Current Research in Pharmacology and Drug Discovery最新文献

The part of sexuality in pharmacology research was not acknowledged, and it was not thought-out to be a determinant that could impact strength and disease. For decades research has mainly contained male, women and animals, leading to a lack of news about syndromes in females. Still, it is critical to guarantee equal likeness so that determine the security, influence, and resistance of healing agents for all individuals. The underrepresentation of female models in preclinical studies over various decades has surpassed to disparities in the understanding, disease, and treatment of ailments 'tween genders. The closeness of sexuality bias has happened recognized as a contributing determinant to the restricted interpretation and replicability of preclinical research. Many demands operation have stressed the significance of including sexuality as a organic changeable, and this view is acquire growing support. Regardless of important progress in incorporating more female models into preclinical studies, differences prevail contemporary. The current review focuses on the part of sexuality and common in biomedical research and, therefore, their potential function in pharmacology and analyze the potential risks guide.

GERD is a very familiar diagnosis among health care providers due to its massive spread, and its symptoms can affect the quality of life for a respectable slice of its patients. Therefore, what can only be described as a logical consequence, a pursuit of a treatment that can both relieve symptoms and have minimal side effects is still ongoing to cover the large demographic affected by GERD. In the following review, analysis will be made of GERD, including possible regulatory activity, of certain drugs to the already discussed pathways involved in GERD patients.

Nucleolar stress induced by stressors like hypoxia, UV irradiation, and heat shock downregulates ribosomal RNA transcription, thereby impairing protein synthesis capacity and potentially contributing to cell senescence and various human diseases such as neurodegenerative disorders and cancer. Live-cell imaging of the nucleolus may be a feasible strategy for investigating nucleolar stress, but currently available nucleolar stains are limited for this application. In this study using mouse hippocampal HT22 cells, we demonstrate that thioflavin T (ThT), a benzothiazole dye that binds RNA with high affinity, is useful for nucleolar imaging in cells where RNAs predominate over protein aggregates. Nucleoli were stained with high intensity simply by adding ThT to the cell culture medium, making it suitable for use even in damaged cells. Further, ThT staining overlapped with specific nucleolar stains in both live and fixed cells, but did not overlap with markers for mitochondria, lysosomes, endoplasmic reticulum, and double-stranded DNA. Ferroptosis, an iron-dependent nonapoptotic cell death pathway characterized by lipid peroxide accumulation, reduced the number of ThT-positive puncta while endoplasmic reticulum stress did not. These findings suggest that ferroptosis is associated with oxidative damage to nucleolar RNA molecules and ensuing loss of nucleolar function.

The significance of mesenchymal stem cells (MSCs) for tissue repair and regeneration is widely recognized. The pleiotropic nature of MSCs is demonstrated by their potential for proliferation and differentiation, and paracrine secretions, thereby making them ideal candidates for cell replacement therapy. Tissue resident MSCs are engaged in homeostasis under normal wear and tear. However, stem cell therapy may be applicable if damage cannot be repaired by normal homeostatic mechanisms. The safety of MSCs has been clearly established in clinical trials but their efficacy remains questionable. The efficacy of MSCs depends on several factors, such as their viability, functional status in terms of secretome secretions, and the in-vivo scenario after transplantation. The performance of MSCs is regulated by their micro-environmental conditions and cues. The so-called MSC niche comprises physical, chemical, and biological components, which play key roles in determining the fate of MSCs. MSCs scaled up for transplantation purposes comprise a disorganized mass of cells, which needs to be directed to perform the required function. Thus, MSCs need to be directed toward an expected target activity in human patients. This review focuses on the various methods that can be used to guide stem cells for cutaneous repair.

Soil-Transmitted Helminthiasis (STH) is one of the most widespread Neglected Tropical Diseases (NTDs), and almost 1.5 billion of the global population is affected, mostly in the indigent, countryside sectors of tropics/subtropics. STH, commonly caused by various nematodes, adversely affects the hosts’ growth, cognatic development, and immunity. Albendazole is most commonly used against STH (Soil-Transmitted Helminths) but resistance has already been reported in different countries. To date, no effective vaccine is present against STH. miRNAs are a unique class of small non-coding RNA, regulating various biological activities indulging host immune responses in host-pathogen interaction of STH. Dysregulation of miRNAs are being considered as one of the most important aspect of host-parasite interactions. Thus, it is the prime importance to identify and characterize parasite-specific as well as host-derived miRNAs to understand the STH infection at the molecular level. Systematic bibliometric analysis reveals a huge knowledge gap in understanding the disease by using both host and parasitic miRNAs as a potential biomarker. In this study, we addressed the present status of the STH prevalence, and therapy under the light of miRNAs. This would further help in designing new inhibitors and therapeutic strategies to control STH.

α₁-Adrenergic Receptors (ARs) are G-protein Coupled Receptors (GPCRs) that regulate the sympathetic nervous system via the binding and activation of norepinephrine (NE) and epinephrine (Epi). α₁-ARs control various aspects of neurotransmission, cognition, cardiovascular functions as well as other organ systems. However, therapeutic drug development for these receptors, particularly agonists, has been stagnant due to unwanted effects on blood pressure regulation. We report the synthesis and characterization of the first positive allosteric modulator (PAM) for the α₁-AR based upon the derivation of the α_1A-AR selective imidazoline agonist, cirazoline. Compound 3 (Cmpd-3) binds the α_1A-AR with high and low affinity sites (0.13pM; 54 ​nM) typical of GPCR agonists, and reverts to a single low affinity site of 100 ​nM upon the addition of GTP. Comparison of Cmpd-3 versus other orthosteric α_1A-AR-selective imidazoline ligands reveal unique properties that are consistent with a type I PAM. Cmpd-3 is both conformationally and ligand-selective for the α_1A-AR subtype. In competition binding studies, Cmpd-3 potentiates NE-binding at the α_1A-AR only on the high affinity state of NE with no effect on the Epi-bound α_1A-AR. Moreover, Cmpd-3 demonstrates signaling-bias and potentiates the NE-mediated cAMP response of the α_1A-AR at nM concentrations with no effects on the NE-mediated inositol phosphate response. There are no effects of Cmpd-3 on the signaling at the α_1B- or α_1D-AR subtypes. Cmpd-3 displays characteristics of a pure PAM with no intrinsic agonist properties. Specific derivation of Cmpd-3 at the R1 ortho-position recapitulated PAM characteristics. Our results characterize the first PAM for the α₁-AR and holds promise for a first-in-class therapeutic to treat various diseases without the side effect of increasing blood pressure intrinsic to classical orthosteric agonists.

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Non-steroidal anti-inflammatory drugs (NSAIDs) injure the proximal and distal gut by different mechanisms. While many drugs reduce gastrointestinal injury, no drug directly stimulates mucosal wound healing. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, induces epithelial sheet migration.

We synthesized and evaluated a water-soluble FAK-activating small molecule, M64HCl, with drug-like properties. Monolayer wound closure and Western blots measured migration and FAK phosphorylation in Caco-2 ​cells, in vitro kinase assays established FAK activation, and pharmacologic tests assessed drug-like properties. 30 ​mg/kg/day M64HCl was administered in two murine small intestine injury models for 4 days.

M64HCl (0.1–1000 ​nM) dose-dependently increased Caco-2 FAK-Tyr 397 phosphorylation, without activating Pyk2 and accelerated Caco-2 monolayer wound closure. M64HCl dose-responsively activates the FAK kinase domain vs. the non-salt M64, increasing the V_max of ATP-binding. Pharmacologic tests suggested M64HCl has drug-like properties and is enterally absorbed. M64HCl 25 ​mg/kg/day continuous infusion promoted healing of ischemic jejunal ulcers and indomethacin-induced small intestinal injury in C57Bl/6 mice. M64HCl-treated mice exhibited smaller ulcers 4 days after ischemic ulcer induction or indomethacin injury. Renal histology and plasma creatinine were normal. Mild hepatic inflammatory changes and ALT elevation were similar among M64HCl-treated mice and controls. M64HCl was concentrated in kidney and gastrointestinal mucosa and functional nephrectomy studies suggested predominantly urinary excretion. Little toxicity was observed in vitro or in single-dose mouse toxicity studies until >1000x higher than effective concentrations. M64HCl, a water-soluble FAK activator, promotes epithelial restitution and intestinal mucosal healing and may be useful to treat gut mucosal injury.

Acute promyelocytic leukemia (APL)/blood cancer is M3 type of acute myeloid leukemia (AML) formed inside bone marrow through chromosomal translocation mutation usually between chromosome 15 & 17. It accounts around 10% cases of AML worldwide. Trisenox (TX/ATO) is used in chemotherapy for treatment of all age group of APL patients with highest efficacy and survival rate for longer period. High concentration of TX inhibits growth of APL cells by diverse mechanism however, it cures only PML-RARα fusion gene/oncogene containing APL patients. TX resistant APL patients (different oncogenic make up) have been reported from worldwide. This review summarizes updated mechanism of TX action via PML nuclear bodies formation, proteasomal degradation, autophagy, p53 activation, telomerase activity, heteromerization of pRb & E2F, and regulation of signaling mechanism in APL cells. We have also provided important information of combination therapy of TX with other molecules mechanism of action in acute leukemia cells. It provides updated information of TX action for researcher which may help finding new target for further research in APL pathophysiology or new TX resistant APL patients drug designing.