Current Pharmaceutical Design - Volume 28, Issue 36, 2022

In 2019, the whole world came together to confront a life-threatening virus named SARS-CoV-2, causing COVID-19 illness. The virus infected the human host by attaching to the ACE2 and CD147 receptors in some human cells, resulting in cytokine storm and death. The new variants of the virus that caused concern are Alpha, Beta, Gamma, Delta, and Epsilon, according to the WHO label. However, Pango lineages designated them as B.1.1.7, B.1.351, P.1, B.1.617.2, and B.1.429. Variants may be progressively formed in one chronic COVID-19 patient and transmitted to others. They show some differences in cellular and molecular mechanisms. Mutations in the receptor-binding domain (RBD) and N-terminal domain (NTD) lead to alterations in the host's physiological responses. They show significantly higher transmissibility rates and viral load while evading neutralizing antibodies at different rates. These effects are through mutations, deletion, and conformational alterations in the virus, resulting in the enhanced affinity of RBD to PD of ACE2 protein, virus entry, and spike conformational change. In the clinical laboratory, new variants may diagnose from other variants using specific primers for RBD or NTD. There are some controversial findings regarding the efficacy of the developed vaccines against the new variants. This research aimed to discuss the cellular and molecular mechanisms beyond COVID-19 pathogenesis, focusing on the new variants. We glanced at why the mutations and the ability to transmit the virus increase and how likely the available vaccines will be effective against these variants.

Cancer nano-therapeutics are rapidly evolving and are often used to overcome a number of concerns with traditional drug delivery methods, including non-specific drug targeting and distribution, low oral bioavailability, and poor hydrophilicity. Modern nano-based targeting techniques have been developed as a result of advances in nano vehicle engineering and materials science, which may bring people with cancer a new hope. Clinical trials have been authorized for a number of medicinal nanocarriers. Nanocarriers with the best feasible size and surface attributes have been developed to optimize biodistribution and increase blood circulation duration. Nanotherapeutics can carry preloaded active medicine towards cancerous cells by preferentially leveraging the specific physiopathology of malignancies. In contrast to passive targeting, active targeting strategies involving antigens or ligands, developed against specific tumor sites, boost the selectivity of these curative nanovehicles. Another barrier that nanoparticles may resolve or lessen is drug resistance. Multifunctional and complex nanoparticles are currently being explored and are predicted to usher in a new era of nanoparticles that will allow for more individualized and customized cancer therapy. The potential prospects and opportunities of stimuli-triggered nanosystems in therapeutic trials are also explored in this review.

Even though an association between inflammation and hypertension has been known for many years, it has not been simple to ascertain the role of several physiological responses involved. The innate immune response plays a critical role in these physiological responses. Innate immune cells can be activated directly by shear stress, activate the inflammasome and produce numerous cytokines and soluble mediators essential in hypertension. NFkB activation is mainly involved in the activation of innate immune cells. Shear stress also stimulates the expression of DAMP and PAMP receptors, enhancing pathogen and danger signals and magnifying inflammation. The adaptative immune response is activated with the increased antigen presentation resulting from the insults mentioned. Chronic inflammation may lead to autoimmunity. Peripheral hypoxia, a consequence of hypertension, activates hypoxia-inducing factors 1-α and 1-β (HIF-1α, HIF-1β), which modulate innate immune cells and promote inflammation. HIF-1α is involved in the upregulation of oxygen and nitrogen radical production proteins. HIF-1β down-regulates antioxidant enzymes. However, the critical evidence of the role of innate immune cells in hypertension came from the results of clinical trials involving therapies blocking inflammatory cytokines and Toll-like receptor expression. Several lines of research have been conducted on this complex disease. Pro-tolerogenic innate immune cells, myeloid suppressor cells, and M2 macrophages may play a crucial role in promoting or resolving inflammation, cardiovascular diseases and hypertension, and should be studied in detail.

COVID-19, which has strongly affected the 21st century, is caused by severe acute respiratory syndrome (SARS)-CoV-2. The emergence of viral variants has rendered even vaccinated people prone to infection; thus, completely eradicating COVID-19 may be impossible. COVID-19 causes hyperinflammation, leading to organ damage and even death. SARS-CoV-2 infects not only the lungs, causing acute respiratory distress syndrome, but also the extrapulmonary organs. Not all patients with COVID-19 respond adequately to treatments with antiviral and anti-inflammatory drugs. Therefore, new treatments are urgently needed. Mesenchymal stem cells (MSCs) exhibit immunomodulatory activity and are used to safely and effectively treat various immune disorders. Evidence has indicated the efficacy of MSCs against COVID-19. However, the safety and efficacy of MSCs must be probed further. For this reason, we explored key clinical challenges associated with MSC therapy for COVID-19, such as sources, administration routes, cell dosage, treatment timepoint, and virus reactivation. We identified several challenges that must be addressed before MSCs can be clinically applied.

Colorectal cancer (CRC) is one of the most prevalent cancers globally. Despite recent progress in identifying etiologies and molecular genetics as well as new therapeutic approaches, the clinical outcome of current CRC therapies remains poor. This fact highlights the importance of further understanding underlying mechanisms involved in colorectal tumor initiation and progression. Abnormal metabolic alterations offer an evolutional advantage for CRC tumor cells and enhance their aggressive phenotype. Therefore, dysregulation of cellular metabolism is intricately associated with colorectal tumorigenesis. This review summarizes recent findings regarding the CRC-related changes in cellular metabolic pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and mitochondrial metabolism. We describe the oncogenic signaling pathways associated with metabolic dysregulation during malignant transformation and tumor progression. Given the crucial role of metabolic pathway alterations in the pathogenesis of CRC, we provide an overview of novel pharmacological strategies for the treatment of CRC by targeting metabolic and signaling pathways.

Background: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. Objective: In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized. Methods: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out. Results: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki). Conclusion: Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 μM, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 ± 0.015 μM), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 ± 0.002 μM. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.

Background: Signal transducers and activators of the transcription (STAT) family is composed of seven structurally similar and highly conserved members, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. The STAT3 signaling cascade is activated by upstream kinase signals and undergoes phosphorylation, homo-dimerization, nuclear translocation, and DNA binding, resulting in the expression of target genes involved in tumor cell proliferation, metastasis, angiogenesis, and immune editing. STAT3 hyperactivation has been documented in a number of tumors, including head and neck, breast, lung, liver, kidney, prostate, pancreas cancer, multiple myeloma, and acute myeloid leukemia. Drug discovery is a timeconsuming and costly process; it may take ten to fifteen years to bring a single drug to the market. Machine learning algorithms are very fast and effective and commonly used in the field, such as drug discovery. These algorithms are ideal for the virtual screening of large compound libraries to classify molecules as active or inactive. Objective: The present work aims to perform machine learning-based virtual screening for the STAT3 drug target. Methods: Machine learning models, such as k-nearest neighbor, support vector machine, Gaussian naïve Bayes, and random forest for classifying the active and inactive inhibitors against a STAT3 drug target, were developed. Ten-fold cross-validation was used for model validation. Then the test dataset prepared from the zinc database was screened using the random forest model. A total of 20 compounds with 88% accuracy was predicted as active against STAT3. Furthermore, these twenty compounds were docked into the active site of STAT3. The two complexes with good docking scores as well as the reference compound were subjected to MD simulation. A total of 100ns MD simulation was performed. Results: Compared to all other models, the random forest model revealed better results. Compared to the standard reference compound, the top two hits revealed greater stability and compactness. Conclusion: In conclusion, our predicted hits have the ability to inhibit STAT3 overexpression to combat STAT3-associated diseases.