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In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein reelin (Re + ECLII neurons). In rodents, neurons located at the dorsal extreme of the EC, which border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here, we test two predictions deducible from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since the mitochondrial turnover rate serves as a proxy for energy expenditure, the mitophagy rate arguably also qualifies as such. Because messenger RNA of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) is known to be highly expressed in the EC, we predicted that Bnip3 would be upregulated in Re + ECLII neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, supporting that the energy requirement of Re + ECLII neurons is generally high and that there is a systematic increase in metabolic rate as one moves successively closer to the rhinal fissure. Intriguingly, the systematic variation in energy requirement of the neurons that manifest the observed reelin gradient appears to be consonant with the level of spatial and temporal detail by which they encode information about the external environment. [ABSTRACT FROM AUTHOR]

Background: Sex differences in neuroinflammation could contribute to women's increased risk of Alzheimer's disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further. Methods: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years. Results: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression. Discussion: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction is one of the main symptoms of Werner syndrome (WS); however, the underlying mechanisms remain unclear. Here, we report that loss of WRN accelerates adipogenesis at an early stage both in vitro (stem cells) and in vivo (zebrafish). Moreover, WRN depletion causes a transient upregulation of late-stage of adipocyte-specific genes at an early stage. Methods: In an in vivo study, we generated wrn−/− mutant zebrafish and performed histological stain and Oil Red O staining to assess the fat metabolism. In an in vitro study, we used RNA-seq and ATAC-seq to profile the transcriptional features and chromatin accessibility in WRN depleted adipocytes. Moreover, we performed ChIP-seq to further study the regulatory mechanisms of metabolic dysfunction in WS. Results: Our findings show that mechanistically WRN deficiency causes SMARCA5 upregulation. SMARCA5 is crucial in chromatin remodeling and gene regulation. Additionally, rescuing WRN could normalize SMARCA5 expression and adipocyte differentiation. Moreover, we find that nicotinamide riboside (NR) supplementation restores adipocyte metabolism in both stem cells and zebrafish models. Conclusions: Our findings unravel a new mechanism for the influence of WRN in the early stage of adipogenesis and provide a possible treatment for metabolic dysfunction in WS. These data provide promising insights into potential therapeutics for ageing and ageing-related diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Werner Syndrome (WS) is an autosomal recessive disorder characterized by premature aging due to mutations of the WRN gene. A classical sign in WS patients is short stature, but the underlying mechanisms are not well understood. Here we report that WRN is indispensable for chondrogenesis, which is the engine driving the elongation of bones and determines height. Zebrafish lacking wrn exhibit impairment of bone growth and have shorter body stature. We pinpoint the function of WRN to its helicase domain. We identify short-stature homeobox (SHOX) as a crucial and direct target of WRN and find that the WRN helicase core regulates the transcriptional expression of SHOX via unwinding G-quadruplexes. Consistent with this, shox−/− zebrafish exhibit impaired bone growth, while genetic overexpression of SHOX or shox expression rescues the bone developmental deficiency induced in WRN/wrn-null mutants both in vitro and in vivo. Collectively, we have identified a previously unknown function of WRN in regulating bone development and growth through the transcriptional regulation of SHOX via the WRN helicase domain, thus illuminating a possible approach for new therapeutic strategies. Short stature is a hallmark of Werner Syndrome, but the underlying mechanisms are not well studied. Here they report that WRN regulates bone development and growth by opening SHOX-G-quadruplexes via its helicase activity both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

These works uncovered a relatively comprehensive understanding of aging, and provided future perspectives for research on aging and aging interventions. Almost every cell in the body goes through the process of senescence, and the contribution of senescent cells to the body's unavoidable aging (we coined this "senescaging") cannot be ignored. Keywords: cellular senescence; aging; microenvironments; cellular communications; senescaging EN cellular senescence aging microenvironments cellular communications senescaging 1 3 3 04/14/22 20220411 NES 220411 Aging is expressed as a deterioration and frailty of various tissues, accompanied by dysregulation of the pathways essential for homeostasis, resilience, and maintenance ([1]; [6]; [7]). In recent years, many novel single-cell examination strategies have been constructed such as single-cell mass spectrometry ([13]), single-cell immunometabolic profiling ([2]), and single-cell-based immune cell research ([12]), allowing further exploration in the field of aging. [Extracted from the article]

Background and Objective: Ventricle volume is closely related to hydrocephalus, brain atrophy, Alzheimer's, Parkinson's syndrome, and other diseases. To accurately measure the volume of the ventricles for elderly patients, we use deep learning to establish a systematic and comprehensive automated ventricle segmentation framework. Methods: The study participation included 20 normal elderly people, 20 patients with cerebral atrophy, 64 patients with normal pressure hydrocephalus, and 51 patients with acquired hydrocephalus. Second, get their imaging data through the picture archiving and communication systems (PACS) system. Then use ITK software to manually label participants' ventricular structures. Finally, extract imaging features through machine learning. Results: This automated ventricle segmentation method can be applied not only to CT and MRI images but also to images with different scan slice thicknesses. More importantly, it produces excellent segmentation results (Dice > 0.9). Conclusion: This automated ventricle segmentation method has wide applicability and clinical practicability. It can help clinicians find early disease, diagnose disease, understand the patient's disease progression, and evaluate the patient's treatment effect. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ribosome-inactivating proteins (RIPs) consist of three varieties. Type 1 RIPs are single-chained and approximately 30-kDa in molecular weight. Type 2 RIPs are double-chained and composed of a type 1 RIP chain and a lectin chain. Type III RIPs, such as maize b-32 barley and JIP60 which are produced as single-domain proenzymes, possess an N-terminal domain corresponding to the A domain of RIPs and fused to a C-terminal domain. In addition to the aforementioned three types of RIPs originating from flowering plants, there are recently discovered proteins and peptides with ribosome-inactivating and protein synthesis inhibitory activities but which are endowed with characteristics such as molecular weights distinctive from those of the regular RIPs. These new/unusual RIPs discussed in the present review encompass metazoan RIPs from Anopheles and Culex mosquitos, antimicrobial peptides derived from RIP of the pokeweed Phytolacca dioica, maize RIP (a type III RIP derived from a precursor form), RIPs from the garden pea and the kelp. In addition, RIPs with a molecular weight smaller than those of regular type 1 RIPs are produced by plants in the Cucurbitaceae family including the bitter gourd, bottle gourd, sponge gourd, ridge gourd, wax gourd, hairy gourd, pumpkin, and Chinese cucumber. A small type II RIP from camphor tree (Cinnamomum camphora) seeds and a snake gourd type II RIP with its catalytic chain cleaved into two have been reported. RIPs produced from mushrooms including the golden needle mushroom, king tuber mushroom, straw mushroom, and puffball mushroom are also discussed in addition to a type II RIP from the mushroom Polyporus umbellatus. Bacterial (Spiroplasma) RIPs associated with the fruitfly, Shiga toxin, and Streptomyces coelicolor RIP are also dealt with. The aforementioned proteins display a diversity of molecular weights, amino acid sequences, and mechanisms of action. Some of them are endowed with exploitable antipathogenic activities. [ABSTRACT FROM AUTHOR]

The article presents a study on physicochemical properties and bioactivity of extracts of New Zealand hoki and southern blue whiting roes, which reveals similar protein, moisture and ash contents in both roes; presence of active protease inhibitors toward trypsin and papain; and absence of lectins.

Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response. [ABSTRACT FROM AUTHOR]

Breast cancer ranks as a common and severe neoplasia in women with increasing incidence as well as high risk of metastasis and relapse. Translational and laboratory-based clinical investigations of new/novel drugs are in progress. Medicinal plants are rich sources of biologically active natural products for drug development. The 27-kDa trichosanthin (TCS) is a ribosome inactivating protein purified from tubers of the Chinese herbal plant Trichosanthes kirilowii Maximowicz (common name Tian Hua Fen). In this study, we extended the potential medicinal applications of TCS from HIV, ferticide, hydatidiform moles, invasive moles, to breast cancer. We found that TCS manifested anti-proliferative and apoptosis-inducing activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cells. Flow cytometric analysis disclosed that TCS induced cell cycle arrest. Further studies revealed that TCS-induced tumor cell apoptosis was attributed to activation of both caspase-8 and caspase-9 regulated pathways. The subsequent events including caspase-3 activation, and increased PARP cleavage. With regard to cell morphology, stereotypical apoptotic features were observed. Moreover, in comparison with control, TCS- treated nude mice bearing MDA-MB-231 xenograft tumors exhibited significantly reduced tumor volume and tumor weight, due to the potent effect of TCS on tumor cell apoptosis as determined by the increase of caspase-3 activation, PARP cleavage, and DNA fragmentation using immunohistochemistry. Considering the clinical efficacy and relative safety of TCS on other human diseases, this work opens up new therapeutic avenues for patients with estrogen-dependent and/or estrogen-independent breast cancers. [ABSTRACT FROM AUTHOR]

Abstract: A pumpkin 2S albumin with ribonuclease (RNase) activity was purified from pumpkin seeds (Cucurbita sp.) by liquid chromatographic techniques. It manifested potent RNase activity toward baker’s yeast RNA and calf liver RNA, and some polyhomoribonucleotides, including poly(A), poly(U) and poly(C) but not poly(G). Moreover, it was able to hydrolyze total RNA of both animal and plant origins. Ions such as Na+, Mg2+, Ca2+, and Zn2+ inhibited its RNase activity. Since RNase activity has not been previously reported in 2S albumins, this work may shed further light on the biological importance of this group of proteins. [ABSTRACT FROM AUTHOR]