Hesperetin protects against rotenone-induced motor disability and neurotoxicity via the regulation of SIRT1/NLRP3 signaling.

Rotenone is a pesticide that causes complex I inhibition and is widely known to induce motor disability and experimental Parkinson's disease (PD) in rodents. Evidence suggests a crucial role for sirtuin/nuclear factor-kappaB/nod-like receptor family, pyrin domain-containing 3 (SIRT1/NFκB/NLRP3) signaling and inflammation in PD and rotenone neurotoxicity. Hesperetin (C16H14O6) is a citrus flavonoid with documented anti-inflammatory activity. We investigated the value of hesperetin in delaying rotenone-induced PD in mice and the possible modulation of inflammatory burden. PD was induced in mice via rotenone injections. Groups were assigned as a vehicle, PD, or PD + hesperetin (50 or 100 mg/kg) and compared for the motor function, protein level (by ELISA), and gene expression (by real-time PCR) of the target proteins, histopathology, and immunohistochemistry for tyrosine hydroxylase enzyme. Hesperetin (50 or 100 mg/kg) alleviated the motor disability and the striatal dopamine level and decreased the expression of NLRP3 and NF-κB but increased SIRT1 expression (p < 0.05). Further, it enhanced the neural viability and significantly decreased neural degeneration in the substantia nigra, hippocampus, and cerebral cortex (p < 0.05). Taken together, we propose that hesperetin mediates its neuroprotective function via alleviating modulation of the SIRT1/NFκB/NLRP3 pathway. Therefore, hesperetin might delay the PD progression.

α-Hederin Saponin Augments the Chemopreventive Effect of Cisplatin against Ehrlich Tumors and Bioinformatic Approach Identifying the Role of SDF1/CXCR4/p-AKT-1/NFκB Signaling.

Stromal cell-derived factor-1 (SDF1) and its C-X-C chemokine receptor type 4 receptor (CXCR4) are significant mediators for cancer cells' proliferation, and we studied their expression in Ehrlich solid tumors (ESTs) grown in mice. α-Hederin is a pentacyclic triterpenoid saponin found in Hedera or Nigella species with biological activity that involves suppression of growth of breast cancer cell lines. The aim of this study was to explore the chemopreventive activity of α-hederin with/without cisplatin; this was achieved by measuring the reduction in tumor masses and the downregulation in SDF1/CXCR4/pAKT signaling proteins and nuclear factor kappa B (NFκB). Ehrlich carcinoma cells were injected in four groups of Swiss albino female mice (Group1: EST control group, Group2: EST + α-hederin group, Group3: EST + cisplatin group, and Group4: EST+α-hederin/cisplatin treated group). Tumors were dissected and weighed, one EST was processed for histopathological staining with hematoxylin and eosin (HE), and the second MC was frozen and processed for estimation of signaling proteins. Computational analysis for these target proteins interactions showed direct-ordered interactions. The dissected solid tumors revealed decreases in tumor masses (~21%) and diminished viable tumor regions with significant necrotic surrounds, particularly with the combination regimens. Immunohistochemistry showed reductions (~50%) in intratumoral NFκß in the mouse group that received the combination therapy. The combination treatment lowered the SDF1/CXCR4/p-AKT proteins in ESTs compared to the control. In conclusion, α-hederin augmented the chemotherapeutic potential of cisplatin against ESTs; this effect was at least partly mediated through suppressing the chemokine SDF1/CXCR4/p-AKT/NFκB signaling. Further studies are recommended to verify the chemotherapeutic potential of α-hederin in other breast cancer models.

Metformin suppresses LRG1 and TGFß1/ALK1-induced angiogenesis and protects against ultrastructural changes in rat diabetic nephropathy.

Diabetic nephropathy (DN) has high prevalence and poor prognosis which make it a research priority for scientists. Since metformin, a hypoglycaemic drug, has been found to prolong the survival of mice with DN. This study aims at investigating the molecular mechanisms leading to DN in rats and to explore the role of leucine-rich α-2-glycoprotein-1 (LRG1), activin-like kinase1 (ALK1), and transforming growth factor-ß (TGFß1) in the pathologic alterations seen in DN. The aim was also extended to explore the protective action of metformin against DN in rats and its influence on LRG1and ALK1/TGFß1 induced renal angiogenesis. 24 male rats were used. Rats were assigned as, the vehicle group, the diabetic control group and diabetic + metformin (100 and 200 mg/kg) groups. Kidney samples were processed for histopathology, immunohistochemistry and biochemical analysis. Bioinformatic analysis of studied proteins was done to determine protein-protein interactions. Metformin reduced serum urea and creatinine significantly, decreased the inflammatory cytokine levels and reduced LRG1, TGFß1, ALK1 and vascular endothelial growth factor (VEGF) proteins in rat kidneys. Bioinformatic analysis revealed interactions between the studied proteins. Metformin alleviated the histopathological changes observed in the diabetic rats such as the glomerular surface area and increased Bowman's space diameter. Metformin groups showed decreased VEGF immunostaining compared to diabetic group. Metformin shows promising renoprotective effects in diabetic model that was at least partly mediated by downregulation of LRG1 and TGFß1/ALK1-induced renal angiogenesis. These results further explain the molecular mechanism of metformin in DN management.

Bloodstream infection in cancer patients; susceptibility profiles of the isolated pathogens, at Khartoum Oncology Hospital, Sudan.

Introduction: Bloodstream infection is one of the major causes of mortality in patients with malignancies. This study aimed to determine the local profile of blood culture isolates and their antibiotic sensitivities in febrile neutropenic cancer patients and to decide if any modifications to antibiotics policies are necessary. Methods: This is a cross-sectional study conducted between the first of October to the end of December 2018 at Khartoum Oncology Hospital, Sudan. Blood samples from febrile neutropenic patients were collected for culture. Isolates were identified, and their antimicrobial susceptibility was determined by standard laboratory procedures. Results: Bloodstream infections were confirmed in 12 % (n = 69/569) of total blood cultures. Gram negative bacilli were the dominant causative agents (63.8%) while (36.2%) of infections were caused by gram positive cocci. Escherichia coli was the most common isolate (30.4%).The proportions of resistance among gram negative bacilli were high for cefuroxime, amoxicillin/clavulanic acid, Ceftazidime, and ceftriaxone. Extended-spectrum ß-lactamase producing isolates were identified in 34.1% of the positive cultures. Gram positive cocci showed high resistance to tetracycline, penicillin and erythromycin but were completely sensitive to vancomycin and gentamicin. Most of Staphylococcus aureus isolates were methicillin resistant. Conclusion: Gram negative bacilli were the predominant etiologic agents of bloodstream infections in our patients. Both Gram-positive and Gram-negative bacteria showed high levels of resistance for most of the common antibiotics used for empiric treatment. Regular surveillance to study bacterial resistance patterns must be conducted to modify antibiotics stewardship in our institution.

Evidence of pre-existing active Zika virus circulation in Sudan prior to 2012.

OBJECTIVE: The purpose of this study is to provide the first evidence of Zika virus circulation (ZIK) in Sudan. Zika virus was first isolated in the Zika forest of Uganda in 1947, and in 2016, the World Health Assembly declared it a public health emergency of international concern. The discovery of Zika virus circulation in Sudan came as a secondary finding in a 2012 country-wide yellow fever prevalence study, when laboratory tests were done to exclude cross-reactions between flaviviruses. The study was cross-sectional community-based, with randomly selected participants through multi-stage cluster sampling. A sub-set of samples were tested for the Zika virus using ELISA, and the ones that demonstrated reactive results were subsequently tested by PRNT. RESULTS: The prevalence of Zika IgG antibodies among ELISA-tested samples was 62.7% (59.4 to 66.1, 95% CI), and only one sample was found positive when tested by PRNT. This provided the first documented evidence for the pre-existing circulation of Zika virus circulation in Sudan. This evidence provides the foundation for future research in this field, and further structured studies should be conducted to determine the epidemiology and burden of the disease.