Current Research in Pharmacology and Drug Discovery最新文献

Curcumin is a well-recognized antioxidant phytoactive isolated from the rhizomes of Curcuma longa. Numerous landmark investigations have proved the antioxidant and hepatoprotective potential of curcumin. The aim of present study was to target curcumin loaded nanocarriers to hepatocytes using asialoglycoprotein receptors targeting strategy. Mannose, a water-soluble carbohydrate, was hydrophobized by anchoring stearylamine with an objective to conjugate mannose on the surface of curcumin loaded nanostructured lipid carriers for targeting asialoglycoprotein receptors on hepatocytes. Mannose conjugated stearylamine was synthesized and characterized using various analytical techniques. The synthesized targeting ligand was incorporated curcumin loaded nanostructured lipid carriers and characterized by photon correlation spectroscopy. Zeta potential measurement was used to confirm the conjugation of the synthesized ligand to the surface of drug-loaded nanostructured lipid carriers. CCl₄ induced hepatotoxicity in male Wistar rats was used as an experimental animal model to evaluate the hepatoprotective potential of formulated drug encapsulated nanostructured lipid carriers. The hepatoprotective potential was assessed by measuring serum liver injury markers and oxidative stress parameters in the liver post–mitochondrial supernatant. Mannose conjugated nanostructured lipid carriers showed acceptable particle size which revealed its suitability for hepatocyte targeting. In addition to this, mannose conjugated nanocarriers revealed significantly better (p ​< ​0.05) reduction of serum liver injury markers and proinflammatory cytokines compared to the unconjugated one which confirmed hepatocytes targeting potential of the synthesized ligand. Asialoglycoprotein receptors targeting could be a landmark strategy for hepatocyte targeting. Thus, the synthesized mannose anchored stearylamine could be a promising novel targeting ligand having hepatocyte targeting potential.

Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), are remitting and relapsing disorders of the gastrointestinal tract, highlighted by the dysregulation of pro- and anti-inflammatory mediators, which lead to mucosal damage. These conditions cause a significant burden worldwide as primary and secondary treatment failure rates remain high even with our current therapeutic options. This emphasizes the need for continued advancement in treatment efficacy with improved safety profiles. Novel disease-targeting therapeutics have been developed, most recently being the Janus kinase inhibitors (JAKi). JAKi serve as a promising new class of non-immunogenic small molecule inhibitors that modulate inflammatory pathways by blocking the critical role that Janus kinase (JAK) proteins play in mediating the innate and adaptive immune responses. Tofacitinib has been shown to be therapeutically efficacious, to have a tolerable safety profile, and to be available for adult patients with moderate-to-severe UC. This review was designed to serve as an overview and as practical guidance for medical practitioners. Author recommendations and appraisals of the quality of evidence throughout this article are based solely on personal opinion and are not the outcome of a formal methodology followed by a consensus group.

Since its inception in late December 2020 in China, novel coronavirus has affected the global socio-economic aspect. Currently, the world is seeking safe and effective treatment measures against COVID-19 to eradicate it. Many established drug molecules are tested against SARS-CoV-2 as a part of drug repurposing where some are proved effective for symptomatic relief while some are ineffective. Drug repurposing is a practical strategy for rapidly developing antiviral agents. Many drugs are presently being repurposed utilizing basic understanding of disease pathogenesis and drug pharmacodynamics, as well as computational methods. In the present situation, drug repurposing could be viewed as a new treatment option for COVID-19. Several new drug molecules and biologics are engineered against SARS-CoV-2 and are under different stages of clinical development. A few biologics drug products are approved by USFDA for emergency use in the covid management. Due to continuous mutation, many of the approved vaccines are not much efficacious to render the individual immune against opportunistic infection of SARS-CoV-2 mutants. Hence, there is a strong need for the cogent therapeutic agent for covid management. In this review, a consolidated summary of the therapeutic developments against SARS-CoV-2 are depicted along with an overview of effective management of post COVID-19 complications.

Organ damage and pathological disease states lead to the rapid release of microRNAs (miRNAs), a class of endogenous small non-coding RNAs, into the blood circulation. Because secreted miRNAs can be detected in biologic fluids such as plasma, they are currently being explored as promising non-invasive biomarkers of infectious and non-infectious diseases. Malaria remains a major global health challenge but still the potential of miRNAs has not been explored extensively in the context of malaria compared to other diseases. Here, we highlight important miRNAs found during different phases of the malaria life cycle in the anopheline vector and the human host. We have also put forward our opinion on how malaria parasite-stage-specific miRNAs can be incorporated into new diagnostic and prognostic tools to detect carrier mosquitoes and infected patients. In addition, we have emphasised the potential of miRNAs to be used as new therapeutics to treat severe malaria patients, an unresearched area of malaria control.

Background

Many of the atypical antipsychotics induce metabolic side effects, limiting their use in clinical practice. Alpha-lipoic acid (ALA) was proposed as a new approach in schizophrenia to improve metabolic effects of atypical antipsychotics. The aim of the study is to evaluate the effect of ALA on metabolic and clinical parameters among schizophrenic subjects.

Methods

15 schizophrenic subjects, in stable atypical antipsychotic monotherapy were included in the study. ALA was administrated at the oral daily dose of 600 ​mg/d in addition to antipsychotic therapy. Metabolic, clinical, and psychopathological parameters were measured at typical antipsychotics. e initial screening, and after 12 weeks.

Results

ALA produced a statistically significant reduction in QTc (p ​= ​0.012), blood glucose (p ​= 0.005), AST (p ​= ​0.021), γGT (p ​= ​0.035), CPK (p ​= ​0.005) and prolactinaemia (p ​= ​0.026). In contrast, there was a significant increase in HbA1c (p ​= ​0.026). No effects on body weight and blood lipid levels (triglycerides, total cholesterol, HDL, LDL) emerged.

Conclusions

ALA treatment appeared to be effective for reducing diabetes risk, liver functionality parameters, hyperprolactinaemia and QTC interval. ALA appears to be safe as adjunctive components in schizophrenia.

Background

Patients with ulcerative proctitis represent a sub-group of ulcerative colitis patients with specific characteristics. Disease-related symptoms, endoscopic findings and patient's personality perspectives create a difficult-to-assess condition in certain cases.

Objectives

To summarize available evidence on the management of refractory ulcerative proctitis and provide insights in treatment options.

Results

/Conclusion: Topical therapy plays a central role due to the location of the disease. However, well-established treatment options may become exhausted in a considerable proportion of ulcerative proctitis patients, indicating the need to advance to more potent therapies in order to induce and maintain clinical response and remission in these refractory cases. Systemic corticosteroids, thiopurines, calcineurin inhibitors, biologic agents and small molecules have all been tested with variable success rates. Investigational interventions as well as surgical procedures are kept as the ultimate resort in multi-treatment resistant cases. Identifying early prognostic factors that herald a disabling disease progression will help in optimizing treatment and avoiding surgery.

Carbon monoxide (CO) is known as a toxic gas inducing “CO poisoning”, which acutely affects the central nervous system (CNS) and which persistently affects brain functions depending on the exposure time and CO concentration. By contrast, in pathological rodent models, intravenous infusion of CO-bound hemoglobin vesicles (CO-HbV) has shown various beneficial effects such as anti-oxidative and anti-inflammatory reactions. This study assessed effects of CO-HbV infusion on CNS using a functional observation battery, sensory reflexes, grip strength, and landing foot splay measurements. The test fluids were CO-HbV and O₂-bound HbV (O₂-HbV) suspended in saline ([Hb] ​= ​10 ​g/dL), and saline alone for comparison. The rats received either 16 or 32 ​mL/kg of fluid intravenously at 1.5 ​mL/min/kg. Observations were made before infusion, and at 5 ​min, 4, 8, 24, 48 and 72 ​h after infusion. Massive doses of 16 and 32 ​mL/kg respectively corresponded to about 29 and 57% of the whole circulating blood volume (56 ​mL/kg). No toxicological effect was observed in any measurement item for any group in comparison to the control saline infusion group. Histopathological examination of hippocampal tissue at 14 days after infusion showed the number of necrotic cells to be minimal. Results obtained from rats in this experiment suggest that the massive intravenous infusion of CO-HbV yields beneficial anti-oxidative and anti-inflammatory effects without showing CO-poisoning-related symptoms of CNS damage.

Plant-derived flavonoids have been the focus of research for many years mainly in the last decade owing to their therapeutic properties. So far, about 4000 flavonoids have been identified from plants and diosmin (a flavone glycoside) is one of them. Online databases, previous studies, and reviews have been used to gather information on anti-oxidant, immunomodulatory, anti-cancer, anti-parasitic, and anti-microbialproperties of diosmin. Effects of diosmin in combination with other flavonoids have been reviewed thoroughly and its administrative routes are also summarized. Additionally, we studied the effect of diosmin on critical protein networks. It exhibits therapeutic effects in diabetes and its associated complications such as neuropathy and dyslipidemia. Combination of diosmin with hesperidin is found to be very effective in the treatment of chronic venous insufficiency and haemorrhoids. Diosmin is an exquisite therapeutic agent alone as well as in combination with other flavonoids.

MicroRNAs (miRNAs) are discovered in science about 23 years ago. These are short, a series of non-coding, single-stranded and evolutionary conserved RNA molecules found in eukaryotic cells. It involved post-transcriptional fine-tune protein expression and repressing the target of mRNA in different biological processes. These miRNAs binds with the 3′-UTR region of specific mRNAs to phosphorylate the mRNA degradation and inhibit the translation process in various tissues. Therefore, aberrant expression in miRNAs induces numerous cardiovascular diseases and developmental defects. Subsequently, the miRNAs and Wnt singling pathway are regulating a cellular process in cardiac development and regeneration, maintain the homeostasis and associated heart diseases. In Wnt signaling pathway majority of the signaling components are expressed and regulated by miRNAs, whereas the inhibition or dysfunction of the Wnt signaling pathway induces cardiovascular diseases. Moreover, inadequate studies about the important role of miRNAs in heart development and diseases through Wnt signaling pathway has been exist still now. For this reason in present review we summarize and update the involvement of miRNAs and the role of Wnt signaling in cardiovascular diseases. We have discussed the mechanism of miRNA functions which regulates the Wnt components in cellular signaling pathway. The fundamental understanding of Wnt signaling regulation and mechanisms of miRNAs is quite essential for study of heart development and related diseases. This approach definitely enlighten the future research to provide a new strategy for formulation of novel therapeutic approaches against cardiovascular diseases.

Central nervous system (CNS)-related diseases are difficult to treat as most therapeutic agents they cannot reach the brain tissue, mainly due to the blood-brain barrier (BBB), arguably the tightest barrier between the human body and cerebral parenchyma, which routinely excludes most xenobiotic therapeutics compounds. The BBB is a multicellular complex that structurally forms the neurovascular unit (NVU) and is organized by neuro-endothelial and glial cells. BBB breakdown and dysfunction from the cerebrovascular cells lead to leakages of systemic components from the blood into the CNS, contributing to neurological deficits. Understanding the molecular mechanisms that regulate BBB permeability and disruption is essential for establishing future therapeutic strategies to restore permeability and improve cerebrovascular health. MicroRNAs (miRNAs), a type of small non-coding RNAs, are emerging as an important regulator of BBB integrity by modulating gene expression by targeting mRNA transcripts. miRNAs is implicated in the development and progression of various illnesses. Conversely, nanoparticle carriers offer unprecedented opportunities for cell-specific controlled delivery of miRNAs for therapeutic purposes. In this sense, we present in this graphical review critical evidence in the regulation of cell junction expression mediated by miRNAs induced by hypoxia and for the use of nanoparticles for the delivery of miRNA-based therapeutics in the treatment of BBB permeability.