sex-differences in the response to immune checkpoint inhibitors (ICIs). In addition to outline the need of robust data on ICI pharmaco-kinetics/dynamics, our survey might provide new insights on sex determinants of ICI efficacy and suggests uncovered pathways that warrant prospective investigations.

Conclusion

According to a sharable view, we propose to widely include sex among the co-variates when assessing the clinical response to ICI in cancer patients.

Advances in understanding miRNAs as endogenous posttranscriptional regulatory units have projected them as novel therapeutics for several untreatable diseases. miRNAs are endogenous non-coding small single-stranded RNA molecules (20–24 nucleotides) with specific gene regulatory functions like repression of mRNA translation by degrading mRNAs. Emerging evidence suggests the role of miRNAs in various stages of bone growth and development. Undoubtedly, due to their critical role in bone remodeling, miRNAs might be projected as a novel approach to treating bone-related diseases. However, the instability associated with miRNAs in their complex environment, such as degradation by nucleases, is a concern. Thus, recent attention is being paid to maintaining the miRNAs' safety and efficacy in the cells. Various efficient delivery systems and chemical modifications of miRNAs are being developed to make them a potential therapeutic option for bone diseases. Here, we have tried to recapitulate the recent advances in the role of miRNAs in bone disease, along with the potential delivery systems for their efficient delivery to the cells.

The purposes of current study were to investigate the effect of ginsenosides from BIOGF1K enriched in compound K (CK) and compound Y (CY) on the skin barrier function, the deposition in in vitro 3-D human tissue model (EpiDermFT™ Full Thickness 400), and to identify and quantify kinetic bioconversion of the ginsenosides in artificial skin by utilizing the Fourier transform infrared spectroscopy (FT-IR) and liquid chromatography mass spectrometry (LC-MS), respectively. Epidermal barrier integrity evaluated using transepithelial electrical resistance (TEER) was significantly higher in the BIOGF1K treatment than the CY or CK individual treatment throughout incubation (p < 0.05). Skin deposition (%) of CY and CK from BIOGF1K treatment was approximately 4 and 2 times higher than the CY and CK single component treatment, respectively. Total amount of CK found in human skin by deposition and bioconversion was approximately 1087.3, 528.82, and 867.76 μM after topical treatment of BIOGF1K, CK, and CY. Results from the current study reveal that topical treatment of BIOGF1K more effectively induced CK deposition as well as bioconversion of CY to CK than that of a single treatment of CY or CK, suggesting that BIOGF1K could be a useful cosmetic preparation for enhancing skin function.

Biofilm refers to microbes that associate with each other or to a surface via self-synthesized exopolysaccharides and other surface-related structures. The presence of biofilms consisting of pathogenic microbes in the food and clinical environment can pose a threat to human health as microbes in biofilms are highly robust and are difficult to remove. Understanding the process of biofilm formation is crucial for the development of novel strategies to control or harness biofilm. The complex network of proteins, small RNA, and diverse molecules regulate biofilm formation at different steps in biofilm development, including triggering the switch from planktonic to sessile cells, maturation of biofilms, and eventual dispersion of microbes from the biofilms. Small non-coding RNAs are relatively small RNAs that are not translated into proteins and play diverse roles in metabolism, physiology, pathogenesis, and biofilm formation. In this review, we primarily focused on non-coding regulatory RNA that regulates biofilm formation in clinically relevant pathogens or threatens human health. Even though many ncRNA have recently been identified in Archaea, much characterization work remains. The mechanisms and regulatory processes controlled by ncRNA in prokaryotes are covered in this review.

Objective

Heme oxygenase (HO) has been shown to have important antioxidant and anti-inflammatory properties, resulting in a vascular antitherogenic effect. This study was undertaken to evaluate the role of HO-2 in atherosclerosis.

Method and results

The expression levels of HO-2 were evaluated in M1 and M2 bone marrow macrophage induced by LPS and IL4. The expression of HO-2 was significantly higher in M2 macrophage than in M1 macrophage. Western diet (WD) caused a significant increase in HO-2 expression in ApoE^−/− mice. The adeno-associated viral (AAV) vectors expressing HO-2 was constructed, and the mice were received saline (ApoE^−/−), AAV (ApoE^−/−), AAV–HO–2 (ApoE^−/−) on WD at 12 weeks and their plasma lipids, inflammatory cytokines, atherosclerosis were evaluated for 16 weeks. The results showed AAV–HO–2 was robust, with a significant decrease in the en face aortas, lipids levels, inflammatory cytokines and M1 macrophage content in AAV–HO–2 ApoE^−/− compared to control AAV-ApoE^−/−.

Conclusion

HO-2 expression in macrophages plays an important role of the antiatherogenic effect, decreasing the inflammatory component of atherosclerotic lesions. These results suggest that HO-2 may be a novel therapeutic target for cardiovascular diseases.

The high levels of bile acids are a critical factor in hepatorenal syndrome. Organic solute transporter α/β (Ostα/β) participate in bile acids reabsorption in the kidney. Fucoidan has the great potential in protecting against liver and kidney injury. However, whether Ostα/β increase bile acids reabsorption in bile duct ligature (BDL)-induced hepatorenal syndrome and the blockade of fucoidan are still not clear. Male mice that received BDL were given to fucoidan (at 12.5, 25 and 50 ​mg/kg) through intraperitoneal injection once daily for three weeks. The serum, liver and kidney samples of these experimental mice were collected to carry out biochemical, pathological and Western blot analysis. In this study, fucoidan significantly lowered serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), decreased serum levels of uric acid, creatinine and uric nitrogen, restored the deregulation of the renal urate transporter 1 (URAT1), organic anion transporter 1 (OAT1), and organic cation/carnitine transporter 1/2 (OCTN1/2), consistence with alleviation BDL-induced liver and kidney dysfunction, inflammation and fibrosis in mice. Furthermore, fucoidan significantly hampered Ostα/β and reduced bile acids reabsorption in BDL-induced mice, protected against AML12 and HK-2 ​cells injury in vitro. These results demonstrate that fucoidan alleviates BDL-induced hepatorenal syndrome through inhibition Ostα/β to reduce bile acids reabsorption in mice. Therefore, suppression of Ostα/β by fucoidan may be a novel strategy for attenuating hepatorenal syndrome.

Activity-based protein profiling (ABPP) is a chemoproteomic technology that employs small chemical probes to directly interrogate protein function within complex proteomes. Since its initial application almost 25 years ago, ABPP has proven to be a powerful and versatile tool for addressing numerous challenges in drug discovery, including the development of highly selective small-molecule inhibitors, the discovery of new therapeutic targets, and the illumination of target proteins in tissues and organisms. This graphical review provides an overview of the rapid evolution of ABPP strategies, highlighting the versatility of the approach with selected examples of its successful application.

Chronic stress is a risk factor for depression and is characterized by elevated levels of brain monoamine oxidase A (MAOA). Mounting evidence has shown that MAOA is a biochemical link between stress and depression. Apigenin (API), a natural flavonoid, as demonstrated in vitro inhibitory effect on MAOA, is suggestive of antidepressant-like activity. However, the in vivo inhibitory effect of API on MAOA and how it affects depression still remain unclear. Here, we report the probable mechanisms of action of API in chronic unpredictable mild stress (CUMS)-induced depression in mice. Treatment with API reversed anhedonia, and reduced anxiety and immobility time in behavioral studies. API reduced brain corticosterone and malondialdehyde (MDA) levels but increased brain levels of glutathione and superoxide dismutase. Furthermore, interleukin-6 and tumor necrosis factor-α were attenuated by API. It also restored cell loss and inhibited the activity of MAOA in the hippocampal brain regions and prefrontal cortex. Comparative binding affinity of API for MAOA (-7.7 kcal/mol) through molecular docking studies was greater than that of reference compound, clorgyline (-6.8 kcal/mol). Favorable hydrophobic interactions important to API binding at MAOA binding cavity was revealed to include conventional hydrogen bond (Cys323 and Tyr444), π-Sulfur (Cys323), π-π Stacked (Tyr407), π-π T-shaped (Phe208), π-lone pair and π-alkyl (Ile335, Ile180) interactions. These results suggest that API is a potent, selective, reversible inhibitor of MAOA with capability of attenuating CUMS-induced depression via inhibiting MAOA enzyme activity and altering other pathomechanisms.