Protective Effects of a Dihydrodiazepine Against Endotoxin Shock Through Suppression of TLR4/NF-κB/IRF3 Signaling Pathways.

Sepsis and septic shock are life-threatening systemic inflammatory conditions and among the most frequent causes of morbidity and mortality globally. Preclinical evidence has identified a number of diazepine-based compounds with therapeutic potential in inflammatory diseases. However, the potential anti-inflammatory properties of diazepines in the overwhelming immune response during sepsis have been rarely examined. Thus, the current study aimed to identify a new diazepine compound with therapeutic potential in sepsis. Assessing the inflammatory response of macrophages to Lipopolysaccharides (LPS) in vitro identified 2-[7-(trifluoromethyl)-2,3-dihydro-1H-1,4-diazepin-5-yl]phenol (2-TDDP) as a potential anti-inflammatory agent. It reduced secretion of Interleukin-1ß (IL-1ß), IL-6, IL-12p70, IL-18, Tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), IFN-ß, and increased the secretion of IL-10. In a mouse model of LPS-induced endotoxin shock, 2-TDDP reduced mortality and attenuated inflammation-induced tissue injury in the spleen, liver, kidney, and lung. This was accompanied by reduced serum levels of IL-1ß, IL-6, IL-12p70, TNF-α, IFN-γ, IFN-ß, and increased levels of IL-10. Importantly, 2-TDDP suppressed the Toll-like receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) and TLR4/Interferon regulatory factor 3 (IRF3) signaling pathways through a reduction in the expression of TLR4, Myeloid differentiation primary response 88 (MyD88), P65, and TNF receptor-associated factor 3 (Traf3). Moreover, 2-TDDP suppressed the expression of CD86, Programmed death-ligand 1 (PD-L1) and C5a receptor (C5aR), but not Major histocompatibility complex II (MHCII). Analysis of splenic lymphocyte populations revealed a decrease in the number of CD4+, CD8+, and B cells. Collectively, these findings introduced the dihydrodiazepine 2-TDDP as a new anti-inflammatory agent with potent therapeutic potential in endotoxin shock, paving an avenue for future clinical application.

Co-delivery of oncolytic virus and chemotherapeutic modality: Vincristine against prostate cancer treatment: A potent viro-chemotherapeutic approach.

Prostate cancer is a prevalent carcinoma among males, and conventional treatment options are often limited. Cytotoxic chemotherapy, despite its drawbacks, remains a mainstay. We propose a targeted co-delivery approach using nanoscale delivery units for Oncolytic measles virus (OMV) and vincristine (VC) to enhance treatment efficacy. The HA-coated OMV + VC-loaded TCs nanoformulation is designed for targeted oncolytic activity in prostate cancer. The CD44 expression analysis in prostate cancer cell lines indicates a significantly high expression in PC3 cells. The optimization of nanoformulations using Design of Expert (DOE) is performed, and the preparation and characterization of HA-coated OMV + VC-loaded TCs nanoformulations are detailed showing average particle size 397.2 ± 0.01 nm and polydispersity index 0.122 with zeta potential 19.7 + 0.01 mV. Results demonstrate successful encapsulation efficiency with 2.4 × 106 TCID50/Ml and sustained release of OMV and VC from the nanoformulation for up to 72 h. In vitro, assays reveal potent anticancer activity at 10 ± 0.71% cell viability in PC3 cells compared to 73 ± 0.66% in HPrEC and significant morphological changes at 90 µg/ml in dose and time-dependent manner. The co-formulation showed positive cell death 49.5 ± 0.02% at 50 µg PI/ml in PBS and 54.3% cell cycle arrest at the G2/M phase, 8.1% G0/G1 and 5.7% at S phase, with significant mitochondrial membrane potential (MMP) at 50 µg/ml, as assessed by flow cytometry (FACS). The surface-integrating ligand approach enhances the targeted delivery of the oncolytic virus and chemotherapeutic drug, presenting a potential alternative for prostate cancer treatment and suggested that co-administering VC and OMV in a nanoformulation could improve therapeutic outcomes while reducing chemotherapeutic drug doses.

A pyrazolopyridine as a novel AhR signaling activator with anti-breast cancer properties in vitro and in vivo.

Breast cancer is one of the main causes of malignancy-related deaths globally and has a significant impact on women's quality of life. Despite significant therapeutic advances, there is a medical need for targeted therapies in breast cancer. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor mediates responses to environment stimuli, is emerging as a unique pleiotropic target. Herein, a combined molecular simulation and in vitro investigations identified 3-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine (3FPP) as a novel AhR ligand in T47D and MDA-MB-231 breast cancer cells. Its agonistic effects induced formation of the AhR-AhR nuclear translocator (Arnt) heterodimer and prompted its binding to the penta-nucleotide sequence, called xenobiotic-responsive element (XRE) motif. Moreover, 3FPP augmented the promoter-driven luciferase activities and expression of AhR-regulated genes encoding cytochrome P450 1A1 (CYP1A1) and microRNA (miR)-212/132 cluster. It reduced cell viability, migration, and invasion of both cell lines through AhR signaling. These anticancer properties were concomitant with reduced levels of B-cell lymphoma 2 (BCL-2), SRY-related HMG-box4 (SOX4), snail family zinc finger 2 (SNAI2), and cadherin 2 (CDH2). In vivo, 3FPP suppressed tumor growth and activated AhR signaling in an orthotopic mouse model. In conclusion, our results introduce the fused pyrazolopyridine 3FPP as a novel AhR agonist with AhR-specific anti-breast cancer potential in vitro and in vivo.

Antioxidant activity of Carica papaya & Persea americana fruits against cadmium induced neurotoxicity, nephrotoxicity, and hepatotoxicity in rats with a computational approach.

BACKGROUND: Cadmium is widely reported to interfere with the proper functioning of cells by disrupting cellular redox balance, causing apoptosis, and leading to hepatocellular damage, neurotoxicity, pulmonary edema, cancer, and cardiac and neurodegenerative diseases. Treatment of Cd toxicity with drugs brings undesirable side effects, making it necessary to remove Cd from the body safely without harmful effects. OBJECTIVE: This study aimed to determine how Cd causing malfunctioning of cells could be treated with antioxidant-rich avocado and papaya fruit juices. This work fixated on elucidating and comparing the effects of avocado and papaya fruit juice on Cd-dependent impairment in memory and spatial learning. In addition, various markers of tissue damage, such as the concentration of biomarkers in liver and kidney tissue, the expression of antioxidant enzymes and Cd-induced lipid peroxidation, were analyzed. METHODOLOGY: in silico studies of the phytochemical constituents of avocado and papaya (ligands) were docked against antioxidant enzymes Catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) as macromolecules showed strong hydrogen binding with significant binding capacities. To develop the Cd in vivo model, rats were administered CdCl2 (200 ppm) in drinking water for 7 weeks. After induction of Cd toxicity, rats were post-treated with avocado and papaya (10% w/v each) in a standard diet. After post-treatment, memory and learning were assessed using the Morris water maze behavioural test. Biochemical tests for liver and kidney biomarkers were monitored. To determine the level of ROS, lipid peroxidation was determined by Malondialdehyde (MDA) assay. Gene expression of SOD, CAT and GPx were determined via qRT-PCR. RESULTS: This study demonstrated that Cd accumulation in the liver, kidney and hippocampal tissues was reduced after treatment with avocado and papaya. SOD, CAT and GPX gene expression were upregulated after avocado and papaya juice treatment. Moreover, a comparative analysis between avocado and papaya fruit juices clarified that papaya has more active potential for improving memory and learning, upregulating the expression of antioxidant enzymes, and reducing lipid peroxidation in the liver, kidney, and hippocampus. CONCLUSION: This study suggests that a diet containing papaya and avocado can help treat the lethal effects caused by Cd. Because their active constituents can improve health at the cellular and molecular levels.

Effects of alginates on the growth, haematological, immunity, antioxidant and pro-inflammatory responses of rabbits under high temperature.

Heat stress (HS) is one of the most severe hurdles impacting rabbit growth, immunity, homeostasis, and productivity. Alginate oligosaccharides (AOS) have considerable beneficial effects due to their plausible antioxidant and immune-stimulatory properties. This work was planned to explore the preventive function of AOS as a new bio-feed additive against the harmful effects caused by environmental HS on growing rabbits. Rabbits were allotted in four experimental groups (25 animals in each group) and fed on a basal diet supplemented with 0.0 (AOS0), 50 (AOS50), 100 (AOS100), and 150 (AOS150) mg AOS/kg diet reared under summer conditions. Dietary AOS supplementation improved significantly (P ≤ 0.001) feed conversion rate, while both AOS100 and AOS150 significantly (P ≤ 0.001) enhanced the final body weight and body weight gain. All AOS addition significantly increased nitric oxide and lysosome activity and significantly reduced interferon-gamma (IFNγ) compared with those in the control group. Tumor necrosis factor α (TNFα), interleukin1ß (IL-1ß), myeloperoxidase and protein carbonyl levels were significantly reduced in rabbits fed diets containing AOS (100 and 150 mg/kg) compared with those in the control group under heat stress conditions. In addition, glutathione (GSH) and catalase (CAT) were significantly (P ≤ 0.001) improved with increasing AOS dietary levels compared with the control group. Still, total antioxidant capacity (TAC), malondialdehyde (MDA), hematocrit, mean corpuscular volume (MCV), eosinophils, and lymphocytes did not change. Erythrocyte's indices improved significantly (P ≤ 0.001), while neutrophils and white blood cell counts were decreased by dietary AOS inclusion. Immunological (IgM and IgG) were markedly reduced in AOS-treated groups compared with the control group. The current investigation exemplified that AOS as a novel bio-feed additive that could be an effective strategy to extenuate prejudicial effects in heat-stressed rabbits via enhancing immunity, and antioxidant defence system, further regulating the inflammation cytokines.

Impact of COVID-19 Pandemic Lockdown on the Prognosis, Morbidity, and Mortality of Patients Undergoing Elective and Emergency Abdominal Surgery: A Retrospective Cohort Study in a Tertiary Center, Saudi Arabia.

The SARS-CoV-2 pandemic's main concerns are limiting the spread of infectious diseases and upgrading the delivery of health services, infrastructure, and therapeutic provision. The goal of this retrospective cohort study was to evaluate the emergency experience and delay of elective abdominal surgical intervention at King Abdul-Aziz University Hospital from October 2019 to October 2020, with a focus on post-operative morbidity and mortality before and during the COVID-19 pandemic. This study compares two groups of patients with emergent and elective abdominal surgical procedures between two different periods; the population was divided into two groups: the control group, which included 403 surgical patients, and the lockdown group, which included 253 surgical patients. During the lockdown, surgical activity was reduced by 37.2% (p = 0.014), and patients were more likely to require reoperations and blood transfusions during or after surgery (p= 0.002, 0.021, and 0.018, respectively). During the lockdown period, the average length of stay increased from 3.43 to 5.83 days (p = 0.002), and the patients who developed complications (53.9%) were more than those in the control period (46.1%) (p = 0.001). Our tertiary teaching hospital observed a significant decline in the overall number of surgeries performed during the COVID-19 pandemic and lockdown period. During the lockdown, abdominal surgery was performed only on four patients; they were positive for COVID-19. Three of them underwent exploratory laparotomy; two of the three developed shock post-operative; one patient had colon cancer (ASA score 3), one had colon disease (ASA score 2), and two had perforated bowels (ASA scores 2 and 4, respectively). Two out of four deaths occurred after surgery. Our results showed the impact of the COVID-19 lockdown on surgical care as both 30-day mortality and total morbidity have risen considerably.

miRNAs in Regulation of Tumor Microenvironment, Chemotherapy Resistance, Immunotherapy Modulation and miRNA Therapeutics in Cancer.

miRNAs are 20-22 long nucleotide non-coding ribonucleic acid molecules critical to the modulation of molecular pathways. Immune evasion and the establishment of a suitable tumor microenvironment are two major contributors that support tumor invasion and metastasis. Tumorigenic miRNAs support these two hallmarks by desensitizing important tumor-sensitive regulatory cells such as dendritic cells, M1 macrophages, and T helper cells towards tumors while supporting infiltration and proliferation of immune cells like Treg cells, tumor-associated M2 macrophages that promote self-tolerance and chronic inflammation. miRNAs have a significant role in enhancing the efficacies of immunotherapy treatments like checkpoint blockade therapy, adoptive T cell therapy, and oncolytic virotherapy in cancer. A clear understanding of the role of miRNA can help scientists to formulate better-targeted treatment modalities. miRNA therapeutics have emerged as diverse class of nucleic acid-based molecules that can suppress oncogenic miRNAs and promote the expression of tumor suppressor miRNAs.

Dietary supplementation of Nile tilapia (Oreochromis niloticus) with ß-glucan and/or Bacillus coagulans: Synergistic impacts on performance, immune responses, redox status and expression of some related genes.

A 14-week feeding study was conducted to assess the effects of feed supplementation with prebiotics ß-glucan (BG group) and/or probiotics Bacillus coagulans (BC group) on O. niloticus growth performance, body analysis, intestinal structure, immunological response, and antioxidant status. The fish were equally divided into six groups, as follows: the fish group fed an un-supplemented diet served as a control group; the other fish groups were fed supplemented diets with 0.1 g ß-glucan kg-1; 1 g Bacillus coagulans kg-1; 2 g B. coagulans kg-1; 0.1 g ß-glucan combined with 1 g B. coagulans kg-1; 0.1 g ß-glucan combined with 2 g B. coagulans kg-1. The findings revealed that supplementing B. coagulans and the ß-glucan mixture improved growth performance and feed efficiency parameters (RGR and SGR) more than the other groups. The fish flesh analysis revealed increased crude protein and dry matter content and lower lipid and ash levels in the BG and BC supplemented groups than in the Control group. On the other hand, ß-glucan and B. coagulans supplementation significantly boosted antioxidant activity and immunological responses in serum as determined by CAT, MDA, lysozyme, and phagocytic activity. Dietary ß-glucan and B. coagulans supplementation remarkedly enhanced anterior intestine villus histomorphometry characteristics. Furthermore, B. coagulans, alone or in combination with ß-glucan, could reduce HSP70 and IL-1ß gene expression while increasing IL-8 and GH gene expression. According to the findings, B. coagulans and/or BG increased growth performance by increasing gut health and morphology. Furthermore, ß-glucan and B. coagulans supplementation enhanced Tilapia's body composition, immunological responses, and antioxidant status.

A Very Rare Basidiobolomycosis Case Presented with Cecal Perforation and Concomitant Hepatic Involvement in an Elderly Male Patient: A Case Study.

This is a case report of Basidiobolomycosis in a 65-year-old male patient from Jizan presenting with colonic perforation and concomitant liver involvement from February 2021 to July 2021. To control the infection, the patient underwent colonic resection and segmental liver resection, as well as three antifungal drugs. The treatment was successful, and the condition was completely resolved.

Green synthesis of hyaluronic acid coated, thiolated chitosan nanoparticles for CD44 targeted delivery and sustained release of Cisplatin in cervical carcinoma.

Cervical carcinoma is one of the most prevalent gynecological cancers throughout the world. Cisplatin is used as first line chemotherapy for treatment of cervical cancer, but it comes with plethora of side effects. The aim of this study was to develop hyaluronic acid coated, thiolated chitosan nanocarriers using green synthesis approach, for CD44 targeted delivery and sustained release of Cisplatin in cervical cancer cells. After synthesis through ionic gelation method, Zeta analysis showed that the nanoparticle size was 265.9 nm with a zeta potential of +22.3 mV and .226 PDI. SEM and TEM analysis confirmed the spherical shape and smooth surface of nanoparticles. FTIR and XRD showed the presence of characteristic functional groups, successful encapsulation of drug, and crystalline nature of nanoparticles respectively. Drug loading and entrapment efficiency were calculated to be 70.1% ± 1.2% and 45% ± .28% respectively. Analysis of in vitro drug release kinetics showed that drug release followed the Higuchi model at pH 6.8 and 7.4 and Cisplatin release for up to 72 h confirmed sustained release. In vitro analysis on cervical cancer cells HeLa and normal cervical epithelial cells HCK1T was done through cell morphology analysis, trypan blue assay (concentration range of 10-80 µg/ml), and MTT cytotoxic assay (concentration range of 10-90 µg/ml). The results showed a higher cytotoxic potential of HA coated, thiolated chitosan encapsulated Cisplatin (HA-ThCs-Cis NP) nanoformulation as compared to pure Cisplatin in HeLa while in HCK1T, pure Cisplatin showed much higher toxicity as compared to HA-ThCs-Cis nanoformulation. These findings suggest that CD44 targeted delivery system can be a useful approach to minimize offtarget toxicities, give sustained release and better cellular uptake in cancer cells.