Current Pharmaceutical Design - Volume 29, Issue 36, 2023

Mood disorders are the leading cause of disability worldwide and their incidence has significantly increased after the COVID-19 pandemic. Despite the continuous surge in the number of people diagnosed with psychiatric disorders, the treatment methods for these conditions remain limited. A significant number of people either do not respond to therapy or discontinue the drugs due to their severe side effects. Therefore, alternative therapeutic interventions are needed. Previous studies have shown a correlation between immunological alterations and the occurrence of mental health disorders, yet immunomodulatory therapies have been barely investigated for combating psychiatric conditions. In this article, we have reviewed the immunological alterations that occur during the onset of mental health disorders, including microglial activation, an increased number of circulating innate immune cells, reduced activity of natural killer cells, altered T cell morphology and functionality, and an increased secretion of pro-inflammatory cytokines. This article also examines key studies that demonstrate the therapeutic efficacy of anti-inflammatory medications in mental health disorders. These studies suggest that immunomodulation can potentially be used as a complementary therapy for controlling psychiatric conditions after careful screening of candidate drugs and consideration of their efficacy and side effects in clinical trials.

Many methods, including solid dispersion, micellization, and inclusion complexes, have been employed to increase the solubility of potent drugs. Beta-cyclodextrin (βCD) is a cyclic oligosaccharide consisting of seven glucopyranoside molecules, and is a widely used polymer for formulating soluble inclusion complexes of hydrophobic drugs. The enzymatic activity of Glycosyltransferase or α-amylase converts starch or its derivatives into a mixture of cyclodextrins. The βCD units are characterized by α -(1-4) glucopyranose bonds. Cyclodextrins possess certain properties that make them very distinctive because of their toroidal or truncated cage-like supramolecular configurations with multiple hydroxyl groups at each end. This allowed them to encapsulate hydrophobic compounds by forming inclusion complexes without losing their solubility in water. Chemical modifications and newer derivatives, such as methylated βCD, more soluble hydroxyl propyl methyl βCD, and sodium salts of sulfobutylether-βCD, known as dexolve® or captisol®, have envisaged the use of CDs in various pharmaceutical, medical, and cosmetic industries. The successful inclusion of drug complexes has demonstrated improved solubility, bioavailability, drug resistance reduction, targeting, and penetration across skin and brain tissues. This review encompasses the current applications of β-CDs in improving the disease outcomes of antimicrobials and antifungals as well as anticancer and anti-tubercular drugs.

Background: Curcuminoids, including curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin, are natural polyphenolic compounds that exhibit various biological properties, such as antioxidant, anti-inflammatory, and anticancer activities. Dysregulation of the interleukin (IL)-6-mediated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway is closely associated with the development of colorectal cancer (CRC). Methods: Here, we have evaluated the modulation of the IL-6/JAK/STAT3 pathway of curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin in LoVo and HT-29 colorectal cancer cells with a single molecular array (Simoa), western blot analysis, real-time polymerase chain reaction (PCR), and pathway analysis system. Results: The study showed that curcuminoids suppressed the amount of IL-6 in LoVo and HT-29 colorectal cancer cells. Meanwhile, curcuminoids inhibited the expression of inflammation regulator-related microRNA (miRNA). We also found that the expression of total STAT3 was downregulated by curcuminoids. Moreover, the pathway analysis system showed that curcuminoids inactivated the JAK/STAT3 signaling pathway. Taken together, we demonstrated that the anti-cancer activities of curcuminoids against colorectal cancer are due to the modulation of the IL-6/JAK/STAT3 cascade. Conclusion: Curcuminoids could be a promising anti-cancer agent for the treatment of human colorectal cancer.

Background: Cervical cancer is a prevalent malignancy among women globally. Objective: We aimed to uncover the mechanism of action of kaempferol in the treatment of cervical cancer using an integrated approach that combines metabolomics with network pharmacology. Methods: Initially, we investigated the specific metabolites and potential pathways influenced by kaempferol in the pathological progression of cervical cancer, employing UHPLC-Q-Orbitrap MS metabolomics. In addition, network pharmacology analysis was performed to ascertain the pivotal targets of kaempferol in the context of CC therapy. Results: Metabolomics analysis indicated that the therapeutic effect of kaempferol on cervical cancer is primarily associated with 11 differential metabolites and 7 metabolite pathways. These pathways include arginine and proline metabolism, the tricarboxylic acid cycle, phenylalanine, tyrosine, and tryptophan biosynthesis, fatty acid biosynthesis, glycerophospholipid metabolism, pantothenate and CoA biosynthesis, and tyrosine metabolism. Additionally, kaempferol was found to regulate 3 differential metabolites, namely palmitic acid, citric acid, and L-tyrosine, by directly targeting 7 specific proteins, including AKR1B1, CS, EGFR, PLA2G1B, PPARG, SLCO2B1, and SRC. Furthermore, molecular docking demonstrated strong binding affinities between kaempferol and 7 crucial targets. Conclusion: This study elucidates the intricate mechanisms by which kaempferol acts against cervical cancer. Furthermore, this research offers a novel approach to investigating the potential pharmacological mechanisms of action exhibited by natural compounds.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), which first appeared in December 2019. Angiotensin I converting enzyme 2 (ACE2) receptor, present on the host cells, interacts with the receptor binding domain (RBD) of spike (S) protein of SARS-CoV-2 and facilitates the viral entry into host cells. Methods: Non-synonymous single nucleotide polymorphisms (nsSNPs) in the ACE2 gene may have an impact on the protein's stability and its function. The deleterious or harmful nsSNPs of the ACE2 gene that can change the strength as well as the pattern of interaction with the RBD of S protein were selected for this study. Results: The ACE2:RBD interactions were analyzed by protein-protein docking study. The missense mutations A242V, R708W, G405E, D292N, Y633C, F308L, and G405E in ACE2 receptor were found to interact with RBD of Omicron subvariants with stronger binding affinity. Among the other selected nsSNPs of human ACE2 (hACE2), R768W, Y654S, F588S, R710C, R710C, A191P, and R710C were found to have lower binding affinity for RBD of Omicron subvariants. Conclusion: The findings of this study suggest that the nsSNPs present in the human ACE2 gene alter the structure and function of the protein and, consequently, the susceptibility to Omicron subvariants.

Objectives: This study aims to design and evaluate (in silico and in vitro) a new nicotinamide derivative as an inhibitor of VEGFR-2, a major mediator of angiogenesis Methods: The following in silico studies were performed; DFT calculations, molecular modelling, MD simulations, MM-GBSA, PLIP, and PCAT studies. The compound's in silico (ADMET) analysis was also conducted. Subsequently, the compound ((E)-N-(4-(1-(2-(4-(4-Chlorobenzamido)benzoyl)hydrazono)ethyl) phenyl)nicotinamide) was successfully synthesized and designated as compound X. In vitro, VEGFR-2 inhibition and cytotoxicity of compound X against HCT-116 and A549 cancer cell lines and normal Vero cell lines were conducted. Apoptosis induction and migration assay of HCT-116 cell lines after treatment with compound X were also evaluated. Results: DFT calculations assigned stability and reactivity of compound X. Molecular docking and MD simulations indicated its excellent binding against VEGFR-2. Furthermore, MM-GBSA analysis, PLIP experiments, and PCAT studies confirmed compound X’s correct binding with optimal dynamics and energy. ADMET analysis expressed its general likeness and safety. The in vitro assays demonstrated that compound X effectively inhibited VEGFR-2, with an IC50 value of 0.319 ± 0.013 μM and displayed cytotoxicity against HCT-116 and A549 cancer cell lines, with IC50 values of 57.93 and 78.82 μM, respectively. Importantly, compound X exhibited minimal toxicity towards the non-cancerous Vero cell lines, (IC50 = 164.12 μM). Additionally, compound X significantly induced apoptosis of HCT-116 cell lines and inhibited their potential to migrate and heal. Conclusion: In summary, the presented study has identified compound X as a promising candidate for the development of a novel apoptotic lead anticancer drug.