New insights into the role of berberine against 3-nitropropionic acid-induced striatal neurotoxicity: Possible role of BDNF-TrkB-PI3K/Akt and NF-κB signaling.

Berberine (Berb) is a major alkaloid with potential protective effects against multiple neurological disorders. Nevertheless, its positive effect against 3-nitropropionic acid (3NP) induced Huntington's disease (HD) modulation has not been fully elucidated. Accordingly, this study aimed to assess the possible action mechanisms of Berb against such neurotoxicity using an in vivo rats model pretreated with Berb (100 mg/kg, p.o.) alongisde 3NP (10 mg/kg, i.p.) at the latter 2 weeks to induce HD symptoms. Berb revealed its capacity to partially protect the striatum as mediated via the activation of BDNF-TrkB-PI3K/Akt signaling and amelioration of neuroinflammation status by blocking NF-κB p65 with a concomitant reduction in its downstream cytokines TNF-α and IL-1ß. Moreover, its antioxidant potential was evidenced from induction of Nrf2 and GSH levels concurrent with a reduction in MDA level. Furthermore, Berb anti-apoptotic effect was manifested through the induction of pro-survival protein (Bcl-2) and down-regulation of the apoptosis biomarker (caspase-3). Finally, Berb intake ascertained its striatum protective action by improving the motor and histopathological abnormalities with concomitant dopamine restoration. In conclusion, Berb appears to modulate 3NP-induced neurotoxicity by moderating BDNF-TrkB-PI3K/Akt signaling besides its anti-inflammatory, antioxidant, as well as anti-apoptotic effect.

The role of miRNAs in ovarian cancer pathogenesis and therapeutic resistance - A focus on signaling pathways interplay.

One of the most prevalent and lethal forms of gynecological cancer is ovarian cancer (OC), which is often diagnosed in its latter, deadly stages. The OC's high mortality and heterogeneity impede early identification and primary prevention. Thus, numerous studies have looked for biomarkers in OC tissue and blood samples to help early diagnosis and decrease the mortality rate using microRNAs (miRNAs). The miRNAs are short, noncoding RNAs (ncRNAs) that are typically approximately 22 nucleotides in length and act as oncogenic or tumor suppressors via degrading or impeding target mRNA translation. By regulating cellular activities and signaling pathways, miRNAs promote carcinogenesis and the invasiveness of OC cells. In this review, we explore the function of miRNAs in the pathophysiology of OC, their use as biomarkers, future implications, and the direction of future research. The review also underlines the involvement of miRNAs in the most significant pathways affecting the pathogenesis of OC and their relevance to treatment resistance.

Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation.

In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds (12d, 12f, 12i, 12l, and 13a) displayed high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member 12 l (IC50 = 10.50 µM and 15.21 µM against HepG2 and MCF-7, respectively) had the most promising VEGFR-2 inhibitory activity (IC50 = 97.38 nM). A further biological evaluation revealed that compound 12l could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound 12l could induce apoptosis in HepG2 cells by 35.13%. likely, compound 12l exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that 12l exhibited interactions with the key amino acids in a similar way to sorafenib.

Critical COVID-19 in a pregnant patient who presented in starvation ketoacidosis with a background history of acrorenal syndrome.

A primiparous woman in her late 30s at 28+1 weeks' gestation presented with a 3-day history of abdominal pain, loss of appetite, nausea and vomiting and was diagnosed with starvation ketoacidosis. A routine admission swab returned positive for COVID-19. She had been diagnosed with acrorenal syndrome from birth. Three days post admission, she deteriorated rapidly into respiratory failure requiring intubation and ventilation. She was treated with dexamethasone, prophylactic enoxaparin, a course of piperacillin/tazobactam followed by meropenem and fluconazole and 8 cycles of proning. An emergency caesarean section was performed on day 12 of hospital admission at 29+5 weeks' gestation to improve maternal oxygenation and ventilation. The baby had deformities consistent with acrorenal syndrome but no evidence of COVID-19. She spent 23 days in the intensive care unit. Our case describes an unusual presentation of COVID-19, the challenges in managing critically ill pregnant patients along with a rare background history of acrorenal syndrome.

The clinical value of ficolin-3 gene polymorphism in rheumatic heart disease. An Egyptian adolescents study.

OBJECTIVE: Ficolin-3 is one of the innate immunity molecules that was thought to play a pivotal role in Streptococcus pyogenes autoimmunity and its complications; rheumatic fever (RF) and rheumatic heart disease (RHD). We aimed to disclose if there is an association between ficolin-3 (FCN3) gene polymorphisms (rs4494157 and rs10794501) and RF with or without RHD for the first time in Egyptian adolescents. RESULTS: Serum ficolin-3 level was significantly elevated in patients suffering from RF with and without RHD in comparison with control. Regarding FCN3 gene (rs4494157) polymorphism, a significant correlation was found between the A allele and the susceptibility to RF with or without RHD (OR = 2.93, P = 0.0002 and OR = 2.23, P = 0.008 respectively). Besides, AA homozygous genotype showed a significant association with RHD risk (OR = 3.47, P = 0.026). Patients carrying the A allele (CA + AA) had significantly higher serum ficolin-3 than those carrying the CC genotype (P ˂ 0.0001). While the frequency of (rs10794501) polymorphism revealed no significant differences between the controls and RF patients with or without RHD (OR = 1.43, P = 0.261 and OR = 1.48, P = 0.208 respectively).

Increase of cystathionine-γ-lyase (CSE) during late wound repair: Hydrogen sulfide triggers cytokeratin 10 expression in keratinocytes.

The gaseous mediators nitric oxide (NO), carbon monoxide (CO) and lately also hydrogen sulfide (H2S) have been described to contribute to the interplay of protein type- and lipid mediators in the regulation of wound healing. In particular, the recently reported role of H2S in skin repair remains largely unresolved. Therefore we assessed the expressional kinetics of potential H2S-producing enzymes during undisturbed skin repair: the cystathionine-γ-lyase (CSE), the cystathionine-ß-synthase (CBS) and the 3-mercaptopyruvate sulfurtransferase (MPST). All three enzymes were not transcriptionally induced upon wounding and remained silent through the acute inflammatory and proliferative phase of skin repair. By contrast, CSE expression started to increase significantly at the later stages of healing, when cellular proliferation ceases within the granulation tissue and neoepidermis. The importance of H2S production in late healing phases was supported by a strong induction of otherwise not-induced CBS to complement the loss of CSE function in CSE-deficient mice. Immunohistochemistry revealed hair follicle keratinocytes and basal keratinocytes of the neo-epidermis covering the wound area as sources of CSE expression. Subsequent in vitro studies implicated a role of CSE-derived H2S for keratinocyte differentiation: the H2S-donor GYY4137 markedly increased the Ca2+-triggered expression of the early keratinocyte differentiation markers cytokeratin 10 (CK10) and involucrin (IVN) in cultured human keratinocytes. Here, GYY4137-derived H2S strongly enhanced CK10 expression by increasing the binding of RNA polymerase II to the CK10 promoter.

Nitric oxide mediates prolyl hydroxylase 3 expression in mesangial cells and in glomerulonephritis.

Renal mesangial cells are regarded as main players in glomerular inflammatory diseases. To investigate a possible crosstalk between inflammatory and hypoxia-driven signaling processes, we stimulated cultured mouse mesangial cells with different inflammatory agents and analyzed the expression of prolyl hydroxylase domain containing proteins (PHDs), the main regulators of hypoxia-inducible factor (HIF) stability. Administration of IL-1ß (1 nM) and TNF-α (1 nM), a combination further referred to as cytokine mix (CM), resulted in a fivefold increase in PHD3 but not PHD1 and PHD2 mRNA expression compared to untreated controls. In contrast, a combination of IL-1ß, TNF-α with lipopolysaccharide (10 µg/ml), and interferon-γ (20 ng/ml) designated as CM+ showed a high (60-fold) induction of PHD3 and a moderate (twofold) induction of PHD2 mRNA expression. Interestingly, CM+ but not CM induced the expression of inducible NO synthase and endogenously produced NO was responsible for the immense induction of PHD3 in mesangial cells treated with CM+. We found that CM+ affected PHD3 expression mainly via the NO/HIF axis, whereas PHD3 regulation by CM occurred in a NF-κB-dependent manner. In turn, silencing of PHD3 expression resulted in a decrease in the mRNA expression of ICAM-1, MIP-2, MCP-1, and CXCL-10, which are under control of NF-κB. In a rat model of mesangio-proliferative glomerulonephritis, PHD3 mRNA and protein expression was markedly induced and this effect was nearly abolished when rats were treated with the iNOS-specific inhibitor L-NIL, thus confirming our findings also in vivo. KEY MESSAGE: PHD3 expression induced by cytokines is NF-κB dependent in mesangial cells. Endogenously produced NO further augments PHD3 expression via HIF-1α. PHD3 expression is induced by NO in anti-Thy-1 glomerulonephritis.