A flavonoid-rich fraction of Euphorbia peplus attenuates hyperglycemia, insulin resistance, and oxidative stress in a type 2 diabetes rat model

Background: Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR) and hyperglycemia. Plants are valuable sources of therapeutic agents for the management of T2D. Euphorbia peplus has been widely used as a traditional medicine for the treatment of various diseases, but its beneficial role in T2D has not been fully explored.Methods: The anti-diabetic efficacy of E. peplus extract (EPE) was studied using rats with T2D induced by high-fat diet (HFD) and streptozotocin (STZ). The diabetic rats received 100, 200, and 400 mg/kg EPE for 4 weeks.Results: Phytochemical fractionation of the aerial parts of E. peplus led to the isolation of seven known flavonoids. Rats with T2D exhibited IR, impaired glucose tolerance, decreased liver hexokinase and glycogen, and upregulated glycogen phosphorylase, glucose-6-phosphatase (G-6-Pase), and fructose-1,6-bisphosphatase (F-1,6-BPase). Treatment with 100, 200, and 400 mg/kg EPE for 4 weeks ameliorated hyperglycemia, IR, liver glycogen, and the activities of carbohydrate-metabolizing enzymes. EPE attenuated dyslipidemia, serum transaminases, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and liver lipid accumulation, nuclear factor (NF)-κB p65, and lipid peroxidation, nitric oxide and enhanced antioxidants. All EPE doses upregulated serum adiponectin and liver peroxisome proliferator-activated receptor γ (PPARγ) in HFD/STZ-induced rats. The isolated flavonoids showed in silico binding affinity toward hexokinase, NF-κB, and PPARγ.Conclusion:E. peplus is rich in flavonoids, and its extract ameliorated IR, hyperglycemia, dyslipidemia, inflammation and redox imbalance, and upregulated adiponectin and PPARγ in rats with T2D

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), interleukin1β (IL-1β), 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.Universidad King Saud, Riad, Arabia Saudita | Ref. RSP2023R439Universidade de Vigo/CISU

Green synthesis of oncolytic Newcastle disease virus-loaded thiolated chitosan nanoformulation for CD44 targeted delivery and sustained release of virus in cervical cancer xenografts

Abstract Background Newcastle disease virus (NDV) Lasota strain has proven oncolytic activity. One shortcoming associated with this treatment modality is the immune neutralization of the virus in body, mediated by natural killer cells and macrophages. This study aims at encapsulating the oncolytic virus in thiolated chitosan nanoparticles, surface functionalized with hyaluronic acid for CD44 targeted delivery and sustained release of NDV in cervical cancer tumors. These nanoparticles were tested for oncolytic potential in HeLa cells and cervical cancer xenograft model. Results NDV-loaded nanoparticles were prepared using TCs concentration of 1.0 mg/mL, HA at 0.5 mg/mL, with a half dose (not less than 500 TCID units) of NDV by using green synthesis approach through ionic gelation method. Viral quantification in nanoparticles was done by TCID50 (50% tissue culture infectious dose) and MOI (multiplicity of infection) determination. Ex vivo NK cell activity was analyzed by quantifying levels of IFN-γ. In vivo analysis was performed on wistar rats, immunocompromised by using ketoconazole (10 mg/kg) and cyclosporin (30 mg/kg) along with 0.1 μg/mL of amoxicillin. WBC profiling on day 7 confirmed immunosuppression, which was followed by tumor implantation. Zeta analysis of NDV nanoparticles showed that nanoparticles are 286.9 nm in size with a zeta potential of 18.1 mV and PDI of 0.241. For estimation of anticancer potential, MTT and trypan blue exclusion assay revealed a higher cytotoxic potential of the encapsulated virus, while TCID50 of HA-TC-NDV was 4.1 as compared to naked NDV virus which had TCID50 of 6.0 on HeLa cells. Histopathology of organs from NDV nanoparticle-treated rats showed syncytia formation in tumors, immunohistochemical analysis showed decrease in expression of TNF-α, COX-II and NF-ƙB which was also confirmed by ELISA. RT-PCR showed high viral copy number in tumor tissue and viral accumulation in lungs and liver. Lower IFN-γ in nanoparticles treated rats showed suppression in immunoreactivity of virus-loaded nanoparticles. Conclusion Our findings suggest that encapsulation of the virus in thiolated chitosan and CD44 targeting enhanced retention and sustained release of the virus in tumors as compared to pure NDV, with increased oncolytic effect both in vitro and in vivo

Evaluation of the anticancer potential of CD44 targeted vincristine nanoformulation in prostate cancer xenograft model: a multi-dynamic approach for advanced pharmacokinetic evaluation

Abstract The in vivo anticancer potential of vincristine (VC) loaded, thiolated chitosan-based nanoformulation (NFs) with an outer hyaluronic acid (VC-loaded in TCs-HA) coating was studied in prostate cancer (PC) xenograft in the immunosuppressed rat model induced by PC3 cell lines. Our previous study has already reported the in vitro efficacy of the said NFs. The ADMET Predictor (TM) Cloud version 10.4.0.5, 64-bit, was used to simulate VC's physicochemical and pharmacokinetic parameters. The percentage of encapsulation efficiency of VC by direct and indirect methods was 81.5 and 90%, respectively. Plasma samples from healthy rats showed improved pharmacokinetic and bioavailability profiles of NFs compared to VC injection via HPLC. The haemolytic analysis of NFs showed two times lesser toxicity to red blood cells. Xenograft rats showed maximum tumour volume up to 235 ± 0.02 mm3 with increased body weight, and it was reduced by 56 ± 0.01 to 107.3 ± 0.03 mm3 during the whole treatment by NFs compared to pure VC. The histopathology of the NFs group showed less malignancy with angiogenesis and significantly less metastasis to the liver and kidney. ELISA showed high expression of apoptotic biomarkers, including Bax, cleaved Caspase 3, and cleaved PARP, while the expression of BCL2, Caspase 3, COX-II, NFκB, and TNF-α was reduced. Immunohistochemical analysis also revealed that post-NF administration, cytoplasmic expressions of TNF-α and COX-II were reduced, as were nuclear expressions of NFκB. Thus, the prepared chemotherapeutic NFs were a comparatively potent oncolytic agent, safe with lesser off-target toxicity, and had an improved pharmacokinetic and bioavailability profile

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

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

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

The melatonin receptor agonist agomelatine protects against acute pancreatitis induced by cadmium by attenuating inflammation and oxidative stress and modulating Nrf2/HO-1 pathway

Pancreatitis is a serious effect of the heavy metal cadmium (Cd) and inflammation and oxidative stress (OS) are implicated in Cd-induced pancreatic injury. This study evaluated the effect of the melatonin receptor agonist agomelatine (AGM) on Cd-induced acute pancreatitis (AP), pointing to its modulatory effect on inflammation, OS, and Nrf2/HO-1 pathway. Rats were supplemented with AGM orally for 14 days and a single injection of cadmium chloride (CdCl2) on day 7. Cd increased serum amylase and lipase and caused pancreatic endocrine and exocrine tissue injury. Malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) were elevated, nuclear factor (NF)-kB p65, inducible NO synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF)-α and CD40 were upregulated, and antioxidants were decreased in the pancreas of Cd-administered rats. AGM ameliorated serum amylase and lipase and pancreatic OS, NF-kB p65, CD40, pro-inflammatory mediators and caspase-3, prevented tissue injury and enhanced antioxidants. AGM downregulated Keap1 and enhanced Nrf2 and HO-1 in the pancreas of Cd-administered rats. In silico findings revealed the binding affinity of AGM with Keap1, HO-1, CD40L and caspase-3. In conclusion, AGM protected against AP induced by Cd by preventing inflammation, OS and apoptosis and modulating Nrf2/HO-1 pathway

Berberine attenuates inflammation and oxidative stress and modulates lymphocyte E-NTPDase in acute hyperlipidemia

Hyperlipidemia is a common clinically encountered health condition worldwide that promotes the development and progression of cardiovascular diseases, including atherosclerosis. Berberine (BBR) is a natural product with acknowledged anti-inflammatory, antioxidant, and metabolic effects. This study evaluated the effect of BBR on lipid alterations, oxidative stress, and inflammatory response in rats with acute hyperlipidemia induced by poloxamer-407 (P-407). Rats were pretreated with BBR (25 and 50 mg/kg) for 14 days and acute hyperlipidemia was induced by a single dose of P-407 (500 mg/kg). BBR ameliorated hypercholesterolemia, hypertriglyceridemia, and plasma lipoproteins in P-407-adminsitered rats. Plasma lipoprotein lipase (LPL) activity was decreased, and hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was enhanced in hyperlipidemic rats. The expression of low-density lipoprotein receptor (LDL-R) and ATP-binding cassette transporter 1 (ABCA1) was downregulated in hyperlipidemic rats. BBR enhanced LPL activity, upregulated LDL-R, and ABCA1, and suppressed HMG-CoA reductase in P-407-administered rats. Pretreatment with BBR ameliorated lipid peroxidation, nitric oxide (NO), pro-inflammatory mediators (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon-γ, IL-4 and IL-18) and enhanced antioxidants. In addition, BBR suppressed lymphocyte ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) as well as NO and TNF-α release by macrophages isolated from normal and hyperlipidemic rats. In silico investigations revealed the binding affinity of BBR toward LPL, HMG-CoA reductase, LDL-R, PSK9, ABCA1, and E-NTPDase. In conclusion, BBR effectively prevented acute hyperlipidemia and its associated inflammatory responses by modulating LPL, cholesterolgenesis, cytokine release, and lymphocyte E-NTPDase and E-ADA. Therefore, BBR is an effective and safe natural compound that might be employed as an adjuvant against hyperlipidemia and its associated inflammation