Long noncoding RNAs (CTC-471J1.2, NeST) as epigenetic risk factors of active juvenile lupus nephritis: a case-control study.

BACKGROUND: Measurement of the circulating levels of long-non-coding RNAs (lncRNAs) in lupus nephritis (LN) patients could dramatically explore more insights about the disease pathogenesis. Hence, we aimed to quantify the level of expression of CTC-471J1.2 and NeST in LN patients and to correlate it with the disease activity. METHOD: This case-control study was conducted on a group of children with juvenile LN attending to Mansoura University Children's Hospital (MUCH). Demographics, clinical, and laboratory findings were collected besides the measurement of lncRNAs by quantitative real-time PCR. RESULTS: The expression level of lncRNAs-CTC-471J1.2 was significantly down-regulated in children with active LN versus inactive cases or controls. In contrast, the NeST was significantly up-regulated in active LN cases. A significant correlation was found between CTC-471J1.2 expression and LN activity parameters. Additionally, both lncRNAs showed a reasonable sensitivity and specificity in differentiation of active LN. A regression analysis model revealed that CTC-471J1.2 and NeST were independent predictors of active nephritis. CONCLUSION: The expression level of circulatory lncRNAs-CTC-471J1.2 and NeST can be used as sensitive and specific biomarkers for active LN. Furthermore, both could serve as predictors for nephritis activity.

Genetic association of ACE2 and TMPRSS2 polymorphisms with COVID-19 severity; a single centre study from Egypt.

BACKGROUND: Since the emergence of the COVID-19 infection in China, it has caused considerable morbidity, mortality, and economic burden. It causes the vast majority of clinical manifestations, ranging from mild or even no symptoms to severe respiratory failure. There are many risk factors for severe COVID-19, such as old age, male gender, and associated comorbidities. A major role for genetic factors may exist. The SARS-CoV-2 virus enters the cell primarily through ACE2 receptors. rs2285666 is one of many polymorphisms found in the ACE2 receptor gene. To enable endosome-independent entry into target cells, the transmembrane protease serine-type 2 (TMPRSS2) is necessary to cleave the virus' spike (S) glycoprotein. TMPRSS2 is characterized by an androgen receptor element. The rs12329760 polymorphism in TMPRSS2 may explain different genetic susceptibilities to COVID-19. METHOD: This cross-sectional study was held in Mansoura University Hospitals during the period from June 2020 to April 2022 on patients who had mild and severe COVID-19. Demographic, clinical, and laboratory data were collected, and the TaqMan real-time polymerase chain was used for allelic discrimination in the genotyping of rs2285666 and rs12329760. RESULTS: This study included 317 Egyptian patients, aged from 0.2 to 87 years. Males were 146, while females were 171. They were divided into mild and severe groups (91 and 226 patients, respectively) based on their clinical symptoms. There was a significant association between COVID-19 severity and male gender, hypertension, diabetes mellitus, and high CRP. The genotype and allele frequency distributions of the ACE2 rs2285666 polymorphism showed no significant association with the severity of COVID-19 in both. In contrast, in TMPRSS2 rs12329760 minor T allele and CT, TT genotypes were significantly associated with a reduced likelihood of developing severe COVID-19. CONCLUSION: Our study indicates that the ACE2 rs2285666 polymorphism is not related to the severity of COVID-19, whether genotypes or alleles. In TMPRSS2 rs12329760, the dominant model and T allele showed significantly lower frequencies in severe cases, with a protective effect against severity. The discrepancies with previous results may be due to variations in other ACE2 receptor-related genes, inflammatory mediators, and coagulation indicators. Haplotype blocks and differences in racial makeup must be taken into consideration. Future research should be done to clarify how ethnicity affects these polymorphisms and how other comorbidities combine to have an additive effect.

Renoprotective effect of N-acetylcystein and vitamin E in bisphenol A-induced rat nephrotoxicity; Modulators of Nrf2/ NF-κB and ROS signaling pathway.

BACKGROUND AND AIM OF THE WORK: Bisphenol A (BPA) is a chemical product that is widely used as a plastic precursor. It acts directly on the kidney mitochondria, causing renal dysfunction. N-acetylcysteine is effective in protecting the kidneys from chemical-induced damage. Vitamin E is an antioxidant that protects cells from the damaging effects of free radicals. The aim of this study is to further evaluate and compare NAC and vitamin E to oppose the nephrotoxicity caused by BPA. RESEARCH DESIGN AND METHODS: Forty-two adult male rats were divided into 7 groups:  control, BPA, NAC, vitamin E, BPA plus NAC, BPA plus vitamin E, and combined BPA, NAC and vitamin E. BPA, NAC, vitamin E were given orally at doses of 50 mg/kg, 200 mg/kg, and 1000 mg/kg respectively, for 5 weeks. RESULTS: NAC and vitamin E groups showed improved kidney function tests and alleviated BPA-induced oxidative stress; increased GSH and decreased MDA, NO and iNOS levels. NAC and vitamin E significantly attenuated inflammation; decreased NF-κB and increased IL-4, and Nrf2, in addition there was alleviation of renal histopathology. To some extent, vitamin E administration showed significant improvement. Moreover, combined NAC and vitamin E treatment showed more significance than either NAC or vitamin E separate groups. CONCLUSIONS: This study determined the substantial protective effects of NAC and/or vitamin E in BPA-induced nephrotoxicity through modulation of Nrf2 with subsequent improvement of oxidative stress and inflammation. The alleviation was more significant in combined NAC and vitamin E treatment mainly through their synergistic effect on Nrf2.

Neuroprotective and therapeutic effects of calcitriol in rotenone-induced Parkinson's disease rat model.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Treatment of PD is challenging, as current treatment strategies are only symptomatic and do not stop disease development. Recent studies reported neuroprotective effects of calcitriol in PD through its antioxidant and anti-inflammatory properties. The exact pathomechanisms of PD are not yet fully understood. So, investigation of different molecular pathways is challenging. Sirtuin-1 (Sirt1) modulates multiple physiological processes, including programmed cell death, DNA repair, and inflammation. Furthermore, defective autophagy is considered a key pathomechanism in PD as it eliminates protein aggregation and dysfunctional cell organelles. The present study investigated the involvement of autophagy and Sirt1/NF-κB molecular pathway in rotenone-induced PD and explored the protective and restorative effects of calcitriol through these mechanisms. Therefore, behavioral tests were used to test the effect of calcitriol on motor disability and equilibrium. Furthermore, the histological and neuronal architecture was assessed. The expression of genes encoding neuroinflammation and autophagy markers was determined by qPCR while their protein levels were determined by Western blot analysis and immune-histochemical staining. Our results indicate that behavioral impairments and dopaminergic neuron depletion in the rotenone-induced PD model were improved by calcitriol administration. Furthermore, calcitriol attenuated rotenone-induced neuroinflammation and autophagy dysfunction in PD rats through up-regulation of Sirt1 and LC3 and down-regulation of P62 and NF-κB expression levels. Thus, calcitriol could induce a neuro-protective and restorative effect in the rotenone-induced PD model by modulating autophagy and Sirt1/NF-κB pathway.

Tubulin and Tau: Possible targets for diagnosis of Parkinson's and Alzheimer's diseases.

Neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by progressive neuronal loss and pathological accumulation of some proteins. Developing new biomarkers for both diseases is highly important for the early diagnosis and possible development of neuro-protective strategies. Serum antibodies (AIAs) against neuronal proteins are potential biomarkers for AD and PD that may be formed in response to their release into systemic circulation after brain damage. In the present study, two AIAs (tubulin and tau) were measured in sera of patients of PD and AD, compared to healthy controls. Results showed that both antibodies were elevated in patients with PD and AD compared to match controls. Curiously, the profile of elevation of antibodies was different in both diseases. In PD cases, tubulin and tau AIAs levels were similar. On the other hand, AD patients showed more elevation of tau AIAs compared to tubulin. Our current results suggested that AIAs panel could be able to identify cases with neuro-degeneration when compared with healthy subjects. More interestingly, it is possible to differentiate between PD and AD cases through identifying specific AIAs profile for each neurodegenerative states.

Dual mTORC1/mTORC2 blocker as a possible therapy for tauopathy in cellular model.

Tauopathy comprises a group of disorders caused by abnormal aggregates of tau protein. In these disorders phosphorylated tau protein tends to accumulate inside neuronal cells (soma) instead of the normal axonal distribution of tau. A suggested therapeutic strategy for tauopathy is to induce autophagy to increase the ability to get rid of the unwanted tau aggregates. One of the key controllers of autophagy is mTOR. Blocking mTOR leads to stimulation of autophagy. Recently, unravelling molecular structure of mTOR showed that it is formed of two subunits: mTORC1/C2. So, blocking both subunits of mTOR seems more attractive as it will explore all abilities of mTOR molecule. In the present study, we report using pp242 which is a dual mTORC1/C2 blocker in cellular model of tauopathy using LUHMES cell line. Adding fenazaquin to LUHMES cells induced tauopathy in the form of increased phospho tau aggregates. Moreover, fenazaquin treated cells showed the characteristic somatic redistribution of tau. PP242 use in the present tauopathy model reversed the pathology significantly without observable cellular toxicity for the used dosage of 1000 nM. The present study suggests the possible use of pp242 as a dual mTOR blocker to treat tauopathy.