Comparative phenotypic and genotypic analysis of community-acquired and hospital-acquired intra-abdominal infections among liver transplanted patients.

AIM: During liver transplantation, both hospital-acquired (HA) and community-acquired (CA) intra-abdominal infections (IAIs) are involved causing life-threatening diseases. Therefore, comparative studies of aerobic and facultative anaerobic HA-IAIs and CA-IAIs after liver transplantation surgery are necessary. METHODS AND RESULTS: The species of detected isolates (310) from intra-abdominal fluid were identified and classified into hospital-acquired intra-abdominal infections (HA-IAIs) and community-acquired intra-abdominal infections (CA-IAIs). Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii were the most commonly detected species. The resistant phenotypes were commonly detected among the HA-IAIs; however, the virulent phenotypes were the predominant strains of CA-IAIs. Regrettably, the resistance profiles were shocking, indicating the inefficacy of monotherapy in treating these isolates. Therefore, we confirmed the use of empirical combination therapies of amikacin and meropenem for treating all IAIs (FICI ≤ 0.5). Unfortunately, the high diversity and low clonality of all identified HA and CA-IAIs were announced with D-value in the range of 0.992-1. CONCLUSION: This diversity proves that there are infinite numbers of infection sources inside and outside healthcare centers.

Isatin-based benzyloxybenzene derivatives as monoamine oxidase inhibitors with neuroprotective effect targeting neurogenerative disease treatment.

Eighteen isatin-based benzyloxybenzaldehyde derivatives from three subseries, ISB, ISFB, and ISBB, were synthesized and their ability to inhibit monoamine oxidase (MAO) was evaluated. The inhibitory activity of all synthesized compounds was found to be more profound against MAO-B than MAO-A. Compound ISB1 most potently inhibited MAO-B with an IC50 of 0.124 ± 0.007 µM, ensued by ISFB1 (IC50 = 0.135 ± 0.002 µM). Compound ISFB1 most potently inhibited MAO-A with an IC50 of 0.678 ± 0.006 µM, ensued by ISBB3 (IC50 = 0.731 ± 0.028 µM), and had the highest selectivity index (SI) value (55.03). The three sub-parental compounds, ISB1, ISFB1, and ISBB1, had higher MAO-B inhibition than the other derivatives, indicating that the substitutions of the 5-H in the A-ring of isatin diminished the inhibition of MAO-A and MAO-B. Among these, ISB1 (para-benzyloxy group in the B-ring) displayed more significant MAO-B inhibition when compared to ISBB1 (meta-benzyloxy group in the B-ring). ISB1 and ISFB1 were identified to be competitive and reversible MAO-B inhibitors, having Ki values of 0.055 ± 0.010, and 0.069 ± 0.025 µM, respectively. Furthermore, in the parallel artificial membrane penetration assay, ISB1 and ISFB1 traversed the blood-brain barrier in the in vitro condition. Additionally, the current study found that ISB1 decreased rotenone-induced cell death in SH-SY5Y neuroblastoma cells. In docking and simulation studies, the hydrogen bonding formed by the imino nitrogen in ISB1 and the pi-pi stacking interaction of the phenyl ring in isatin significantly aided in the protein-ligand complex's stability, effectively inhibiting MAO-B. According to these observations, the MAO-B inhibitors ISB1 and ISFB1 were potent, selective, and reversible, making them conceivable therapies for neurological diseases.

Cytotoxic and Antioxidant Potential of Launaea mucronata Forssk Essential Oil Growing in Northern Saudi Arabia.

Essential oils are naturally occurring multicomponent combinations of isoprenoids with distinctive odors that are produced by aromatic plants from mevalonic acid. They are extensively applied in aromatherapy for the treatment of various ailments. To investigate the potential therapeutic value of the ingredients in Launaea mucronata essential oil (EO), gas chromatography-mass spectrometry (GC-MS) analysis was used for essential oil characterization. Then, 2,2-diphenyl-1-picrylhydrazyl (DPPH), ß-carotene/linoleic acid, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays were used to evaluate the antioxidants. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to estimate the cytotoxicity. Following a thorough analysis of the GC-MS chromatogram, 87 components representing 97.98% of the entire EO mixture were identified. N-eicosane (10.92%), 2E,6Z-farnesol (10.74%), and 2Z,6E-farnesyl acetone (46.35%) were determined to be the major components of the oil. When the produced EO was evaluated for its antioxidant properties, it showed a strong inhibitory effect (%) of 65.34 at a concentration of 80 µg/mL. The results (g/mL) showed a positive response against the tested cell lines for HCT-116, MCF-7, and HepG2 (8.45, 10.24, and 6.78 g/mL, respectively). A high-concentration mixture of deadly components consisting of farnesol, bisabolol, eicosane, and farnesyl acetone may be responsible for this significant cytotoxic action, which was especially noticeable in the HepG2 cell line. Molecular docking occurred between farnesol and farnesyl acetone with the target residues of topoisomerases I and II, CDK4/cyclD1, and Aurora B kinases; these showed binding free energies ranging from -4.5 to -7.4 kcal/mol, thus demonstrating their antiproliferative action. In addition, farnesol and farnesyl acetone fulfilled most of the ADME and drug-likeness properties, indicating their activity.

Hesperidin Attenuates Titanium Dioxide Nanoparticle-Induced Neurotoxicity in Rats by Regulating Nrf-2/TNF-α Signaling Pathway, the Suppression of Oxidative Stress, and Inflammation.

Background: Titanium dioxide nanoparticles (TiO2NPs) are widely utilized and consumed mainly as food additives. Oxidative stress is considered to be the basic effect of TiO2NPs through biological interactions. Hesperidin (HSP) is a bioflavonoid (flavanone glycoside) with lipid-lowering, inflammation, oxidative stress suppression, antihypertensive, cancer-fighting, and antiedema effects. Objective: This study was to investigate the possible protective influences of HSP of subchronic oral TiO2NP exposure on the brains of rats, including neurotransmitters, oxidative stress/antioxidant parameters, inflammatory markers, and histological changes in the brains of adult male albino rats. Methodology: The experiment was executed on 80 albino rats. The animals were randomly divided into 4 equal groups. The first group served as a control; the second group was treated with oral doses of HSP (100 mg/kg Bw daily); the third group received TiO2NPs (200 mg/kg Bw orally daily); and the fourth group was treated with TiO2NPs and an oral dose of HSP daily for 8 weeks. Blood samples were obtained for biochemical analysis. Neurotransmitters, oxidative stress biomarker levels, and inflammatory markers were measured in brain homogenates. Histological examination of the brain was performed through H&E staining. Results: Coadministration of hesperidin with TiO2NPs orally for 8 weeks decreased the levels of MDA, TNF-α, AChE, and dopamine in brain homogenates, which were increased in the TiO2NP group. It increased the other oxidative biomarkers (SOD, CAT, and GPx) and Nrf-2 expression levels. Brain histological sections of the TiO2NP-treated group show degeneration, necrosis, congestion, and inflammatory cell infiltration that decreased markedly in the coadministration of hesperidin with the TiO2NP group. Conclusion: Hesperidin cotreatment offers significant protection against TiO2NP-induced oxidative stress and biochemical and histological alteration in the brain.

A computational investigation of thymidylate synthase inhibitors through a combined approach of 3D-QSAR and pharmacophore modelling.

Thymidylate synthase (TS) is a crucial target of cancer drug discovery and is mainly involved in the De novo synthesis of the DNA precursor thymine. In the present study, to generate reliable models and identify a few promising molecules, we combined QSAR modelling with the pharmacophore hypothesis-generating technique. Input molecules were clustered on their similarity, and a cluster of 74 molecules with a pyrimidine moiety was chosen as the set for 3D-QSAR and pharmacophore modelling. Atom-based and field-based 3D-QSAR models were generated and statistically validated with R2 > 0.90 and Q2 > 0.75. The common pharmacophore hypothesis(CPH) generation identified the best six-point model ADHRRR. Using these best models, a library of FDA-approved drugs was screened for activity and filtered via molecular docking, ADME profiling, and molecular dynamics simulations. The top ten promising TS-inhibiting candidates were identified, and their chemical features profitable for TS inhibitors were explored.Communicated by Ramaswamy H. Sarma.

Piperidine: A Versatile Heterocyclic Ring for Developing Monoamine Oxidase Inhibitors.

The monoamine oxidase enzyme (MAO), which is bound on the membrane of mitochondria, catalyzes the oxidative deamination of endogenous and exogenous monoamines, including monoamine neurotransmitters such as serotonin, adrenaline, and dopamine. These enzymes have been proven to play a significant role in neurodegeneration; thus, they have recently been researched as prospective therapeutic targets for neurodegenerative illness treatment and management. MAO inhibitors have already been marketed as neurodegeneration illness treatments despite their substantial side effects. Hence, researchers are concentrating on developing novel molecules with selective and reversible inhibitory properties. Piperine, which is a phytochemical component present in black pepper, has been established as a potent MAO inhibitor. Piperine encompasses a piperidine nucleus with antibacterial, anti-inflammatory, antihypertensive, anticonvulsant, antimalarial, antiviral, and anticancer properties. The current Review focuses on the structural changes and structure-activity relationships of piperidine derivatives as MAO inhibitors.

Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease.

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 µM, followed by IHC2 (IC50 = 16.934 µM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 µM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 µM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.

Efficiency of Bone Marrow-Derived Mesenchymal Stem Cells and Hesperetin in the Treatment of Streptozotocin-Induced Type 1 Diabetes in Wistar Rats.

Type 1 diabetes mellitus (T1DM) was established to be ameliorated by islet transplantation, but the shortage of the transplanted human islet tissue and the use of immunosuppressive drugs to inhibit the rejection of allogeneic grafts make this type of therapy is limited. Nowadays, therapy with stem cells is one of the most promising future treatments. This kind of therapy could have a profound impact on both replacement, as well as regenerative therapies, to improve or even cure various disorders, including diabetes mellitus. Flavonoids have also been shown to possess anti-diabetic effects. Thus, this study aims to evaluate the effectiveness of the bone marrow-derived mesenchymal stem cells (BM-MSCs) and hesperetin in the treatment of a T1DM rat model. T1DM was induced in male Wistar rats that had been starved for 16 h via intraperitoneal injection of STZ at a dose of 40 mg/kg body weight (b.wt.). After 10 days of STZ injection, the diabetic rats were allocated into four groups. The first diabetic animal group was considered a diabetic control, while the other three diabetic animal groups were treated for six weeks, respectively, with hesperetin (given orally at a dose of 20 mg/kg b.wt.), BM-MSCs (injected intravenously at a dose of 1 × 106 cells/rat/week), and their combination (hesperetin and BM-MSCs). The use of hesperetin and BM-MSCs in the treatment of STZ-induced diabetic animals significantly improved the glycemic state, serum fructosamine, insulin and C-peptide levels, liver glycogen content, glycogen phosphorylase, glucose-6-phosphatase activities, hepatic oxidative stress, and mRNA expressions of NF-κB, IL-1ß, IL-10, P53, and Bcl-2 in pancreatic tissue. The study suggested the therapy with both hesperetin and BM-MSCs produced marked antihyperglycemic effects, which may be mediated via their potencies to ameliorate pancreatic islet architecture and insulin secretory response, as well as to decrease hepatic glucose output in diabetic animals. The improvement effects of hesperetin and BM-MSCs on the pancreatic islets of diabetic rats may be mediated via their antioxidant, anti-inflammatory, and antiapoptotic actions.

Design, synthesis, and docking of novel thiazolidine-2,4-dione multitarget scaffold as new approach for cancer treatment.

Novel thiazolidine-2,4-diones have been developed and estimated as conjoint inhibitors of EGFRT790M and VEGFR-2 against HCT-116, MCF-7, A549, and HepG2 cells. Compounds 6a, 6b, and 6c were known to be the dominant advantageous congeners against HCT116 (IC50 = 15.22, 8.65, and 8.80 µM), A549 (IC50 = 7.10, 6.55, and 8.11 µM), MCF-7 (IC50 = 14.56, 6.65, and 7.09 µM) and HepG2 (IC50 = 11.90, 5.35, and 5.60 µM) mass cell lines, correspondingly. Although compounds 6a, 6b, and 6c disclosed poorer effects than sorafenib (IC50 = 4.00, 4.04, 5.58, and 5.05 µM) against the tested cell sets, congeners 6b and 6c demonstrated higher actions than erlotinib (IC50 = 7.73, 5.49, 8.20, and 13.91 µM) against HCT116, MCF-7 and HepG2 cells, yet lesser performance on A549 cells. The hugely effective derivatives 4e-i and 6a-c were inspected versus VERO normal cell strains. Compounds 6b, 6c, 6a, and 4i were found to be the most effective derivatives, which suppressed VEGFR-2 by IC50 = 0.85, 0.90, 1.50, and 1.80 µM, respectively. Moreover, compounds 6b, 6a, 6c, and 6i could interfere with the EGFRT790M performing strongest effects with IC50 = 0.30, 0.35, 0.50, and 1.00 µM, respectively. What is more, 6a, 6b, and 6c represented satisfactory in silico computed ADMET profile.

Promoter methylation might shift the balance of Galectin-3 & 12 expression in de novo adult acute myeloid leukemia patients.

Acute myeloid leukemia (AML) was reported as the most common type of leukemia among adults. Galectins constitute a family of galactose-binding proteins reported to play a critical role in many malignancies including AML. Galectin-3 and -12 are members of the mammalian galectin family. To understand the contribution of galectin-3 and -12 promoter methylation to their expression, we performed bisulfite methylation-specific (MSP)-PCR and bisulfite genomic sequencing (BGS) of primary leukemic cells in patients with de novo AML before receiving any therapy. Here, we show a significant loss of LGALS12 gene expression in association with promoter methylation. The lowest degree of expression was found in the methylated (M) group while the highest degree was in the unmethylated (U) group and the partially methylated (P) group expression lies in between. This was not the case with galectin-3 in our cohort unless the CpG sites analyzed were outside the frame of the studied fragment. We were also able to identify four CpG sites (CpG number 1, 5, 7& 8) in the promoter region of galectin-12; these sites must be unmethylated so that expression can be induced. As far as the authors know, these findings were not previously concluded in earlier studies.

Royal Jelly and Chlorella vulgaris Mitigate Gibberellic Acid-Induced Cytogenotoxicity and Hepatotoxicity in Rats via Modulation of the PPARα/AP-1 Signaling Pathway and Suppression of Oxidative Stress and Inflammation.

Gibberellic acid (GA3) is a well-known plant growth regulator used in several countries, but its widespread use has negative effects on both animal and human health. The current study assesses the protective effect of royal jelly (RJ) and Chlorella vulgaris (CV) on the genotoxicity and hepatic injury induced by GA3 in rats. Daily oral administration of 55 mg/kg GA3 to rats for 6 constitutive weeks induced biochemical and histopathological changes in the liver via oxidative stress and inflammation. Co-administration of 300 mg/kg RJ or 500 mg/kg CV with GA3 considerably ameliorated the serum levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), γGT (gamma-glutamyl transferase), total bilirubin, and albumin. Lowered malondialdehyde, tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) levels along with elevated SOD (superoxide dismutase), CAT (catalase), and GPx (glutathione peroxidase) enzyme activities indicated the antioxidant and anti-inflammatory properties of both RJ and CV. Also, they improved the histological structure and reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions along with up-regulating peroxisome proliferator activated receptor α (PPARα) and down-regulating activator protein 1 (AP-1) gene expression. Additionally, chromosomal abnormalities and mitotic index were nearly normalized after treatment with RJ and CV. In conclusion, RJ and CV can protect against GA3-induced genotoxicity and liver toxicity by diminishing oxidative stress and inflammation, and modulating the PPARα/AP-1 signaling pathway.

Curcumin and vitamin C improve immunity of kidney via gene expression against diethyl nitrosamine induced nephrotoxicity in rats:In vivo and molecular docking studies.

Kidney has a crucial role in immunity, so any toxicity occurs for the kidney will result in reduced immunity. The aim of this study is to improve the immune response of insufficient kidneys through immune-related genes. Diethyl Nitrosamine has been used to cause kidney damage in animal models, vitamin C and curcumin have been used to treat impaired kidney. Renal function (urea, uric acid and creatinine) and oxidative stress parameters (superoxide dismutase, malondialdehyde and glutathione peroxidase) will be evaluated in this research work. Molecular docking also will be performed to investigate the role of vitamin C and curcumin in targeting immune response proteins. Also, Complementary component 3, Lipocalin-2, Toll-like receptor 2,Toll-like receptor 4, Kidney injury molecule-1, Interleukin 6, Interleukin-10, Tumor necrosis factor and p38 mitogen-activated protein kinases will be investigated. The obtained results showed that vitamin C and curcumin have good effects in the treatment of impaired kidneys, this was also observed in renal function and oxidative stress parameters, expression levels of proteins and histopathological examinations.

Anti-Tumor Activity of Orally Administered Gefitinib-Loaded Nanosized Cubosomes against Colon Cancer.

Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the most important trends in overcoming such problems is the use of a vesicular system. Cubosomes are considered one of the most important vesicular systems used to improve solubility and oral bioavailability. In this study, GFT cubosomal nanoparticles (GFT-CNPs) were prepared by the emulsification method. The selected formulation variables were analyzed and optimized by full factorial design and response surface methodology. Drug entrapment efficiency (EE%), transmission electron microscopy, particle size, polydispersity index, in vitro release and its kinetics, and the effect of storage studies were estimated. The chosen GFT-CNPs were subjected to further investigations as gene expression levels of tissue inhibitors of metalloproteinases-1 (TIMP-1) and matrix metalloproteinases-7 (MMP-7), colon biomarkers, and histopathological examination of colon tissues. The prepared GFT-CNPs were semi-cubic in shape, with high EE%, smaller vesicle size, and higher zeta potential values. The in vivo data showed a significant decrease in the serum level of embryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and gene expression level of TIMP-1 and MMP-7. Histopathological examination showed enhancement in cancer tissue and highly decreased focal infiltration in the lamina propria after treatment with GFT-CNPs.

Urachal carcinoma: The journey so far and the road ahead.

Urachal carcinoma, a rare cancer arising from urachus, accounts for about 1% of bladder cancer. The diagnosis at stage I shows about 63% 5-year survival whereas only 8% of the patients at stage IV shows a 5-year survival. Above 90% of urachal carcinomas are adenocarcinomas and most of the urachal carcinoma cases are invasive, showing a high resemblance to adenocarcinoma of various origins, making it hard for a conclusive diagnosis. Even though inconclusive, immunohistochemistry can play a significant role in identifying urachal carcinoma. Most cases show the biomarkers CK20 and CDX2, whereas CK7 and ß-catenin are expressed at a lesser frequency. Due to the few cases available, there is a lack of evidence regarding specific markers differentiating urachal carcinoma from colorectal or primary bladder adenocarcinomas. In addition to immunohistochemistry, genomic characterization is emerging to play a role in the classification and treatment of the disease. Urachal carcinoma has been reported to have a molecular level similarity with colorectal malignancies regarding certain gene expressions. The TP53 mutations inactivating the tumor suppressor can probably be explored as a possible target in treating urachal carcinoma. Additionally, certain targets identified in gastric and breast cancer along with anti-HER2 treatment strategies can be explored. Immuno-oncology utilizes immune checkpoint inhibitors for the treatment of MSI-H tumors whereas a combination of tyrosine kinase inhibitors along with immune checkpoint inhibitors are being studied to treat MSI stable tumors. The article is an in-depth overview of urachal carcinoma addressing the current landscape with an emphasis on the future scenario.

Phthalazone tethered 1,2,3-triazole conjugates: In silico molecular docking studies, synthesis, in vitro antiproliferative, and kinase inhibitory activities.

New phthalazone tethered 1,2,3-triazole derivatives 12-21 were synthesized utilizing the Cu(I)-catalyzed click reactions of alkyne-functionalized phthalazone 1 with functionalized azides 2-11. The new phthalazone-1,2,3-triazoles structures 12-21 were confirmed by different spectroscopic tools, like IR; 1H, 13C, 2D HMBC and 2D ROESY NMR; EI MS, and elemental analysis. The antiproliferative efficacy of the molecular hybrids 12-21 against four cancer cell lines was evaluated, including colorectal cancer, hepatoblastoma, prostate cancer, breast adenocarcinoma, and the normal cell line WI38. The antiproliferative assessment of derivatives 12-21 showed potent activity of compounds 16, 18, and 21 compared to the anticancer drug doxorubicin. Compound 16 showed selectivity (SI) towardthe tested cell lines ranging from 3.35 to 8.84 when compared to Dox., that showed SI ranged from 0.75 to 1.61. Derivatives 16, 18 and 21 were assessed towards VEGFR-2 inhibitory activity and result in that derivative 16 showed the potent activity (IC50 = 0.123 µM) in comparison with sorafenib (IC50 = 0.116 µM). Compound 16 caused an interference with the cell cycle distribution of MCF7 and increased the percentage of cells in S phase by 1.37-fold. In silico molecular docking of the effective derivatives 16, 18, and 21 against vascular endothelial growth factor receptor-2 (VEGFR-2) confirmed the formation of stable protein-ligand interactions within the pocket.

Computational and Molecular Docking Studies of New Benzene Sulfonamide Drugs with Anticancer and Antioxidant Effects.

BACKGROUND: The studies on the potential usage of benzene sulfonamide derivatives as anticancer agents are limited. benzene sulfonamide derivatives are currently used as anticancer agents against different breast cancer cell lines, such as MCF-7, lung cancer cells (A549), prostate cancer cells (Du-145), and cervical cells (HeLa). OBJECTIVE: A series of new sulfonamide drugs are synthesized by reacting aldehydes thio-semi-carbazones derivatives with benzene sulphonyl chloride to form benzylidene-N-(phenylsulfonyl) hydrazine-1-carbothioamide derivatives. Studying the anticancer effects against MCF-7 breast carcinoma cell lines and the antioxidant activities of these newly synthesized compounds. METHODS: Studying the anticancer effects against MCF-7 breast carcinoma cell lines and the antioxidant activities of these newly synthesized compounds. To study the anti-breast cancer activity of the newly synthesized compounds, a molecular docking study is used to analyze the binding energy for the nonbonding interactions between the ligands (studied compounds) and receptor (4PYP (pdb code: 4FA2)) against human breast cancer (MCF-7) cells. The bioavailability of all studied compounds is confirmed by pharmacological investigations using Mol inspiration and absorption, distribution, metabolism, excretion, and toxicity online servers. RESULTS: The two derivatives, 2-(4- methoxy benzylidene)-N-(phenylsulfonyl) hydrazine-1-carbothioamide (4c) and 2-(4-dimethylamino) benzylidene)-N-(phenylsulfonyl) hydrazine-1-carbothioamide (4e) show the most potent anticancer effects against MCF-7 breast carcinoma cell lines. Meanwhile, these two derivatives show the lowest antioxidant activities. CONCLUSION: The different spectral techniques were used to confirm the structure of the novel synthesized compounds. Further, 2-(4-(dimethyl amino) benzylidene)-N- (phenylsulfonyl)hydrazine-1-carbothioamide (4e) and 2-(4- methoxy benzylidene)-N-(phenylsulfonyl) hydrazine-1 carbothioamide (4c) were the most potent anticancer derivatives against MCF-7 breast carcinoma cell lines. Furthermore, they exhibited the most potent antioxidant activities. Meanwhile, the 2-benzylidene-N-(phenylsulfonyl) hydrazine-1-carbothioamide (4a) and 2-(4-chloro benzylidene)-N-(phenylsulfonyl) hydrazine-1-carbothioamide (4d) had the lowest antioxidant potentials. The estimated binding energies, inhibition constant, intermolecular energies, and reference RMSD produced from docking for all studied compounds were reported. These values showed that all studied compounds formed stable complexes with the receptor with high binding affinity. It was further noted from the ADMET analysis that compounds 4c, 4d, and 4e have good absorption, low toxicity in the human liver, and medium BBB penetration. Hence, these studied compounds (4c-4e) may be suggested as potential compounds against human breast cancer MCF-7 cells.

Recent Advancement in Drug Design and Discovery of Pyrazole Biomolecules as Cancer and Inflammation Therapeutics.

Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile, viz., anti-inflammatory, anti-microbial, anti-anxiety, anticancer, analgesic, antipyretic, etc. Due to the expansion of pyrazolecent red pharmacological molecules at a quicker pace, there is an urgent need to put emphasis on recent literature with hitherto available information to recognize the status of this scaffold for pharmaceutical research. The reported potential pyrazole-containing compounds are highlighted in the manuscript for the treatment of cancer and inflammation, and the results are mentioned in % inhibition of inflammation, % growth inhibition, IC50, etc. Pyrazole is an important heterocyclic moiety with a strong pharmacological profile, which may act as an important pharmacophore for the drug discovery process. In the struggle to cultivate suitable anti-inflammatory and anticancer agents, chemists have now focused on pyrazole biomolecules. This review conceals the recent expansion of pyrazole biomolecules as anti-inflammatory and anticancer agents with an aim to provide better correlation among different research going around the world.

Silk Fibroin as an Efficient Biomaterial for Drug Delivery, Gene Therapy, and Wound Healing.

Silk fibroin (SF), an organic material obtained from the cocoons of a silkworm Bombyx mori, is used in several applications and has a proven track record in biomedicine owing to its superior compatibility with the human body, superb mechanical characteristics, and its controllable propensity to decay. Due to its robust biocompatibility, less immunogenic, non-toxic, non-carcinogenic, and biodegradable properties, it has been widely used in biological and biomedical fields, including wound healing. The key strategies for building diverse SF-based drug delivery systems are discussed in this review, as well as the most recent ways for developing functionalized SF for controlled or redirected medicines, gene therapy, and wound healing. Understanding the features of SF and the various ways to manipulate its physicochemical and mechanical properties enables the development of more effective drug delivery devices. Drugs are encapsulated in SF-based drug delivery systems to extend their shelf life and control their release, allowing them to travel further across the bloodstream and thus extend their range of operation. Furthermore, due to their tunable properties, SF-based drug delivery systems open up new possibilities for drug delivery, gene therapy, and wound healing.

PI3K/Akt/mTOR Pathways Inhibitors with Potential Prospects in Non-Small-Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related mortality across the globe. The most prevalent pathological form of lung cancer is non-small-cell lung cancer (NSCLC). Elevated stimulation of the PI3K/Akt/mTOR pathway causes a slew of cancer-related symptoms, making it a promising target for new anticancer drugs. The PI3K/Akt/mTOR path is involved extensively in carcinogenesis and disease advancement in NSCLC. Several new inhibitors targeting this pathway have been discovered in preclinical investigations and clinical trials. The etiology and epidemiology of NSCLC and biology of the PI3K/Akt/mTOR cascade and its role in NSCLC pathogenesis have all been discussed in this article. In this article, we've reviewed PI3K/Akt/mTOR cascade inhibitors that have been proven in vitro and in preclinical trials to be effective in NSCLC. Drugs targeting the PI3K/Akt/mTOR path in the treatment of NSCLC were also addressed. A better knowledge of the underlying molecular biology, including epigenetic changes, is also critical to detecting relevant biomarkers and guiding combination methods. Additionally, improved clinical trial designs will increase the capacity to test novel drugs and combinations for accounting for genomic variation and eventually improve patient outcomes.

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain.

Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these two during Mn toxicity has not been fully deduced. The mouse neuroblastoma (N2a) and SD rats are treated with LPS and MnCl2 to evaluate the expression of KHSRP and NLRP3. Further, the effect of the NLRP3 inhibitor MCC950 is checked on the expression of NLRP3, KHSRP and pro-inflammatory markers (TNFα, IL-18 and IL-1ß) as well as the caspase-1 enzyme. Our results demonstrated an increment in NLRP3 and KHSRP expression post-MnCl2 exposure in N2a cells and rat brain, while on the other hand with LPS exposure only NLRP3 expression levels were elevated and KHSRP was found to be unaffected. An increased expression of KHSRP, NLRP3, pro-inflammatory markers and the caspase-1 enzyme was observed to be inhibited with MCC950 treatment in MnCl2-exposed cells and rats. Manganese exposure induces NLRP3 and KHSRP expression to induce neuroinflammation, suggesting a correlation between both which functions in toxicity-related pathways. Furthermore, MCC950 treatment reversed the role of KHSRP from anti-inflammatory to pro-inflammatory.