Current Research in Pharmacology and Drug Discovery最新文献

Cancer continues to increase global morbidity and mortality rates. Despite substantial progress in the development of various chemically synthesized anti-cancer drugs, the poor prognosis of the disease still remains a big challenge. The most common drawback of conventional cancer therapies is the emergence of drug resistance eventually leading to the discontinuation of chemotherapy. Moreover, advanced target-specific therapies including immunotherapy and stem cell therapy are expensive enough and are unaffordable for most patients in poorer nations. Therefore, alternative and cheaper therapeutic strategies are needed to complement the current cancer treatment approaches. Phytochemicals are bioactive compounds produced naturally by plants and have great potential in human health and disease. These compounds possess antiproliferative, anti-oxidant, and immunomodulatory properties. Among the phytochemicals, flavonoids are very effective in treating a wide range of diseases from cardiovascular diseases and immunological disorders to cancer. They scavenge reactive oxygen species (ROS), inhibit cancer metastasis, modulate the immune system and induce apoptotic or autophagic cell death in cancers. This review will discuss the potential of various phytochemicals particularly flavonoids in attempts to target various cancers.

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.

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.

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The prevalence, incidence, and severity of a wide variety of diseases and ailments are significantly influenced by the significant disparities that occur between the sexes. The way that men and women react to pharmacological treatment also varies. Therefore, it is crucial to comprehend these reactions in order to conduct risk assessment correctly and to develop safe and efficient therapies. Even from that limited vantage point, the manner and timing of our drug usage might have unintended and unanticipated consequences. There are sex-specific differences in the incidence and mortality of certain malignancies. One of the most important discoveries in cancer epidemiology is the gender inequalities. Cancer incidence differences between the sexes are thought to be regulated at the genetic and molecular levels and by sex hormones like oestrogen. Differences based on sex and gender are among the least investigated factors impacting cancer susceptibility, progression, survival, and therapy response despite their established importance in clinical care. The molecular mechanisms underlying sex differences in particular are poorly known, hence the majority of precision medicine approaches employ mutational or other genetic data to assign therapy without taking into account how the patient's sex may affect therapeutic efficacy. In patients receiving chemotherapy, there are definite gender-dependent disparities in response rates and the likelihood of side effects. This review explores the influence of sex as a biological variable in drug effects or toxicity in oncology.

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.

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.