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Abstract: 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.

There is accumulating evidence that interfering with the basic aging mechanisms can enhance healthy longevity. The interventional/therapeutic strategies targeting multiple aging hallmarks could be more effective than targeting one hallmark. While health-promoting qualities of marine oils have been extensively studied, the underlying molecular mechanisms are not fully understood. Lipid extracts from Antarctic krill are rich in long-chain omega-3 fatty acids choline, and astaxanthin. Here, we used C. elegans and human cells to investigate whether krill oil promotes healthy aging. In a C. elegans model of Parkinson´s disease, we show that krill oil protects dopaminergic neurons from aging-related degeneration, decreases alpha-synuclein aggregation, and improves dopamine-dependent behavior and cognition. Krill oil rewires distinct gene expression programs that contribute to attenuating several aging hallmarks, including oxidative stress, proteotoxic stress, senescence, genomic instability, and mitochondrial dysfunction. Mechanistically, krill oil increases neuronal resilience through temporal transcriptome rewiring to promote anti-oxidative stress and anti-inflammation via healthspan regulating transcription factors such as SNK-1. Moreover, krill oil promotes dopaminergic neuron survival through regulation of synaptic transmission and neuronal functions via PBO-2 and RIM-1. Collectively, krill oil rewires global gene expression programs and promotes healthy aging via abrogating multiple aging hallmarks, suggesting directions for further pre-clinical and clinical explorations.

Supplementary Figures 1-3 from Momordica Charantia Lectin, a Type II Ribosome Inactivating Protein, Exhibits Antitumor Activity toward Human Nasopharyngeal Carcinoma Cells In Vitro and In Vivo

Alzheimer’s disease (AD) is a common and devastating disease characterized by pathological aggregations of beta-amyloid (Aβ) plaques extracellularly, and Tau tangles intracellularly. While our understandings of the aetiologies of AD have greatly expanded over the decades, there is no drug available to stop disease progression. Here, we demonstrate the potential of P. edulis pericarp extract in protecting against Aβ-mediated neurotoxicity in mammalian cells and Caenorhabditis elegans models of AD. We show P. edulis pericarp protects against memory deficit, neuronal loss, and promotes longevity in the Aβ model of AD via stimulation of mitophagy, a selective cellular clearance of damaged and dysfunctional mitochondria. P. edulis pericarp also restores memory and increases neuronal resilience in a C. elegans Tau model of AD. While defective mitophagy-induced accumulation of damaged mitochondria contributes to AD progression, P. edulis pericarp improves mitochondrial homeostasis through NIX/DCT1-dependent mitophagy and SOD3-dependent mitochondrial resilience, both via increased nuclear translocation of the upstream transcriptional regulator FOXO3/DAF-16. Further studies to identify active molecules in P. edulis pericarp that could maintain neuronal mitochondrial homeostasis may enable the development of potential drug candidates for AD.

Nicotinamide adenine dinucleotide (oxidized form, NAD

The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer’s disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention.

Werner syndrome (WS) is an accelerated ageing disease caused by multiple mutations in the gene encoding the Werner DNA helicase (WRN). The major clinical features of WS include wrinkles, grey hair, osteoporosis, and metabolic phenomena such as atherosclerosis, diabetes, and fatty liver, and resemble those seen in normal ageing, but occur earlier, in middle age. Defective DNA repair resulting from mutations in WRN explain the majority of the clinical features of WS, but the underlying mechanisms driving the larger metabolic dysfunction remain elusive. Recent studies in animal models of WS and in WS patient cells and blood samples suggest the involvement of impaired mitophagy, NAD+ depletion, and accumulation of damaged mitochondria in metabolic dysfunction. This mini-review summarizes recent progress in the understanding of the molecular mechanisms of metabolic dysfunction in WS, with the involvement of DNA damage, mitochondrial dysfunction, mitophagy reduction, stem cell impairment, and senescence. Future studies on NAD+ and mitophagy may shed light on potential therapeutic strategies for the WS patients.

This article reviews mushrooms with anti-breast cancer activity. The mushrooms covered which are better known include the following: button mushroom Agaricus bisporus, Brazilian mushroom Agaricus blazei, Amauroderma rugosum, stout camphor fungus Antrodia camphorata, Jew’s ear (black) fungus or black wood ear fungus Auricularia auricula–judae, reishi mushroom or Lingzhi Ganoderma lucidum, Ganoderma sinense, maitake mushroom or sheep’s head mushroom Grifola frondosa, lion’s mane mushroom or monkey head mushroom Hericium erinaceum, brown beech mushroom Hypsizigus marmoreus, sulfur polypore mushroom Laetiporus sulphureus, Lentinula edodes (shiitake mushroom), Phellinus linteus (Japanese “meshimakobu,” Chinese “song gen,” Korean “sanghwang,” American “black hoof mushroom”), abalone mushroom Pleurotus abalonus, king oyster mushroom Pleurotus eryngii, oyster mushroom Pleurotus ostreatus, tuckahoe or Fu Ling Poria cocos, and split gill mushroom Schizophyllum commune. Antineoplastic effectiveness in human clinical trials and mechanism of anticancer action have been reported for Antrodia camphorata, Cordyceps sinensis, Coriolus versicolor, Ganoderma lucidum, Grifola frondosa, and Lentinula edodes.

An outbreak of a novel coronavirus disease (i.e., COVID-19) has been recorded in Wuhan, China since late December 2019, which subsequently became pandemic around the world. Although COVID-19 is an acutely treated disease, it can also be fatal with a risk of fatality of 4.03% in China and the highest of 13.04% in Algeria and 12.67% Italy (as of 8th April 2020). The onset of serious illness may result in death as a consequence of substantial alveolar damage and progressive respiratory failure. Although laboratory testing, e.g., using reverse transcription polymerase chain reaction (RT-PCR), is the golden standard for clinical diagnosis, the tests may produce false negatives. Moreover, under the pandemic situation, shortage of RT-PCR testing resources may also delay the following clinical decision and treatment. Under such circumstances, chest CT imaging has become a valuable tool for both diagnosis and prognosis of COVID-19 patients. In this study, we propose a weakly supervised deep learning strategy for detecting and classifying COVID-19 infection from CT images. The proposed method can minimise the requirements of manual labelling of CT images but still be able to obtain accurate infection detection and distinguish COVID-19 from non-COVID-19 cases. Based on the promising results obtained qualitatively and quantitatively, we can envisage a wide deployment of our developed technique in large-scale clinical studies., 21 pages, 7 figures

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.

Autophagy plays a fundamental role in maintaining intracellular homeostasis and cell survival by degrading damaged and unnecessary subcellular components via the lysosome. Impaired autophagy is evident in otherwise “normal” elderly individuals and patients with neurodegenerative diseases, such as Alzheimer's disease (AD). As the most common type of dementia, AD is an age-associated disease with memory loss as the primary clinical feature as well as extracellular Aβ plaques and intracellular Tau tangles as disease-defining pathological features. Recent studies in animal models of AD, AD patient-derived stem cells, and AD postmortem brain tissues suggest that compromised mitophagy/autophagy plays a causative role in AD progression. Supporting this hypothesis, pharmacological approaches to induce mitophagy/autophagy—e.g., the use of the small natural molecule oxidized nicotinamide adenine dinucleotide (NAD+)—slow AD progression in animal models. This chapter reviews the extant literature on autophagy in AD and covers recent progress on the molecular mechanisms of NAD+-dependent mitophagy/autophagy regulation and mechanisms underlying the anti-AD potential of NAD+. Further studies to define the NAD+-mitophagy/autophagy axis may shed light on novel therapeutics to treat AD and potentially provide insights into other neurodegenerative diseases.

Targeting Nicotinamide adenine dinucleotide (NAD) metabolism has emerged as a promising anti-cancer strategy; we aimed to explore the health benefits of boosting NAD levels with nicotinamide riboside (NR) on hepatocellular carcinoma (HCC). We established three in vivo tumor models, including subcutaneous transplantation tumor model in both Balb/c nude mice (xenograft), C57BL/6J mice (allograft), and hematogenous metastatic neoplasm in nude mice. NR (400 mg/kg bw) was supplied daily in gavage. In-situ tumor growth or noninvasive bioluminescence were measured to evaluate the effect of NR on the HCC process. HepG2 cells were treated with transforming growth factor-β (TGF-β) in the absence/presence of NR in vitro. We found that NR supplementation alleviated malignancy-induced weight loss and metastasis to lung in nude mice in both subcutaneous xenograft and hematogenous metastasis models. NR supplementation decreased metastasis to the bone and liver in the hematogenous metastasis model. NR supplementation also significantly decreased the size of allografted tumors and extended the survival time in C57BL/6J mice. In vitro experiments showed that NR intervention inhibited the migration and invasion of HepG2 cells triggered by TGF-β. In summary, our results supply evidence that boosting NAD levels by supplementing NR alleviates HCC progression and metastasis, which may serve as an effective treatment for the suppression of HCC progression.

Background: The epithelial tight junction is an important intestinal barrier whose disruption can lead to the release of harmful intestinal substances into the circulation and cause damage to systemic injury. The maintenance of intestinal epithelial tight junctions is closely related to energy homeostasis and mitochondrial function. Nicotinamide riboside (NR) is a NAD booster that can enhance mitochondrial biogenesis in liver. However, whether NR can prevent ethanol-induced intestinal barrier dysfunction and the underlying mechanisms remain unclear. Methods: We applied the mouse NIAAA model (chronic plus binge ethanol feeding) and Caco-2 cells to explore the effects of NR on ethanol-induced intestinal barrier dysfunction and the underlying mechanisms. NAD homeostasis and mitochondrial function were measured. In addition, knockdown of SirT1 in Caco-2 cells was further applied to explore the role of SirT1 in the protection of NR. Results: We found that ethanol increased intestinal permeability, increased the release of LPS into the circulation and destroyed the intestinal epithelial barrier structure in mice. NR supplementation attenuated intestinal barrier injury. Both in vivo and in vitro experiments showed that NR attenuated ethanol-induced decreased intestinal tight junction protein expressions and maintained NAD homeostasis. In addition, NR supplementation activated SirT1 activity and increased deacetylation of PGC-1α, and reversed ethanol-induced mitochondrial dysfunction and mitochondrial biogenesis. These effects were diminished with the knockdown of SirT1 in Caco-2 cells. Conclusion: Boosting NAD by NR alleviates ethanol-induced intestinal epithelial barrier damage via protecting mitochondrial function in a SirT1-dependent manner.

NAD+ supplementation has significant benefits in compromised settings, acting largely through improved mitochondrial function and DNA repair. Elevating NAD+ to physiological levels has been shown to improve the function of some adult stem cells, with implications that these changes will lead to sustained improvement of the tissue or system. Here, we examined the effect of elevating NAD+ levels in models with reduced hematopoietic stem cell (HSC) potential, ATM-deficient and aged WT mice, and showed that supplementation of nicotinamide riboside (NR), a NAD+ precursor, improved lymphoid lineage potential during supplementation. In aged mice, this improved lymphoid potential was maintained in competitive transplants and was associated with transcriptional repression of myeloid gene signatures in stem and lineage-committed progenitor cells after NR treatment. However, the altered transcriptional priming of the stem cells toward lymphoid lineages was not sustained in the aged mice after NR removal. These data characterize significant alterations to the lineage potential of functionally compromised HSCs after short-term exposure to NR treatment.

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.

NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer’s, Parkinson’s, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD+-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.

Frailty is a common geriatric syndrome and a risk factor for many diseases, even mortality. However, the specific molecular biomarkers for diagnosis and therapeutic targets of frailty are still lacking. Studies focusing on molecular profiling in the development of frailty will help address this problem and others. Recently, a series of high-throughput “-omics” technologies have been used to measure thousands of dynamic molecules, including genetic, metabolic, microorganic variables and so on. These omics data extend our understanding of the pathological processes that change with frailty. In this review, we introduce frailty syndrome and summarize current advancements in the applications of omics technologies in the field of frailty. Keywords: Frailty, Ageing, Biomarker, Omics, High throughput technologies

Background: Neuronal death is a major hallmark of Alzheimer's disease (AD). Necroptosis, as a programmed necrotic process, is activated in AD. However, what signals and factors initiate necroptosis in AD is largely unknown. Methods: We examined the expression levels of critical molecules in necroptotic signaling pathway by immunohistochemistry (IHC) staining and immunoblotting using brain tissues from AD patients and AD mouse models of APP/PS1 and 5×FAD. We performed brain stereotaxic injection with recombinant TNF-α, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 mice. For in vitro studies, we used TNF-α combined with zVAD-fmk and Smac mimetic to establish neuronal necroptosis models and utilized pharmacological or molecular biological approaches to study the signaling pathways. Results: We find that activated neuronal necroptosis is dependent on upstream TNF-α/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-α stimulation, accumulated p62 recruits RIPK1 and induces its self-oligomerization, and activates downstream RIPK1/RIPK3/MLKL cascade, leading to neuronal necroptosis. Ectopic accumulation of p62 is caused by impaired autophagy flux, which is mediated by UVRAG downregulation during the TNF-α-promoted necroptosis. Notably, UVRAG overexpression inhibits neuronal necroptosis in cell and mouse models of AD. Conclusions: We identify a finely controlled regulation of neuronal necroptosis in AD by coordinated TNF-α signaling, RIPK1/3 activity and autophagy machinery. Strategies that could fine-tune necroptosis and autophagy may bring in promising therapeutics for AD.

DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD+), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer’s disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD.

The entorhinal-hippocampal system contains distinct networks subserving declarative memory. This system is selectively vulnerable to changes of ageing and pathological processes. The entorhinal cortex (EC) is a pivotal component of this memory system since it serves as the interface between the neocortex and the hippocampus. EC is heavily affected by the proteinopathies of Alzheimer’s disease (AD). These appear in a stereotypical spatiotemporal manner and include increased levels of intracellular amyloid-beta Aβ (iAβ), parenchymal deposition of Aβ plaques, and neurofibrillary tangles (NFTs) containing abnormally processed Tau. Increased levels of iAβ and the formation of NFTs are seen very early on in a population of neurons belonging to EC layer II (EC LII), and recent evidence leads us to believe that this population is made up of highly energy-demanding reelin-positive (RE+) projection neurons. Mitochondria are fundamental to the energy supply, metabolism, and plasticity of neurons. Evidence from AD postmortem brain tissues supports the notion that mitochondrial dysfunction is one of the initial pathological events in AD, and this is likely to take place in the vulnerable RE + EC LII neurons. Here we review and discuss these notions, anchored to the anatomy of AD, and formulate a hypothesis attempting to explain the vulnerability of RE + EC LII neurons to the formation of NFTs. We attempt to link impaired mitochondrial clearance to iAβ and signaling involving both apolipoprotein 4 and reelin, and argue for their relevance to the formation of NFTs specifically in RE + EC LII neurons during the prodromal stages of AD. We believe future studies on these interactions holds promise to advance our understanding of AD etiology and provide new ideas for drug development. © 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy remains elusive. Here, we have screened for regulators of PRKN-independent mitophagy using an siRNA library targeting 197 proteins containing lipid interacting domains. We identify Cyclin G-associated kinase (GAK) and Protein Kinase C Delta (PRKCD) as regulators of PRKN-independent mitophagy, with both being dispensable for PRKN-dependent mitophagy and starvation-induced autophagy. We demonstrate that the kinase activity of both GAK and PRKCD are required for efficient mitophagy in vitro, that PRKCD is present on mitochondria, and that PRKCD facilitates recruitment of ULK1/ATG13 to early autophagic structures. Importantly, we demonstrate in vivo relevance for both kinases in the regulation of basal mitophagy. Knockdown of GAK homologue (gakh-1) in C. elegans or knockout of PRKCD homologues in zebrafish led to significant inhibition of basal mitophagy, highlighting the evolutionary relevance of these kinases in mitophagy regulation., The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy remain elusive. Here the authors use an siRNA library to screen lipid-binding proteins, and identify the kinases GAK and PRKCD as positive regulators of PRKN-independent mitophagy.

Biomedical knowledge graphs (KGs), which can help with the understanding of complex biological systems and pathologies, have begun to play a critical role in medical practice and research. However, challenges remain in their embedding and use due to their complex nature and the specific demands of their construction. Existing studies often suffer from problems such as sparse and noisy datasets, insufficient modeling methods and non-uniform evaluation metrics. In this work, we established a comprehensive KG system for the biomedical field in an attempt to bridge the gap. Here, we introduced PharmKG, a multi-relational, attributed biomedical KG, composed of more than 500 000 individual interconnections between genes, drugs and diseases, with 29 relation types over a vocabulary of ~8000 disambiguated entities. Each entity in PharmKG is attached with heterogeneous, domain-specific information obtained from multi-omics data, i.e. gene expression, chemical structure and disease word embedding, while preserving the semantic and biomedical features. For baselines, we offered nine state-of-the-art KG embedding (KGE) approaches and a new biological, intuitive, graph neural network-based KGE method that uses a combination of both global network structure and heterogeneous domain features. Based on the proposed benchmark, we conducted extensive experiments to assess these KGE models using multiple evaluation metrics. Finally, we discussed our observations across various downstream biological tasks and provide insights and guidelines for how to use a KG in biomedicine. We hope that the unprecedented quality and diversity of PharmKG will lead to advances in biomedical KG construction, embedding and application.