Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA2021 in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA2021 withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA2021 contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA2021, at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA2021 increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA2021 alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA2021 bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA2021 stably interacted with Hsp90α more efficiently compared with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA2021 showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-𝜅B) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90α genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA2021 to confirm its anticancer capabilities.

No abstract

This study evaluates the quality variation for twenty-seven capsicum fruit (CF) samples, in terms of their volatile oil composition and biological activities. The GCMS analysis revealed the presence of seventy one chemical compounds from different chemical classes with an average (%) composition of: 26.13 (alcohols) > 18.82 (hydrocarbons) > 14.97 (esters) > 3.08 (ketones) > 1.14 (others) > 1.07 (acids) > 0.72 (sugar) > 0.42 (aldehydes) > 0.15 (amino compounds). Alcohols and hydrocarbons were the most abundant in these CF samples with 1-Decanol, 2-octyl- and docosanoic acid, docosyl ester as the major components, respectively. The % inhibition in cytotoxicity assays was observed in the range of 9–47 (MCF7) and 4–41 (HCT116) whereas, the zone of inhibition (mm) for the antimicrobial activity was found to be 0.0–17 (P. aeruginosa) > 0.0–13 (E. coli and S. aureus). Moreover, the samples with the largest zone of inhibition in the agar-well-diffusion method (C16, C19, and C26) upon further evaluation presented the least MIC and MBC values against P. aeruginosa with an MIC and MBC (µg/mL) of 6.3 and 12.5, respectively. The outcome for GCMS and biological activities were further supported by statistical tools of PCA and K-mean cluster analysis which confirmed the C16 CF sample with the best activity followed by C5, C13 (the best cytotoxic), and C19, C26 (the best antimicrobial). The statistical analysis exhibited a high Chi-square value of 5931.68 (GCMS) and 32.19 (biological activities) with p = 0.00 for KMO and Bartlett’s Test of Sphericity. The 27-CF samples were effectively distinguished based on quality variation, and the C16 CF sample exhibited significant potential for further study.

Feralolide, a dihydroisocoumarin, was isolated from the methanolic extract of resin of Aloe vera. The present study aims to investigate the in vivo ability of feralolide to ameliorate memory impairment induced by scopolamine using a battery of in vitro assays, such as antioxidant and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, and in vivo animal models, including elevated plus maze, Morris water maze, passive avoidance, and novel object recognition tests. Feralolide caused a concentration-dependent inhibition of AChE and BuChE enzymes with IC50 values of 55 and 52 μg/mL, respectively, and antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) with IC50 values 170 and 220 μg/mL, respectively. Feralolide reversed the scopolamine-induced amnesia as indicated by a dose-dependent decrease in escape latency, path length, and passing frequency in the Morris water maze test compared with the relevant control. The compound also significantly increased the discrimination index in a dose-dependent manner in NORT and decreased transfer latency in EPM, reflective of its memory-enhancing effect. Furthermore, feralolide also caused significant dose-dependent elevation in the step-down latency (SDL) in the passive avoidance test. The results indicated that feralolide might be a helpful memory restorative mediator in treating cognitive disorders such as Alzheimer’s disease.

Fluorescein angiography (FA) is an important tool for the diagnosis and management of diabetic retinopathy. However, the safety of fluorescein sodium on renal functions is not fully understood. One hundred type 2 diabetes patients, within the Ophthalmology Outpatient Clinic at Alexandria Main University Hospital, Egypt, were enrolled in this prospective observational study to determine the safety of FA on renal function. Serum creatinine and cystatin C were measured pre- and 2 days post-FA. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) was measured pre- and 4 hours post-FA. Renal injury was defined as a 25% increase in serum creatinine, cystatin C, or uNGAL. The study included 71 females and 29 males, with a mean age of 55.73 ± 7.29 years. Baseline serum cystatin C and uNGAL were 0.89 ± 0.34 mg/L and 21.7 ± 2.39 ng/mL, respectively. Serum cystatin C and uNGAL significantly increased after FA to 0.95 ± 0.36 and 27 ± 2.81, respectively (P <0.001). Eleven patients (11%) experienced more than a 25% rise in serum cystatin C from baseline, whereas 40 patients (40%) experienced more than a 25% increase in uNGAL levels after FA. However, the mean serum creatinine level did not change significantly after FA (P = 0.061). Only one patient experienced more than a 25% rise in serum creatinine from baseline. FA showed a significant increase in early sensitive acute kidney injury biomarkers (as serum cystatin C and uNGAL) in substantial number of patients, suggesting but still not proving, a potential harmful effect of FA on kidney functions. These findings were not demonstrated using ordinary serum creatinine.

The current research reports the synthesis of 14 para-substituted thiosemicarbazone derivatives in good to excellent yields using standard procedures. Initially, 4-ethoxybenzaldehyde (1) and 4-nitrobenzaldehyde (2) were refluxed with thiosemicarbazide in the presence of acetic acid in ethanol for 4–5 h. Then, various substituted phenacyl bromides were treated with the desired thiosemicarbazones (3 and 4) in the presence of triethylamine in ethanol with constant stirring for 5–6 h. The resulting derivatives were confirmed through electron impact mass spectrometry and 1H NMR spectroscopy and evaluated for anticholinesterase inhibitory activity. Among the series, four compounds, 19, 17, 7, and 6, showed potent inhibitory activity against the acetylcholinesterase (AChE) enzyme, having IC50 values of 110.19 ± 2.32, 114.57 ± 0.15, 140.52 ± 0.11, and 160.04 ± 0.02 μM, respectively, compared with standard galantamine (IC50 = 104.5 ± 1.20 μM). Similarly, compounds 19 (IC50 = 145.11 ± 1.03 μM), 9 (IC50 = 147.20 ± 0.09 μM), 17 (IC50 = 150.36 ± 0.18 μM), and 6 (IC50 = 190.21 ± 0.13 μM) were the most excellent inhibitors of butyrylcholinesterase (BChE) when compared with the standard drug galantamine (IC50 = 156.8 ± 1.50 μM). In silico studies were accomplished on the produced derivatives in order to explain the binding interface of compounds with the active sites of AChE and BChE enzymes.

Crimean–Congo haemorrhagic fever (CCHF), caused by Crimean–Congo haemorrhagic fever virus (CCHFV), is a disease of worldwide importance (endemic yet not limited to Asia, Middle East, and Africa) and has triggered several outbreaks amounting to a case fatality rate of 10–40% as per the World Health Organization. Genetic diversity and phylogenetic data revealed that the Asia-1 genotype of CCHFV remained dominant in Pakistan, where 688 confirmed cases were reported between the 2012–2022 period. Currently, no approved vaccine is available to tackle the viral infection. Epitope-based vaccine design has gained significant attention in recent years due to its safety, timeliness, and cost efficiency compared to conventional vaccines. In the present study, we employed a robust immunoinformatics-based approach targeting the structural glycoproteins G1 and G2 of CCHFV (Asia-1 genotype) to design a multi-epitope vaccine construct. Five B-cells and six cytotoxic T-lymphocytes (CTL) epitopes were mapped and finalized from G1 and G2 and were fused with suitable linkers (EAAAK, GGGS, AAY, and GPGPG), a PADRE sequence (13 aa), and an adjuvant (50S ribosomal protein L7/L12) to formulate a chimeric vaccine construct. The selected CTL epitopes showed high affinity and stable binding with the binding groove of common human HLA class I molecules (HLA-A*02:01 and HLA-B*44:02) and mouse major histocompatibility complex class I molecules. The chimeric vaccine was predicted to be an antigenic, non-allergenic, and soluble molecule with a suitable physicochemical profile. Molecular docking and molecular dynamics simulation indicated a stable and energetically favourable interaction between the constructed antigen and Toll-like receptors (TLR2, TLR3, and TLR4). Our results demonstrated that innate, adaptive, and humoral immune responses could be elicited upon administration of such a potent muti-epitope vaccine construct. These results could be helpful for an experimental vaccinologist to develop an effective vaccine against the Asia-1 genotype of CCHFV.