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Summary: Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA-deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD+-SIRT1-PGC-1α axis triggered by hyperactivation of the DNA damage sensor PARP-1. This phenotype is rescued by PARP-1 inhibition or by supplementation with NAD+ precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a nuclear-mitochondrial crosstalk that is critical for the maintenance of mitochondrial health. [ABSTRACT FROM AUTHOR]

Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD + precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes., Competing Interests: Competing Interests: E.F.F. has a CRADA arrangement with ChromaDex (USA) and a commercialization agreement with Molecule AG/VITADAO and is consultant to Aladdin Healthcare Technologies (UK and Germany), the Vancouver Dementia Prevention Centre (Canada), Intellectual Labs (Norway), and MindRank AI (China). All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The author(s).)

Mitochondria are the main sites of energy production and a major source of metabolic stress. Not surprisingly, impairment of mitochondrial homeostasis is strongly associated with the development and progression of a broad spectrum of human pathologies, including neurodegenerative disorders. Mitophagy mediates the selective degradation of damaged organelles, thus promoting cellular viability and tissue integrity. Defective mitophagy triggers cellular senescence and prolonged neuroinflammation, leading eventually to cell death and brain homeostasis collapse. Here, we survey the intricate interplay between mitophagy and neuroinflammation, highlighting that mitophagy can be a focal point for therapeutic interventions to tackle neurodegeneration., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nicotinamide adenine dinucleotide (oxidized form, NAD + ) is a critical coenzyme, with functions ranging from redox reactions and energy metabolism in mitochondrial respiration and oxidative phosphorylation to being a central player in multiple cellular signaling pathways, organ resilience, health, and longevity. Many of its cellular functions are executed via serving as a co-substrate for sirtuins (SIRTs), poly (ADP-ribose) polymerases (PARPs), and CD38. Kidney damage and diseases are common in the general population, especially in elderly persons and diabetic patients. While NAD + is reduced in acute kidney injury (AKI) and chronic kidney disease (CKD), mounting evidence indicates that NAD + augmentation is beneficial to AKI, although conflicting results exist for cases of CKD. Here, we review recent progress in the field of NAD + , mainly focusing on compromised NAD + levels in AKI and its effect on essential cellular pathways, such as mitochondrial dysfunction, compromised autophagy, and low expression of the aging biomarker αKlotho (Klotho) in the kidney. We also review the compromised NAD + levels in renal fibrosis and senescence cells in the case of CKD. As there is an urgent need for more effective treatments for patients with injured kidneys, further studies on NAD + in relation to AKI/CKD may shed light on novel therapeutics.

We identified SARS-CoV-2 specific antigen epitopes by HLA-A2 binding affinity analysis and characterized their ability to activate T cells. As the pandemic continues, variations in SARS-CoV-2 virus strains have been found in many countries. In this study, we directly assess the immune response to SARS-CoV-2 epitope variants. We first predicted potential HLA-A*02:01-restricted CD8 + T-cell epitopes of SARS-CoV-2. Using the T2 cell model, HLA-A*02:01-restricted T-cell epitopes were screened for their binding affinity and ability to activate T cells. Subsequently, we examined the identified epitope variations and analyzed their impact on immune response. Here, we identified specific HLA-A2-restricted T-cell epitopes in the spike protein of SARS-CoV-2. Seven epitope peptides were confirmed to bind with HLA-A*02:01 and potentially be presented by antigen-presenting cells to induce host immune responses. Tetramers containing these peptides could interact with specific CD8 + T cells from convalescent COVID-19 patients, and one dominant epitope (n-Sp1) was defined. These epitopes could activate and generate epitope-specific T cells in vitro , and those activated T cells showed cytolytic activity toward target cells. Meanwhile, n-Sp1 epitope variant 5L>F significantly decreased the proportion of specific T-cell activation; n-Sp1 epitope 8L>V variant showed significantly reduced binding to HLA-A*02:01 and decreased proportion of n-Sp1-specific CD8 + T cell, which potentially contributes to the immune escape of SARS-CoV-2. Our data indicate that the variation of a dominant epitope will cause the deficiency of HLA-A*02:01 binding and T-cell activation, which subsequently requires the formation of a new CD8 + T-cell immune response in COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qiu, Xiao, Wang, Zhu, Mao, Chen, Gao, Deng, Su, Su, Fang, Zhang, Zhang, Xie, Yuan, Luo, Huang, Wang and Chen.)

Neurodegenerative diseases are highly debilitating illnesses and a growing cause of morbidity and mortality worldwide. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes underlying neurodegeneration. Defective mitophagy has been highlighted as the cause of the accumulation of damaged mitochondria, which consequently leads to cellular dysfunction and/or death in neurodegenerative diseases. Here, we highlight the recent advances in the molecular mechanisms of mitochondrial homeostasis and mitophagy in neurodegenerative diseases. In particular, we evaluate how mitophagy is altered in Alzheimer's, Parkinson's, and Huntington's diseases, as well as in amyotrophic lateral sclerosis, and the potential of restoring mitophagy as a therapeutic intervention. We also discuss the interlinked connections between mitophagy and innate immunity (e.g., the involvement of Parkin, interferons and TRIM21) as well as the opportunity these pathways provide to develop combinational therapeutic strategies targeting them and related molecular mechanisms in such neurodegenerative diseases., Competing Interests: Declaration of interests E.F.F. has CRADA arrangements with ChromaDex and is consultant to Aladdin Healthcare Technologies and Vancouver Dementia Prevention Centre., (© 2020 Elsevier Inc. All rights reserved.)

Lectins have been reported from various tissues of a diversity of fish species including Japanese eel, conger eel, electric eel, bighead carp, gibel carp, grass carp, Arabian Gulf catfish, channel catfish, blue catfish, catfish, pike perch, perch, powan, zebrafish, toxic moray, cobia fish, steelhead trout, Japanese trout, Atlantic salmon, chinook salmon, olive rainbow smelt, rainbow smelt, white-spotted charr, tilapia, blue gourami, ayu, Potca fish, Spanish mackerel, gilt head bream, tench, roach, rudd, common skate, and sea lamprey. The tissues from which the lectins were isolated comprise gills, eggs, electric organ, stomach, intestine, and liver. Lectins have also been isolated from skin, mucus serum, and plasma. The lectins differ in molecular weight, number of subunits, glycosylation, sugar binding specificity and amino acid sequence. Their activities include antimicrobial, antitumor, immunoregulatory and a role in development.

A 64-kDa hemagglutinin from a Phaseolus vulgaris cultivar, the northeast red bean, was purified by a protocol composed of three chromatographic steps involving affinity chromatography on Affi-gel blue gel, cation exchange chromatography on SP-Sepharose and FPLC-gel filtration on Superdex 75. The purified hemagglutinin appeared as a single 32-kDa band in SDS-PAGE indicating its dimeric nature. The N-terminal amino acid sequence of the hemagglutinin resembled the sequences of lectins and hemagglutinins from a number of Phaseolus species. The hemagglutinin manifested moderate thermostability and pH stability. It retained full activity up to 65 °C and in the pH range 2-12. It did not interact with simple sugars such as glucose, mannose and galactose. The hemagglutinin exerted immunostimulatory effects by upregulating the expression of cytokines like interferon-γ and tumor necrosis factor-α. It also exhibited antiproliferative activity on a number of tumor cells including MCF7 (breast cancer), HepG2 (liver cancer), CNE1 and CNE2 (nasopharyngeal cancer) cells, with stronger activity toward MCF7 and CNE1 cells. The hemagglutinin induced phophatidylserine externalization, mitochondrial depolarization and DNA condensation in MCF7 cells, indicating initiation of apoptosis. However, at high hemagglutinin concentrations, severe damage to the MCF7 cells was detected., Competing Interests: The authors confirm that this article content has no conflict of interest.

A new 15-kDa Bowman-Birk type trypsin inhibitor (termed VFTI-G1) was isolated from the seeds of Faba bean (Vicia faba cv. Giza 843) using cation exchange chromatography on an SP-Sepharose column, anion exchange chromatography on Q-Sepharose and Mono Q columns, and finally size exclusion chromatography on a Superdex 75 column. VFTI-G1 manifested significant antiproteolytic activity against trypsin (5761 BAEE units/mg, K(i) 20.4 × 10(-9) M), but only a slight chymotrypsin inhibitory activity (< 10 BTEE units/mg). The suitable environment to sustain its trypsin inhibitory activity was at temperatures below 60 °C and at pH 7. Its trypsin inhibitory activity was inhibited by the reducing agent dithiothreitol in a dose-dependent manner, indicating the significance of intact disulfide bonds to the trypsin inhibitory activity. It inhibited HIV-1 reverse transcriptase (RT) activity with an IC(50) of about 0.76 µM. Furthermore, VFTI-G1 showed specific antiproliferative activity toward HepG2 hepatoma cells by inducing chromatin condensation and cell apoptosis. The HIV-1 RT inhibitory activity of VFTI-G1 and its specific antiproliferative activity toward Hep G2 cells may find medical applications.