Current Pharmaceutical Design - Volume 28, Issue 43, 2022

Antimicrobial resistance is an aggravating global issue therefore it has been under extensive research in an attempt to reduce the number of antibiotics that are constantly reported as obsolete jeopardizing the lives of millions worldwide. Thiazoles possess a reputation as one of the most diverse biologically active nuclei, and phenylthiazoles are no less exceptional with an assorted array of biological activities such as anthelmintic, insecticidal, antimicrobial, antibacterial, and antifungal activity. Recently phenyl thiazoles came under the spotlight as a scaffold having strong potential as an anti-MRSA lead compound. It is a prominent pharmacophore in designing and synthesizing new compounds with antibacterial activity against multidrug-resistant bacteria such as MRSA, which is categorized as a serious threat pathogen, that exhibited concomitant resistance to most of the first-line antibiotics. MRSA has been associated with soft tissue and skin infections resulting in high death rates, rapid dissemination, and loss of millions of dollars of additional health care costs. In this brief review, we have focused on the advances of phenylthiazole derivatives as potential anti-MRSA from 2014 to 2021. The review encompasses the effect on biological activity due to combining this molecule with various synthetic pharmacophores. The physicochemical aspects were correlated with the pharmacokinetic properties of the reviewed compounds to reach a structure-activity relationship profile. Lead optimization of phenyl thiazole derivatives has additionally been outlined where the lipophilicity of the compounds was balanced with the metabolic stability and oral solubility to aid the researchers in medicinal chemistry, design, and synthesizing effective anti- MRSA phenylthiazoles in the future.

Colorectal cancer is the second leading cause of cancer deaths worldwide and has engrossed researchers' attention toward its detection and prevention at early stages. Primarily associated with genetic and environmental risk factors, the disease has also shown its emergence due to dysbiosis in microbiota. The microbiota not only plays a role in modulating the metabolisms of metastatic tissue but also has a keen role in cancer therapy. The immune cells are responsible for secreting various chemokines and cytokines, and activating pattern recognition receptors by different microbes can lead to the trail by which these cells regulate cancer. Furthermore, mixed immune reactions involving NK cells, tumor-associated macrophages, and lymphocytes have shown their connection with the microbial counterpart of the disease. The microbes like Bacteroides fragilis, Fusobacterium nucleatum, and Enterococcus faecalis and their metabolites have engendered inflammatory reactions in the tumor microenvironment. Hence the interplay between immune cells and various microbes is utilized to study the changing metastasis stage. Targeting either immune cells or microbiota could not serve as a key to tackling this deadly disorder. However, harnessing their complementation towards the disease can be a powerful weapon for developing therapy and diagnostic/prognostic markers. In this review, we have discussed various immune reactions and microbiome interplay in CRC, intending to evaluate the effectiveness of chemotherapy and immunotherapy and their parallel relationship.

Background: Inflammatory bowel disease (IBD) is a significant health problem with an increasing financial burden worldwide. Although various treatment strategies have been used, the results were not satisfactory. More and more researches have proved that the application of phosphatidylcholine (PC) may become an alternative therapy for IBD. Objective: This review aims to provide an overview of the possible mechanisms of PC and promote the potential application of PC for IBD therapy further. Methods: A comprehensive literature search was performed in PubMed with the following keywords: ‘phosphatidylcholine’, ‘inflammatory bowel disease’, ‘Crohn's disease’, ‘inflammation’, ‘ulcerative colitis’, ‘therapy’, ‘nanomedicines’, ‘PKCζ’, ‘lysophosphatidylcholine’, ‘microbiota’ and ‘drug carrier’. The logical operators “AND” and “OR” were applied to combine different sets of the search results. Results: Studies suggested that PC displays a significant effect in the treatment of IBD by modulating gut barrier function, remodeling gut microbiota structure, regulating polarization of macrophages, and reducing the inflammatory response. PC has also been exploited as a drug carrier for anticancer or anti-inflammation agents in multiple forms, which implies that PC has immense potential for IBD therapy. Conclusion: PC has shown promising potential as a new therapeutic agent or a drug carrier, with a novel, stable, prolonged mechanism of action in treating IBD. However, more high-quality basic and clinical studies are needed to confirm this.

Background: Several studies have linked high Lipoprotein (a) (Lp(a)) concentrations to cardiovascular events, including the formation of Abdominal Aortic Aneurysms (AAA). We review and meta-analyze existing evidence on the association of Lp(a) levels with AAA. Methods: Studies evaluating the link of Lp(a) with AAA, up to December 27th 2021, were identified by a systematic search of PubMed, SCOPUS, and Web of Science databases. The results were qualitatively and quantitatively synthesized according to PRISMA guidelines. Results are presented as standardized mean differences (SMD) with 95% confidence intervals (CI). Results: A total of 5,078 subjects (1,637 patients with AAA vs. 3,441 controls) from 11 studies were included in the meta-analysis, with a mean age of 69.9 years and a male sex prevalence of 85.8%. Based on the qualitative synthesis, high Lp(a) concentrations are linked to abdominal aortic wall degradation and extracellular matrix disarrangement. Moreover, despite the considerable variability among races, high Lp(a) levels are related to increased AAA risk, independently of race differences. Accordingly, patients with AAA displayed significantly higher Lp(a) levels compared to controls (SMD: 0.86, 95% CI: 0.55-1.17, p < 0.001). The outcome was not affected in a sensitivity analysis excluding three outlying studies (SMD: 0.40, 95% CI: 0.22-0.58, p < 0.001). Conclusion: This meta-analysis indicates the association between high Lp(a) levels and the presence of AAA, although existing literature presents high heterogeneity. Further studies are needed to standardize Lp(a) measurements and to conclude whether Lp(a) can be used as a sensitive biomarker of early presymptomatic AAA diagnosis.

Background: The interplay of oxidative stress, proinflammatory microparticles, and proinflammatory cytokines in recurrent arrhythmias is unknown in elderly patients with coronary restenosis and reocclusions after coronary stenting. Objective: This research sought to investigate the potential diagnostic and therapeutic targets for recurrent arrhythmias in patients with coronary restenosis and reocclusions after coronary stenting. Methods: We examined whether oxidative stress, proinflammatory microparticles, and proinflammatory cytokines could have effects that lead to recurrent arrhythmias in elderly patients with coronary restenosis and reocclusions. We measured the levels of malondialdehyde (MDA), CD31 + endothelial microparticle (CD31 EMP), CD62E + endothelial microparticle (CD62E + EMP), high-sensitivity C-reactive protein (hs-CRP), interleukin- 1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), as well as oxidized low-density lipoprotein (OX-LDL), and assessed the effects of relationship between oxidative stress, proinflammatory microparticles, and proinflammatory cytokines on recurrent atrial and ventricular arrhythmias in elderly patients with coronary restenosis and reocclusions after coronary stenting. Results: The levels of CD31 + EMP, CD62E + EMP, MDA, hs-CRP, IL-1β, IL-6, IL-8, TNF-α and OX-LDL were found to be increased significantly in coronary restenosis + recurrent atrial arrhythmia group compared to without coronary restenosis and coronary restenosis + without recurrent atrial arrhythmia groups, respectively (P < 0.001). Patients in the coronary reocclusion + recurrent ventricular arrhythmia group also exhibited significantly increased levels of CD31 + EMP, CD62E + EMP, MDA, hs-CRP, IL-1β, IL-6, IL-8, TNF-α and OXLDL compared to without coronary reocclusion and coronary reocclusion + without recurrent ventricular arrhythmia groups, respectively (P < 0.001). Conclusion: Proinflammatory microparticles, proinflammatory cytokines, and oxidative stress might act as potential targets for recurrent arrhythmias in patients with coronary restenosis and reocclusions after coronary stenting.

Background: Aluminum phosphide (ALP) intoxication either accidentally or intentionally, is one of the major health concerns in developing countries. Its poisoning causes severe damage to organs including the heart and liver. Objectives: This study aimed to investigate the hepato- and cardioprotective effects of quercetin (QCN) on the acute/subacute toxicity of ALP in rodent models. Methods: Acute (single dose, 12.5 mg/kg, orally) and subacute (2 mg/kg, orally and 7 days) intoxication of ALP were induced in rats and the protective effects of QCN on altered hepatic/cardiac functional enzyme concentrations, myeloperoxidase activity, oxidative stress biomarkers, and histopathological changes were studied at three doses of 10, 50 and 100 mg/kg BW. To record any heart abnormality, an electrocardiogram (ECG) was recorded 3 h after the last treatment. Results: Quercetin reduced the ALP-increased hepatic and cardiac functional enzyme concentrations and myeloperoxidase activity. Moreover, QCN improved remarkably the ALP-induced ECG abnormalities (T inversion, bigeminy in R waves) and arrhythmias. QCN attenuated significantly (p < 0.05) the ALP-induced oxidative/ nitrosative stress and histopathological injuries in the liver and heart. Conclusion: Our results suggest that QCN is able to protect the ALP-induced cardiac and hepatic injuries in both acute and subacute models and its effects attribute to its antioxidant and anti-inflammatory properties.