Mitochondrial Function, Oxidative Stress and Parkinson's Disease

The loss of the activity of mitochondrial respiratory chain (MRC) complexes, particularly complex I, has been implicated in Parkinson’s disease (PD) pathogenesis. However, it is still uncertain whether altered MRC activity is an early event in the pathophysiology of PD, or a late consequence of cellular stress. Therefore, this thesis contributes differently from other studies as to the ongoing investigations about MRC activity in PD post-mortem brain based on pathological severity. This study demonstrates that loss of complex I activity occurs in regions with both moderate and mild pathology in PD brain. Furthermore, multiple complex defects were noted in the moderate pathology region. However, the activity of complex II which is entirely encoded by nuclear DNA appeared to be preserved. The exact mechanism of multiple complex defects remain elusive. However, the possibility arises that impairment of complex I results in secondary damage to the other complexes. Here, neuroblastoma cells were employed to study the effect of pharmacologically induced MRC complex I deficiency upon the activity of the other complexes. In this model, rotenone-treated (100 nM; 24-48 hours) SH-SY5Y cells induced an inhibition of complex I. At 24 hours no effect was observed on the other complexes. However at 48 hours, multiple complex defects were noted, but the activity of complex II appeared to be preserved. Additionally, bioenergetics and glutathione status were compromised. By utilizing this model, the effectiveness of antioxidants in alleviating the progression of complex I deficiency on other complexes were also evaluated. Furthermore, the use of the Oxygraph-2K® instrument together with a step-wise protocol was developed to assess the integrated mitochondrial function in cultured SH-SY5Y cells. Additionally, the focus of attention was also to validate the fibroblast growth factor-21 ELISA assay. Based on the results, this assay appears to be a useful as a biomarker for mitochondrial dysfunction

Origin and Impact of COVID-19 on Socioeconomic Status

The coronavirus pandemic, known as COVID-19, is an evolving pandemic caused by a coronavirus, the SARS-CoV-2. The virus was first detected in Wuhan, China, in December 2019. In January 2020, the World Health Organization (WHO) notified this upsurge as an international emergency concerning public health. It was declared a pandemic later in March 2020. By May 12, 2021, 160,363,284 cases had been registered, and 3,332,762 deaths have been reported, caused by COVID-19, characterized as a horrific pandemic in the history of humankind. Scientists have reached a consensus about the origin of COVID-19, a zoonotic virus arising from bats or other animals in a natural habitat. The economic impact of this outbreak has left far-reaching repercussions on world business transactions, along with bond, commodity, and stock markets. One of the crucial incidents that popped up was the oil price war among OPEC countries. It caused plummeting oil prices and the collapse of stock markets globally in March 2020, as the OPEC agreement failed. However, COVID-19 plays a crucial role in the economic recession. The monetary deficit impact on the travel and trade industries is likely to be huge, in billions of pounds, increasing daily. Other sectors have also suffered significantly

Impact of Male Obesity on Semen Quality and Serum Sex Hormones

Introduction. To investigate the association of high Body Mass Index (BMI) with semen parameters and reproductive hormones in men of reproductive age. Setting. The Saudi Center for Assisted Reproduction. Method. This study was conducted during the period from February 2009 to February 2011. Subjects were exposed through medical history evaluation as well as physical examination. BMI was calculated. Two semen samples about 1 week apart were taken from each participant by masturbation after 2–5 days of abstinence. The samples were assessed according to the WHO Criteria. Blood samples (5 ml) were withdrawn; centrifuged and the resulting sera were preserved at −4 degrees Centigrade. Serum FSH, LH, PRL, and Testosterone levels were estimated by the ELISA method. Results. There was no significant correlation between BMI and any of semen and hormonal parameters. There was significant negative correlation between age and total motility. Only the advanced paternal age has shown significant association with low motility (=0.007). Conclusion. Our study showed a significant effect of aging on sperm motility and concentration

Identification of New Mycobacterium tuberculosis Proteasome Inhibitors Using a Knowledge-Based Computational Screening Approach

Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen. The proteasome is vital to the survival of Mtb and is therefore validated as a potential target for anti-TB therapy. Mtb resistance to existing antibacterial agents has enhanced drastically, becoming a worldwide health issue. Therefore, new potential therapeutic agents need to be developed that can overcome the complications of TB. With this purpose, in the present study, 224,205 natural compounds from the ZINC database have been screened against the catalytic site of Mtb proteasome by the computational approach. The best scoring hits, ZINC3875469, ZINC4076131, and ZINC1883067, demonstrated robust interaction with Mtb proteasome with binding energy values of −7.19, −7.95, and −7.21 kcal/mol for the monomer (K-chain) and −8.05, −9.10, and −7.07 kcal/mol for the dimer (both K and L chains) of the beta subunit, which is relatively higher than that of reference compound HT1171 (−5.83 kcal/mol (monomer) and −5.97 kcal/mol (dimer)). In-depth molecular docking of top-scoring compounds with Mtb proteasome reveals that amino acid residues Thr1, Arg19, Ser20, Thr21, Gln22, Gly23, Asn24, Lys33, Gly47, Asp124, Ala126, Trp129, and Ala180 are crucial in binding. Furthermore, a molecular dynamics study showed steady-state interaction of hit compounds with Mtb proteasome. Computational prediction of physicochemical property assessment showed that these hits are non-toxic and possess good drug-likeness properties. This study proposed that these compounds could be utilized as potential inhibitors of Mtb proteasome to combat TB infection. However, there is a need for further bench work experiments for their validation as inhibitors of Mtb proteasome

Mitochondrial dysfunction is a key pathological driver of early stage Parkinson's

BACKGROUND: The molecular drivers of early sporadic Parkinson’s disease (PD) remain unclear, and the presence of widespread end stage pathology in late disease masks the distinction between primary or causal disease-specific events and late secondary consequences in stressed or dying cells. However, early and mid-stage Parkinson’s brains (Braak stages 3 and 4) exhibit alpha-synuclein inclusions and neuronal loss along a regional gradient of severity, from unaffected-mild-moderate-severe. Here, we exploited this spatial pathological gradient to investigate the molecular drivers of sporadic PD. METHODS: We combined high precision tissue sampling with unbiased large-scale profiling of protein expression across 9 brain regions in Braak stage 3 and 4 PD brains, and controls, and verified these results using targeted proteomic and functional analyses. RESULTS: We demonstrate that the spatio-temporal pathology gradient in early-mid PD brains is mirrored by a biochemical gradient of a changing proteome. Importantly, we identify two key events that occur early in the disease, prior to the occurrence of alpha-synuclein inclusions and neuronal loss: (i) a metabolic switch in the utilisation of energy substrates and energy production in the brain, and (ii) perturbation of the mitochondrial redox state. These changes may contribute to the regional vulnerability of developing alpha-synuclein pathology. Later in the disease, mitochondrial function is affected more severely, whilst mitochondrial metabolism, fatty acid oxidation, and mitochondrial respiration are affected across all brain regions. CONCLUSIONS: Our study provides an in-depth regional profile of the proteome at different stages of PD, and highlights that mitochondrial dysfunction is detectable prior to neuronal loss, and alpha-synuclein fibril deposition, suggesting that mitochondrial dysfunction is one of the key drivers of early disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01424-6

Additional file 2 of Mitochondrial dysfunction is a key pathological driver of early stage Parkinson’s

Additional file 2: Figure S2. Candidates for validation workflow A pie chart showing the proportion of mitochondrial proteins out of the total proteins that were detected. The box outlines the method used to select candidate proteins for validation. The final pie chart shows the proportion of mitochondrial proteins within the list of proteins that were selected for validation