Biofluid GPNMB/osteoactivin as a potential biomarker of ageing: A cross-sectional study.

Background: Glycoprotein non-metastatic melanoma B (GPNMB)/osteoactivin was first identified in the human melanoma cell lines. GPNMB plays a key role in the anti-inflammatory and antioxidative functions as well as osteoblast differentiation, cancer progression, and tissue regeneration. Recently, GPNMB was used as an anti-aging vaccine for mice. The present study aimed to investigate the potential of biofluid GPNMB as an aging biomarker in humans using serum and urine samples from an aging Chinese population. Methods: We analyzed RNA-sequencing data (GSE132040) from 17 murine organs across different ages to assess the gene expression of potential ageing biomarkers. Spearman's correlation coefficients were used to evaluate the relationship between gene expression and age. Meanwhile, a cross-sectional population study was conducted, which included 473 participants (aged 25-91 years), a representative subset of participants from the Peng Zu Study on Healthy Ageing in China (Peng Zu Cohort). Biofluid GPNMB levels were measured by ELISA. The associations of serum and urine GPNMB levels with various clinical and anthropometrical indices were assessed using ANOVA, Kruskal-Wallis H test, and univariate and multivariate linear regression analyses. Results: In mice, the Gpnmb mRNA expression levels showed a significant positive association with age in multiple organs in mice (P < 0.05). In Peng Zu Cohort, biofluid (both serum and urine) GPNMB levels showed a positive correlation with age (P < 0.05). Univariate linear regression analysis revealed that serum GPNMB levels were negatively associated with skeletal muscle mass index (SMI, P < 0.05) and insulin-like growth factor 1 (IGF-1, P < 0.05), and urine GPNMB levels showed a negative association with total bile acids (TBA, P < 0.05). Multivariate linear regression analysis further indicated that serum GPNMB levels negatively correlated with the systemic immune-inflammation index (SII, P < 0.05), and the urine GPNMB levels maintained a negative association with TBA (P < 0.05), additionally, urine GPNMB levels in men were significantly lower than in women (P < 0.05). Conclusions: The biofluid GPNMB was a strong clinical biomarker candidate for estimating biological aging.

Serum glycoprotein non-metastatic melanoma protein B (GPNMB) level as a potential biomarker for diabetes mellitus-related cataract: A cross-sectional study.

Background: Diabetes mellitus (DM), a metabolic disease that has attracted significant research and clinical attention over the years, can affect the eye structure and induce cataract in patients diagnosed with DM. Recent studies have indicated the relationship between glycoprotein non-metastatic melanoma protein B (GPNMB) and DM and DM-related renal dysfunction. However, the role of circulating GPNMB in DM-associated cataract is still unknown. In this study, we explored the potential of serum GPNMB as a biomarker for DM and DM-associated cataract. Methods: A total of 406 subjects were enrolled, including 60 and 346 subjects with and without DM, respectively. The presence of cataract was evaluated and serum GPNMB levels were measured using a commercial enzyme-linked immunosorbent assay kit. Results: Serum GPNMB levels were higher in diabetic individuals and subjects with cataract than in those without DM or cataract. Subjects in the highest GPNMB tertile group were more likely to have metabolic disorder, cataract, and DM. Analysis performed in subjects with DM elucidated the correlation between serum GPNMB levels and cataract. Receiver operating characteristic (ROC) curve analysis also indicated that GPNMB could be used to diagnose DM and cataract. Multivariable logistic regression analysis illustrated that GPNMB levels were independently associated with DM and cataract. DM was also found to be an independent risk factor for cataract. Further surveys revealed the combination of serum GPNMB levels and presence of DM was associated with a more precise identification of cataract than either factor alone. Conclusions: Increased circulating GPNMB levels are associated with DM and cataract and can be used as a biomarker of DM-associated cataract.

Long-Term High-Fat High-Fructose Diet Induces Type 2 Diabetes in Rats through Oxidative Stress.

Long-term consumption of a Western diet is a major cause of type 2 diabetes mellitus (T2DM). However, the effects of diet on pancreatic structure and function remain unclear. Rats fed a high-fat, high-fructose (HFHF) diet were compared with rats fed a normal diet for 3 and 18 months. Plasma biochemical parameters and inflammatory factors were used to reflect metabolic profile and inflammatory status. The rats developed metabolic disorders, and the size of the islets in the pancreas increased after 3 months of HFHF treatment but decreased and became irregular after 18 months. Fasting insulin, C-peptide, proinsulin, and intact proinsulin levels were significantly higher in the HFHF group than those in the age-matched controls. Plasmatic oxidative parameters and nucleic acid oxidation markers (8-oxo-Gsn and 8-oxo-dGsn) became elevated before inflammatory factors, suggesting that the HFHF diet increased the degree of oxidative stress before affecting inflammation. Single-cell RNA sequencing also verified that the transcriptional level of oxidoreductase changed differently in islet subpopulations with aging and long-term HFHF diet. We demonstrated that long-term HFHF diet and aging-associated structural and transcriptomic changes that underlie pancreatic islet functional decay is a possible underlying mechanism of T2DM, and our study could provide new insights to prevent the development of diet-induced T2DM.

Mesencephalic astrocyte-derived neurotrophic factor (MANF): Structure, functions and therapeutic potential.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel evolutionarily conserved protein present in both vertebrate and invertebrate species. MANF shows distinct structural and functional properties than the traditional neurotrophic factors (NTF). MANF is composed of an N-terminal saposin-like lipid-binding domain and a C-terminal SAF-A/B, Acinus and PIAS (SAP) domain connected by a short linker. The two well-described activities of MANF include (1) role as a neurotrophic factor that plays direct neuroprotective effects in the nervous system and (2) cell protective effects in the animal models of non-neuronal diseases, including retinal damage, diabetes mellitus, liver injury, myocardial infarction, nephrotic syndrome, etc. The main objective of the current review is to provide up-to-date insights regarding the structure of MANF, mechanisms regulating its expression and secretion, physiological functions in various tissues and organs, protective effects during aging, and potential clinical applications. Together, this review highlights the importance of MANF in reversing age-related dysfunction and geroprotection.

Biomimetic material degradation for synergistic enhanced therapy by regulating endogenous energy metabolism imaging under hypothermia.

Inefficient tumour treatment approaches often cause fatal tumour metastases. Here, we report a biomimetic multifunctional nanoplatform explicitly engineered with a Co-based metal organic framework polydopamine heterostructure (MOF-PDA), anethole trithione (ADT), and a macrophage membrane. Co-MOF degradation in the tumour microenvironment releases Co2+, which results in the downregulation of HSP90 expression and the inhibition of cellular heat resistance, thereby improving the photothermal therapy effect of PDA. H2S secretion after the enzymatic hydrolysis of ADT leads to high-concentration gas therapy. Moreover, ADT changes the balance between nicotinamide adenine dinucleotide/flavin adenine dinucleotide (NADH/FAD) during tumour glycolysis. ATP synthesis is limited by NADH consumption, which triggers a certain degree of tumour growth inhibition and results in starvation therapy. Potentiated 2D/3D autofluorescence imaging of NADH/FAD is also achieved in liquid nitrogen and employed to efficiently monitor tumour therapy. The developed biomimetic nanoplatform provides an approach to treat orthotopic tumours and inhibit metastasis.

Specific Metabolites Involved in Antioxidation and Mitochondrial Function Are Correlated With Frailty in Elderly Men.

BACKGROUND: As an age-related syndrome, frailty may play a central role in poor health among older adults. Sarcopenia overlaps with the physical domain of frailty, and most existing studies have analyzed the associated factors of frailty and sarcopenia as an isolated state. Perturbations in metabolism may play an important role in the presence of frailty or sarcopenia; however, the metabolites associated with frailty, especially overlapping with sarcopenia remain unclear. In this study, we aimed to explore whether amino acids, carnitines, acylcarnitines and lysophosphatidylcholines, as specific panels, are significantly correlated with frailty, especially overlapping with sarcopenia, to gain insight into potential biomarkers and possible biological mechanisms and to facilitate their management. METHODS: We applied a targeted high-performance liquid chromatography-tandem mass spectrometry approach in serum samples from 246 Chinese older men (age 79.2 ± 7.8 years) with frailty (n = 150), non-frailty (n = 96), frailty and sarcopenia (n = 52), non-frail and non-sarcopenic control (n = 85). Frailty was evaluated using Freid phenotype criteria, sarcopenia was defined by diagnostic algorithm of Asian Working Group on Sarcopenia, and the participants were diagnosed as frailty and sarcopenia when they met the evaluation criteria of both frailty and sarcopenia. A panel of 29 metabolomic profiles was assayed and included different classes of amino acids, carnitines, acylcarnitines, and lysophosphatidylcholines (LPCs). Multivariate logistic regression was used to screen the metabolic factors contributing to frailty status, and orthogonal partial least squares discriminant analysis was used to explore important factors and distinguish different groups. RESULTS: In older men demonstrating the frail phenotype, amino acid perturbations included lower tryptophan and higher glycine levels. With regard to lipid metabolism, the frailty phenotype was characterized by lower concentrations of isovalerylcarnitine (C5), LPC16:0 and LPC18:2, while higher levels of octanoyl-L-carnitine (C8), decanoyl-L-carnitine (C10), dodecanoyl-L-carnitine (C12) and tetradecanoyl-L-carnitine (C14). After adjusting for several clinical confounders, tryptophan, LPC18:2, LPC 16:0 and C5 were negatively correlated with frailty, and C8 and C12 were positively related to frailty. We preliminarily identified metabolic profiles (LPC16:0, LPC18:2, glycine and tryptophan) that may distinguish older men with frailty from those without frailty. Importantly, a set of serum amino acids and LPCs (LPC16:0, LPC18:2, and tryptophan) was characterized in the metabotype of older adults with an overlap of frailty and sarcopenia. The metabolites that were most discriminating of frailty status implied that the underlying mechanism might be involved in antioxidation and mitochondrial dysfunction. CONCLUSIONS: These present metabolic analyses may provide valuable information on the potential biomarkers and possible biological mechanisms of frailty, and overlapping sarcopenia. The findings obtained may offer insight into their management in older adults.

Increased systemic RNA oxidative damage and diagnostic value of RNA oxidative metabolites during Shigella flexneri-induced intestinal infection.

BACKGROUND: Shigella flexneri (S. flexneri) is a major pathogen causing acute intestinal infection, but the systematic oxidative damage incurred during the course of infection has not been investigated. AIM: To investigate the incurred systemic RNA oxidative damage and the diagnostic value of RNA oxidative metabolites during S. flexneri-induced intestinal infection. METHODS: In this study, a Sprague-Dawley rat model of acute intestinal infection was established by oral gavage with S. flexneri strains. The changes in white blood cells (WBCs) and cytokine levels in blood and the inflammatory response in the colon were investigated. We also detected the RNA and DNA oxidation in urine and tissues. RESULTS: S. flexneri infection induced an increase in WBCs, C-reactive protein, interleukin (IL)-6, IL-10, IL-1ß, IL-4, IL-17a, IL-10, and tumor necrosis factor α (TNF-α) in blood. Of note, a significant increase in urinary 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn), an important marker of total RNA oxidation, was detected after intestinal infection (P = 0.03). The urinary 8-oxo-Gsn level returned to the baseline level after recovery from infection. In addition, the results of a correlation analysis showed that urinary 8-oxo-Gsn was positively correlated with the WBC count and the cytokines IL-6, TNF-α, IL-10, IL-1ß, and IL-17α. Further detection of the oxidation in different tissues showed that S. flexneri infection induced RNA oxidative damage in the colon, ileum, liver, spleen, and brain. CONCLUSION: Acute infection induced by S. flexneri causes increased RNA oxidative damage in various tissues (liver, spleen, and brain) and an increase of 8-oxo-Gsn, a urinary metabolite. Urinary 8-oxo-Gsn may be useful as a biomarker for evaluating the severity and prognosis of infection.

Systemic RNA oxidation can be used as a biomarker of infection in challenged with Vibrio parahaemolyticus.

More and more evidence support the concept that RNA oxidation plays a substantial role in the progress of multiple diseases; however, only a few studies have reported RNA oxidation caused by microbial pathogens. Urinary 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGsn), which are broadly used as indicators of oxidative damage of RNA and DNA, were analyzed in this study to determine which can be used as a biomarker of infection in challenged with Vibrio parahaemolyticus (V. parahaemolyticus). In this work, 24 specific-pathogen-free (SPF) male SD rats were randomly divided into two groups: an infection group and a phosphate-buffered saline (PBS) control group. Our results proved that 8-oxo-Gsn rather than 8-oxo-dGsn was significantly increased after challenged with V. parahaemolyticus in urine and tissue samples of SD rats compared with the PBS control group. Simultaneously, white blood cells (WBCs) counts, intestinal inflammation and inflammatory factors (including CRP, IL-6, IL-1ß, TNF-α, IL-10, and IL-17A) were also increased sharply. Which has more clinical value is that the trend of urinary 8-oxo-Gsn was consistent with WBCs, intestinal inflammation and all kinds of inflammatory factors. More importantly is that urinary 8-oxo-Gsn of infection group was positively correlated with WBCs and various inflammatory cytokines. In a word, our results demonstrated that as a systemic RNA oxidation biomarker, we hope 8-oxo-Gsn can be used as a biomarker of the severity of microbial pathogens infection, rather than a specific biomarker of microbial pathogens infection.

The high expression of MTH1 and NUDT5 promotes tumor metastasis and indicates a poor prognosis in patients with non-small-cell lung cancer.

MutT Homolog 1 (MTH1) is a mammalian 8-oxodGTPase for sanitizing oxidative damage to the nucleotide pool. Nudix type 5 (NUDT5) also sanitizes 8-oxodGDP in the nucleotide pool. The role of MTH1 and NUDT5 in non-small-cell lung cancer (NSCLC) progression and metastasis remains unclear. In the present study, we reported that MTH1 and NUDT5 were upregulated in NSCLC cell lines and tissues, and higher levels of MTH1 or NUDT5 were associated with tumor metastasis and a poor prognosis in patients with NSCLC. Their suppression also restrained tumor growth and lung metastasis in vivo and significantly inhibited NSCLC cell migration, invasion, cell proliferation and cell cycle progression while promoting apoptosis in vitro. The opposite effects were observed in vitro following MTH1 or NUDT5 rescue. In addition, the upregulation of MTH1 or NUDT5 enhanced the MAPK pathway and PI3K/AKT activity. Furthermore, MTH1 and NUDT5 induce epithelial-mesenchymal transition both in vitro and in vivo. These results highlight the essential role of MTH1 and NUDT5 in NSCLC tumor tumorigenesis and metastasis as well as their functions as valuable markers of the NSCLC prognosis and potential therapeutic targets.