Current Research in Pharmacology and Drug Discovery最新文献

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.

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.

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.

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.

We study for the first time whether triphenylphosphonium (TPP) moiety can improve cellular delivery and redox properties of amphipathic cationic peptides based on YRFK/YrFK cell-penetrating and cytoprotective motif. TPP moiety was found to increase reducing activity of both stereoisomeric peptides in solution and on electrode surface in association with TPP-mediated intramolecular interactions. Among TPP-conjugated peptides, newly synthesized TPP3-YrFK featured both increased antioxidant efficacy and proteolytic resistance. TPP-conjugated peptides preferably mitigated endogenic ROS in mitochondria and cytoplasm of model glioblastoma cells with increased oxidative status. This anti-ROS effect was accompanied by mild reversible decrease of reduced glutathione level in the cells with relatively weak change in glutathione redox forms ratio. Such low interference with cell redox status is in accordance with non-cytotoxic nature of the compounds. Intracellular concentrations of label-free peptides were analyzed by LC–MS/MS, which showed substantial TPP-promoted penetration of YrFK motif across cell plasma membrane. However, according to ΔΨ_m analysis, TPP moiety did not profoundly enhance peptide interaction with mitochondrial inner membrane. Our study clarifies the role of TPP moiety in cellular delivery of amphipathic cationic oligopeptides. The results suggest TPP moiety as a multi-functional modifier for the oligopeptides which is capable of improving cellular pharmacokinetics and antioxidant activity as well as targeting increased ROS levels. The results encourage further investigation of TPP3-YrFK as a peptide antioxidant with multiple benefits.

Neurodegeneration and synaptic loss in Alzheimer's disease (AD) lead to impairment in memory functions. Neuroinflammation causes activation of microglia and astrocytes cells that locally and systemically produces inflammatory cytokines which can serve as early diagnostic markers or therapeutic targets in AD. Pro-inflammatory cytokines (Interleukins (IL-1β, IL-6 and IL-10) and tumor necrosis factor (TNF α)) levels were estimated in serum, cerebral tissue, hepatic tissue, and renal tissue in treatment groups of scopolamine-induced amnesia mice model using ELISA protocol. The results showed that cerebral tissue of AD mice exhibited elevated levels of IL1β, IL6, IL10 and TNFα which indicate contribution of pro-inflammatory cytokines in the progression of AD. A significant reduction in the concentration of IL1β, IL-10 and TNF-α were noticed in serum, cerebral tissue and hepatic tissue of animal group treated with marketed memantine tablet (Admenta), pure memantine drug (MEMp), memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds (MEM-PLGA) SANs, Polyethylene Glycol coated memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds [(PEG-MEM-PLGA) SANs] and Polyethylene Glycol coated memantine-poly [(lactic-co-glycolic acid)] self-assembled nanoscaffolds grafted with Bone Marrow Derived Stem Cell ((PEG-MEM-PLGA) SANs-BMSc), whereas a high level of IL-6 was observed in hepatic tissue, cerebral tissue and renal tissues of normal and AD induced mice which showed the emerging potential of IL-6 cytokines that can trigger either neurons survival after injury or causing neurodegeneration and cell apoptosis. The Neuroregenerative potential of stem cells helps in the proliferation of neuronal cell and thus improves cognition in AD animal model.

Carnosine is a naturally occurring endogenous dipeptide composed by the ligation of β-alanine and L-histidine performed particularly by tissues with an increased oxidative metabolism such as muscles and brain. In the last 50 years different studies have assessed the role and function of carnosine through numerous in vitro, in vivo, and clinical studies, demonstrating the multimodal mechanism of action of this dipeptide that includes anti-aggregant, antioxidant, and anti-inflammatory activities. In particular its activity has been investigated in experimental models of cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and neurodegenerative disorders, such as cerebral ischemia and Alzheimer's disease (AD). In the present review, we examined the protective role that carnosine could exert in the context of T2DM, CVD, and AD, which show common pathogenic mechanisms including oxidative stress, inflammation, and aggregation phenomena. Carnosine's pharmacodynamic profile is multimodal and combines the systemic anti-inflammatory and antioxidant activities with its anti-aggregant and neuroprotective efficacy in the central nervous system. This enlarged pharmacological activity opens a new path to explore the therapeutic potential of carnosine in all the three diseases, and in particular in patients with T2DM, who often show a history of CVD and also have an increased risk to develop mild cognitive impairment and AD.

α₁-Adrenergic Receptors (ARs) regulate the sympathetic nervous system by the binding of norepinephrine (NE) and epinephrine (Epi) through different subtypes (α_1A, α_1B, α_1D). α_1A-AR activation is hypothesized to be memory forming and cognitive enhancing but drug development has been stagnant due to unwanted side effects on blood pressure. We recently reported the pharmacological characterization of the first positive allosteric modulator (PAM) for the α_1A-AR with predictive pro-cognitive and memory properties. In this report, we now demonstrate the in vivo characteristics of Compound 3 (Cmpd-3) in two genetically-different Alzheimer’s Disease (AD) mouse models. Drug metabolism and pharmacokinetic studies indicate sufficient brain penetrance and rapid uptake into the brain with low to moderate clearance, and a favorable inhibition profile against the major cytochrome p450 enzymes. Oral administration of Cmpd-3 (3–9 mg/kg QD) can fully rescue long-term potentiation defects and AD biomarker profile (amyloid β-40, 42) within 3 months of dosing to levels that were non-significant from WT controls and which outperformed donepezil (1 mg/kg QD). There were also significant effects on paired pulse facilitation and cognitive behavior. Long-term and high-dose in vivo studies with Cmpd-3 revealed no effects on blood pressure. Our results suggest that Cmpd-3 can maintain lasting therapeutic levels and efficacy with disease modifying effects with a once per day dosing regimen in AD mouse models with no observed side effects.

The rationale for using thalidomide (THD) as a treatment for nausea and vomiting during pregnancy in the late 1950s appears to have been based on its sedative or hypnotic properties. In contrast to contemporaneous studies on the anti-emetic activity of phenothiazines, we were unable to identify publications reporting preclinical or clinical evaluation of THD as an anti-emetic. Our survey of the literature revealed a clinical study in 1965 showing THD reduced vomiting in cancer chemotherapy which was substantiated by similar studies from 2000, particularly showing efficacy in the delayed phase of chemotherapy-induced nausea and vomiting. To identify the mechanism(s) potentially involved in thalidomide's anti-emetic activity we reviewed its pharmacology in the light of nausea and vomiting mechanisms and their pharmacology with a particular emphasis on chemotherapy and pregnancy. The process identified the following potential mechanisms: reduced secretion of Growth Differentiation Factor 15, suppression of inflammation/prostaglandin production, downregulation of cytotoxic drug induced upregulation of iNOS, and modulation of BK (K_Ca1.1) channels and GABA_A/glutamate transmission at critical points in the emetic pathways (nucleus tractus solitarius, area postrema). We propose ways to investigate these hypothesized mechanisms and discuss the associated challenges (e.g., objective quantification of nausea) in addition to some of the more general aspects of developing novel drugs to treat nausea and vomiting.