[Hydrochemical Characteristics and Formation Mechanism of Groundwater in the Western Region of Hepu Basin, Beihai City].

Beihai City is a typical coastal city where groundwater provides a strong support for social and economic development. Studies on the hydrochemical characteristics and formation mechanism in Beihai City play an important role in the scientific management of water resources and coastal ecological environment protection. In this study, we revealed the main hydrogeochemical processes controlling groundwater quality by means of groundwater survey and water sample collection in the western region of Hepu Basin, Beihai City, combined with hydrochemistry and isotope theories and methods. The results showed that groundwater had the remarkable features of low pH value and low mineralization degree. For pore water, hydrochemistry type by primarily NO3 type water and concentrations of Na+ and Cl- were modestly increased along the flow path. Ca-HCO3, Ca-Cl·HCO3, Ca·Na-HCO3, and Na-Cl·HCO3 types were predominant in fissure water. The groundwater was of meteoric origin, hydrogeochemical evolutions were mainly affected by water-rock interactions, cation exchange, and anthropogenic activities. Na+, K+, and Cl- were mainly derived from evaporite and silicate rocks; Ca2+, Mg2+, HCO3-, and SO42- were from carbonatite and evaporite; and NO3- principally arose from anthropogenic activities. This study suggests that the groundwater pollution prevention and control should be carried out as soon as possible in the area where the NO3 type water occurs to avoid the further deterioration of water quality.

Neuronal survival factor TAFA2 suppresses apoptosis through binding to ADGRL1 and activating cAMP/PKA/CREB/BCL2 signaling pathway.

AIMS: TAFA2, a cytokine specifically expressed in the central nervous system, plays a vital role in neuronal cell survival. TAFA2 deficiency has been correlated to various neurological disorders in mice and humans. However, the underlying mechanism remains elusive, especially its membrane-binding receptor through which TAFA2 functions. This study aimed to identify the specific binding receptor responsible for the anti-apoptotic effects of TAFA2. MAIN METHOD: Co-immunoprecipitation (Co-IP) and quantitative mass spectrometry-based proteomic analysis were employed to identify potential TAFA2 binding proteins in V5 knockin mouse brain lysates. Subsequent validation involved in vitro and in vivo Co-IP and pull-down using specific antibodies. The functional analysis included evaluating the effects of ADGRL1 knockout, overexpression, and Lectin-like domain (Lec) deletion mutant on TAFA2's anti-apoptotic activity and analyzing the intracellular signaling pathways mediated by TAFA2 through ADGRL1. KEY FINDINGS: Our study identified ADGRL1 as a potential receptor for TAFA2, which directly binds to TAFA2 through its lectin-like domain. Overexpression ADGRL1, but not ADGRL1ΔLec, induced apoptosis, which could be effectively suppressed by recombinant TAFA2 (rTAFA2). In ADGRL1-/- cells or re-introducing with ADGRL1ΔLec, responses to rTAFA2 in suppressing cell apoptosis were compromised. Increased cAMP, p-PKA, p-CREB, and BCL2 levels were also observed in response to rTAFA2 treatment, with these responses attenuated in ADGRL1-/- or ADGRL1ΔLec-expressing cells. SIGNIFICANCE: Our results demonstrated that TAFA2 directly binds to the lectin-like domain of ADGRL1, activating cAMP/PKA/CREB/BCL2 signaling pathway, which is crucial in preventing cell death. These results implicate TAFA2 and its receptor ADGRL1 as potential therapeutic targets for neurological disorders.

Smartphone Addiction Among University Students' During the Post-COVID-19 Era: The Role of Emotional Intelligence and Future Anxiety.

OBJECTIVE: Coronavirus disease-2019 (COVID-19) pandemic-related psychological symptoms can lead to smartphone addiction (SPA) risk and other behavioral disorders, thus impacting individuals' mental health and well-being. The present study aims to propose a mediation model to investigate the association between emotional intelligence (EI) and SPA, and the mediating role of future anxiety (FA) during the post-COVID-19 era. METHODS: An online questionnaire including the Emotional Intelligence Scale, the Dark Future Scale, and the Smartphone Addiction Scale among university students from China, was conducted between September 14 and November 22, 2022. Finally, 1,154 valid questionnaires were collected. The reliability and confirmatory factor analysis results showed that all three scales had good reliability and validity. RESULTS: Structural Equation Model demonstrated that EI significantly and negatively influenced SPA (ß=0.211, p<0.001), university students' FA significantly and positively effected SPA (ß=0.315, p<0.001), EI significantly predicted SPA in university students, and FA partially mediated the association between EI and SPA. The mediation effect of FA was 0.110, which accounted for 34.27% of the total effect. Bootstrap results furthermore tested the rigor of the mediating effect. CONCLUSION: These findings broaden our understanding regarding the relationship between EI and SPA and the mediating role of FA, providing new sights for educators on how to reduce the risk of SPA when confronting the ongoing and possible future pandemics.

Type I/type III IFN and related factors regulate JEV infection and BBB endothelial integrity.

BACKGROUND: Japanese encephalitis virus (JEV) remains a predominant cause of Japanese encephalitis (JE) globally. Its infection is usually accompanied by disrupted blood‒brain barrier (BBB) integrity and central nervous system (CNS) inflammation in a poorly understood pathogenesis. Productive JEV infection in brain microvascular endothelial cells (BMECs) is considered the initial event of the virus in penetrating the BBB. Type I/III IFN and related factors have been described as negative regulators in CNS inflammation, whereas their role in JE remains ambiguous. METHODS: RNA-sequencing profiling (RNA-seq), real-time quantitative PCR, enzyme-linked immunosorbent assay, and Western blotting analysis were performed to analyze the gene and protein expression changes between mock- and JEV-infected hBMECs. Bioinformatic tools were used to cluster altered signaling pathway members during JEV infection. The shRNA-mediated immune factor-knockdown hBMECs and the in vitro transwell BBB model were utilized to explore the interrelation between immune factors, as well as between immune factors and BBB endothelial integrity. RESULTS: RNA-Seq data of JEV-infected hBMECs identified 417, 1256, and 2748 differentially expressed genes (DEGs) at 12, 36, and 72 h post-infection (hpi), respectively. The altered genes clustered into distinct pathways in gene ontology (GO) terms and KEGG pathway enrichment analysis, including host antiviral immune defense and endothelial cell leakage. Further investigation revealed that pattern-recognition receptors (PRRs, including TLR3, RIG-I, and MDA5) sensed JEV and initiated IRF/IFN signaling. IFNs triggered the expression of interferon-induced proteins with tetratricopeptide repeats (IFITs) via the JAK/STAT pathway. Distinct PRRs exert different functions in barrier homeostasis, while treatment with IFN (IFN-ß and IFN-λ1) in hBMECs stabilizes the endothelial barrier by alleviating exogenous destruction. Despite the complex interrelationship, IFITs are considered nonessential in the IFN-mediated maintenance of hBMEC barrier integrity. CONCLUSIONS: This research provided the first comprehensive description of the molecular mechanisms of host‒pathogen interplay in hBMECs responding to JEV invasion, in which type I/III IFN and related factors strongly correlated with regulating the hBMEC barrier and restricting JEV infection. This might help with developing an attractive therapeutic strategy in JE.

COVID-19 victimization experience and university students' smartphone addiction: the mediating role of emotional intelligence.

OBJECTIVES: During the post-COVID-19 era, everyone has the risk of contracting the virus and becoming the victims of COVID-19. Examining the relationship between the COVID-19 victimization experience and its effects is more urgent. The aim of present study is to propose a mediation model to investigate the association between COVID-19 victimization experience and smartphone addiction, and the mediating role of emotional intelligence. METHODS: A online questionnaire including the COVID-19 Victimization Experience Scale, the Smartphone Addiction Scale, and the Emotional Intelligence Scale among Chinese university students, were employed in this study. Finally, 1154 valid questionnaires were collected. The reliability and confirmatory factor analysis results showed that all three scales had good reliability and validity. RESULTS: Structural Equation Model (SEM) demonstrated that COVID-19 victimization experience significantly predicted smartphone addiction in university students, and emotional intelligence partially mediated the association between COVID-19 victimization experience and smartphone addiction. Bootstrap results furthermore tested the rigor of the mediating effect. CONCLUSION: COVID-19 victimization experience was a important variables in predicting university students's martphone addiction, and emotional intelligence was a protective factor in decreasing the negative effect of COVID-19 victimization experience on addictive behaviors. It is suggested that instructors should integrate emotional intelligence training programs into mental health courses so as to improve students' emotional intelligence ability.

Stk10 Deficiency in Mice Promotes Tumor Growth by Dysregulating the Tumor Microenvironment.

Serine-threonine kinase 10 (STK10) is a member of the STE20/p21-activated kinase (PAK) family and is predominantly expressed in immune organs. Our previous reports suggested that STK10 participates in the growth and metastasis of prostate cancer via in vitro and in vivo data. However, the correlation between STK10 and the tumor microenvironment (TME) remains unclear. In this study, we assessed the relationship between STK10 and the immune cells in the tumor microenvironment of prostate cancer through bioinformatic analysis, and investigated the role of Stk10 in tumor growth using an Stk10 knockout mouse model. The results showed that STK10 is significantly associated with the tumor-infiltrating immune cells including lymphocytes, neutrophils, macrophages and dendritic cells. The target deletion of host Stk10 results in increased tumor growth, due to decreased activated/effector cytotoxic T lymphocytes (CTLs) and increased vessel density in the TME. In conclusion, we demonstrate that host Stk10 is involved in the host anti-tumor response by modulating the activated tumor-infiltrated CTLs and angiogenesis.

Increased Anxiety-like Behaviors in Adgra1-/- Male But Not Female Mice are Attributable to Elevated Neuron Dendrite Density, Upregulated PSD95 Expression, and Abnormal Activation of the PI3K/AKT/GSK-3ß and MEK/ERK Pathways.

Adhesion G protein-coupled receptor A1 (ADGRA1) belongs to the G protein-coupled receptor (GPCR) family, and its physiological function remains largely unknown. We found that Adgra1 is highly and exclusively expressed in the brain, suggesting that Adgra1 may be involved in the regulation of neurological behaviors including anxiety, depression, learning and memory. To this end, we comprehensively analyzed the potential role of ADGRA1 in the neurobehaviors of mice by comparing Adgra1-/- and their wild-type (wt) littermates. We found that Adgra1-/- male but not female mice exhibited elevated anxiety levels in the open field, elevated plus maze, and light-dark box tests, with normal depression levels in the tail-suspension and forced-swim tests, and comparable learning and memory abilities in the Morris water maze, Y maze, fear condition, and step-down avoidance tests. Further studies showed that ADGRA1 deficiency resulted in higher dendritic branching complexity and spine density as evidenced by elevated expression levels of SYN and PSD95 in amygdalae of male mice. Finally, we found that PI3K/AKT/GSK-3ß and MEK/ERK in amygdalae of Adgra1-deficient male mice were aberrantly activated when compared to wt male mice. Together, our findings reveal an important suppressive role of ADGRA1 in anxiety control and synaptic function by regulating the PI3K/AKT/GSK-3ß and MEK/ERK pathways in amygdalae of male mice, implicating a potential, therapeutic application in novel anti-anxiety drug development.

EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection.

The establishment of Japanese encephalitis virus (JEV) infection in brain microvascular endothelial cells (BMECs) is thought to be a critical step to induce viral encephalitis with compromised blood-brain barrier (BBB), and the mechanisms involved in this process are not completely understood. In this study, we found that epidermal growth factor receptor (EGFR) is related to JEV escape from interferon-related host innate immunity based on a STRING analysis of JEV-infected primary human brain microvascular endothelial cells (hBMECs) and mouse brain. At the early phase of the infection processes, JEV induced the phosphorylation of EGFR. In JEV-infected hBMECs, a rapid internalization of EGFR that co-localizes with the endosomal marker EEA1 occurred. Using specific inhibitors to block EGFR, reduced production of viral particles was observed. Similar results were also found in an EGFR-KO hBMEC cell line. Even though the process of viral infection in attachment and entry was not noticeably influenced, the induction of IFNs in EGFR-KO hBMECs was significantly increased, which may account for the decreased viral production. Further investigation demonstrated that EGFR downstream cascade ERK, but not STAT3, was involved in the antiviral effect of IFNs, and a lowered viral yield was observed by utilizing the specific inhibitor of ERK. Taken together, the results revealed that JEV induces EGFR activation, leading to a suppression of interferon signaling and promotion of viral replication, which could provide a potential target for future therapies for the JEV infection.

RIG-I acts as a tumor suppressor in melanoma via regulating the activation of the MKK/p38MAPK signaling pathway.

Studies have indicated that RIG-I may act as a tumor suppressor and participate in the tumorigenesis of some malignant diseases. However, RIG-I induces distinct cellular responses via different downstream signaling pathways depending on the cell type. To investigate the biological function and underlying molecular mechanism of RIG-I in the tumorigenesis of melanoma, we constructed RIG-I knockout, RIG-I-overexpressing B16-F10 and RIG-I knockdown A375 melanoma cell lines, and analyzed the RIG-I-mediated change in the biological behavior of tumor cells in spontaneous and poly (I:C)-induced RIG-I activation. Cell proliferation, cell cycling, apoptosis and migration were detected by CCK-8 assay, BrdU incorporation assay, Annexin V-PI staining assay and Transwell assay, respectively. In vivo tumorigenicity was evaluated by tumor xenograft growth in nude mice and subsequently by Ki67 staining and TUNEL assays. Furthermore, Western blotting was utilized to explore the underlying mechanism of RIG-I in melanoma cells. Our data showed that RIG-I promotes apoptosis and inhibits proliferation by G1 phase cell cycle arrest in the melanoma cell lines. Mechanistically, RIG-I induced the phosphorylation of p38 MAPK and MAPK kinases MKK3 and MKK4. In conclusion, the current study demonstrated that RIG-I suppressed the development of melanoma by regulating the activity of the MKK/p38 MAPK signaling pathway, which is relevant to research on novel therapeutic targets for this malignant disease.

STK10 knockout inhibits cell migration and promotes cell proliferation via modulating the activity of ERM and p38 MAPK in prostate cancer cells.

Prostate cancer (PCa) is one of the most common types of cancer and is a serious threat to men's health due to the high rate of incidence and metastasis. However, the exact underlying pathology of this malignant disease has yet to be fully elucidated. The ezrin-radixin-moesin (ERM) family of proteins are associated with the development and metastasis of various types of cancer. Serine threonine kinase 10 (STK10) is an ERM kinase that is involved in the activation of ERM proteins and serves essential roles in the aggregation and adhesion of lymphocytes. To evaluate the functional roles of STK10 in the pathogenesis of PCa, a STK10-knockout (KO) DU145 PCa cell line was generated using the CRISPR-Cas9 gene editing system, and the effects of STK10 deletion on tumor biological behaviors were further analyzed. The present data suggested that STK10 KO promoted PCa cell proliferation by inhibiting p38 MAPK activation and suppressed migration primarily via the inhibition of p38 MAPK signaling and ERM protein activation. To the best of our knowledge, this is the first study to provide evidence that STK10 plays important roles in the proliferation and migration of PCa cells, which will be useful for further investigation into the pathogenesis of this disease.

Positional Isomeric Effects on the Optical Properties, Multivalent Glycosidase Inhibition Effect, and Hypoglycemic Effect of Perylene Bisimide-deoxynojirimycin Conjugates.

Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.

ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus-pituitary-thyroid axis in male mice.

Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1-/-) model. The results show that Adgra1-/- male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and ß3-adrenergic receptor (ß3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus-pituitary-thyroid axis. Finally, Adgra1-/- male mice present abnormal activation of PI3K/AKT/GSK3ß and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1-/- female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus-pituitary-thyroid axis by regulating PI3K/AKT/GSK3ß and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance.

Chlorin e6-1,3-diphenylisobenzofuran polymer hybrid nanoparticles for singlet oxygen-detection photodynamic abaltion.

A dual-functional nanosysterm is developed by means of Chlorin e6 (Ce6) as photosensitizer and 1,3-Diphenylisobenzofuran (DPBF) as fluorescent singlet oxygen (1O2) probe. Under 660 nm laser irradiation, Ce6 exhibites efficient 1O2 generation, and subsequently the production of 1O2 is assessed by the ratiometric fluorescence of PFO and DPBF under one-photon and two-photon excitation mode. The nanoparticles with excellent biocompatibility can be internalized into Hela cells and applied for tumor treatment. For intracellular PDT, the nanoparticles perform a high phototoxicity, while the PDT proccess can be evaluated in time by monitoring fluorescence signals of DPBF. This theranostic nanosysterm provides a facile strategy to fabricate 1O2-detection PDT, which can realize accurate and efficient photodynamic therapy based on singlet oxygen detection.

[Hydrogeochemical Investigations of Groundwater in the Lingbei Area, Leizhou Peninsula].

Groundwater is an important source of water supply in the Leizhou Peninsula. In August 2018, five surface water samples, 18 shallow pore water samples, 14 middle-deep pore water samples, and 27 pore fissure water samples were collected in the Lingbei area, the northern part of the Leizhou Peninsula. Major ion concentrations, as well as H, O isotope composition (of δ18O and δ2H) were analyzed. The results show that groundwater pH values, total hardness, concentrations of K+, TDS, Cl-, and SO42- are low, while H2SiO3(aq) and NO3- concentrations are relatively high. For pores and fissures water, hydrochemical types are mainly Mg-Ca-HCO3, Mg-Ca-HCO3-Cl, and Cl- loadings are significantly increased along the flow path. Ca-Cl, Na-Ca-HCO3-Cl, and Na-Ca-Mg-HCO3-Cl types predominate in shallow pore water. For middle-deep pore water, the types are primarily Mg-Ca-HCO3, Na-Ca-Mg-HCO3, K-Na-HCO3-SO4, and concentrations of K+, Na+, Cl-, and SO42- are modestly increased along the flow path. We find that the groundwater is of meteoric origin, groundwater Cl- and Na+ originate from marine atmospheric precipitation, Mg+, Ca2+, and HCO3- are mainly derived from silicate weathering, and NO3- principally arises from chemical fertilizer. Shallow pore water and fissure pore water are affected by evaporation concentration, whereas cation exchange is important for middle-deep pore water. The milligram equivalent ratio of nitrate in groundwater reaches 28.3%. After taking into account the nitrate, 50.85% of the sampling water is NO3 type, and displays a pollution trend. Our results contribute to the sustainable utilization of groundwater in the study area and other similar areas.

Transcriptomic evidence that insulin signalling pathway regulates the ageing of subterranean termite castes.

Insulin is a protein hormone that controls the metabolism of sugar, fat and protein via signal transduction in cells, influencing growth and developmental processes such as reproduction and ageing. From nematodes to fruit flies, rodents and other animals, glucose signalling mechanisms are highly conserved. Reproductive termites (queens and kings) exhibit an extraordinarily long lifespan relative to non-reproductive individuals such as workers, despite being generated from the same genome, thus providing a unique model for the investigation of longevity. The key reason for this molecular mechanism, however, remains unclear. To clarify the molecular mechanism underlying this phenomenon, we sequenced the transcriptomes of the primary kings (PKs), primary queens (PQs), male (WMs) and female (WFs) workers of the lower subterranean termite Reticulitermes chinensis. We performed RNA sequencing and identified 33 insulin signalling pathway-related genes in R. chinensis. RT-qPCR analyses revealed that EIF4E and RPS6 genes were highly expressed in WMs and WFs workers, while mTOR expression was lower in PKs and PQs than in WMs and WFs. PQs and PKs exhibited lower expression of akt2-a than female workers. As the highly conserved insulin signalling pathway can significantly prolong the healthspan and lifespan, so we infer that the insulin signalling pathway regulates ageing in the subterranean termite R. chinensis. Further studies are recommended to reveal the biological function of insulin signalling pathway-related genes in the survival of termites to provide new insights into biomolecular homeostasis maintenance and its relationship to remarkable longevity.

Knockout of STK10 promotes the migration and invasion of cervical cancer cells.

BACKGROUND: Serine threonine kinase 10 (STK10) is an ERM kinase involved in the activation of ERM proteins and plays an essential role in the aggregation and adhesion of lymphocytes. STK10 is expressed in about 17 cancer types, including cervical cancer. Cervical cancer is the fourth most common cancer that seriously threatens women's health worldwide. Previous studies have shown that STK10 may affect LFA-1-mediated cell adhesion. Other studies reported a mutation (R634H) of STK10 detected in peripheral T-cell lymphoma. This study aimed to evaluate the functional roles of STK10 in the pathogenesis of cervical cancer. METHODS: We generated STK10 knockout cervical cancer cell lines using the CRISPR-Cas9 gene-editing system, and further analyzed the effects of STK10 deficiency on tumor biological behaviors. The proliferation, apoptosis, migration and invasive activity of these cells were respectively detected by BrdU incorporation, AnnexinV/propidium iodide (PI) staining, wound healing assay and Transwell assays without and with Matrigel. The phosphorylation and expression level of indicated proteins were analyzed by Western blot. The differential expression genes between STK10 knockout and control cells were identified by RNA-seq analysis and further confirmed using qRT-PCR. RESULTS: Our data revealed that target deletion of STK10 does not affect cell proliferation and apoptosis, but promotes the adhesion, migration, and invasion of cervical cancer cells. Most strikingly, the phosphorylation and expression level of ezrin and other ERM proteins in STK10 knockout cells was comparable with that in the control cells. Further, RNA-seq analysis indicated that the knockout of STK10 resulted in a profound alteration of gene expression in cervical cancer cells. CONCLUSIONS: This is the first study to provide evidence that STK10 executes various physiological functions in addition to phosphorylation of ERM proteins, and plays a vital role in the migration and invasion of cervical cancer cells.

Zinc Deficiency Promoted Fibrosis via ROS and TIMP/MMPs in the Myocardium of Mice.

Zinc (Zn) is an important trace element in the body that has antioxidant effects. It has been proven that Zn deficiency can cause oxidative stress. The purpose of the present study was to clarify the effect and mechanism of Zn deficiency on myocardial fibrosis. Mice were fed with different Zn levels dietary for 9 weeks: Zn-normal group (ZnN, 34 mg Zn/kg), Zn-deficient group (ZnD, 2 mg Zn/kg), and Zn-adequate group (ZnA, 100 mg Zn/kg). We found that the Zn-deficient diet reduced the Zn concentration in myocardial tissue. Moreover, the TUNEL results demonstrated that cardiomyocytes in the ZnD group died in large numbers. Furthermore, ROS levels were significantly increased, and metallothionein (MT) expression levels decreased in the ZnD group. The results of Sirius Red staining indicated an increase in collagen in the ZnD group. Moreover, the ELISA results showed that collagen I, III, and IV and fibronectin (FN) were increased. In addition, the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) was detected by RT-qPCR. The results showed that the expression of TIMP-1 in the ZnD group was increased, while MMPs were decreased. Immunohistochemical results showed an increase in the content of α-smooth muscle actin (α-SMA), while H&E staining showed an increase in interstitial width and a decrease in the number of cardiac cells. All data suggest that Zn deficiency enhances the oxidative stress response of myocardial tissue and eventually triggers myocardial fibrosis.

Zinc Deficiency Induces Oxidative Damage and Causes Spleen Fibrosis.

Zinc (Zn) is an essential trace element for animals. Zn controls the action of more than 300 enzymes and plays an important role in the regulation of gene expression. Evidence has shown that Zn has an antioxidant function, and oxidative damage can occur with Zn deficiency. To assess the effect of Zn deficiency-induced spleen fibrosis, Zn-deficient mice, normal mice, and high-Zn mice were generated and assessed. The Zn content of the spleen in each group was determined, and histopathological examination of the spleens of each group was performed. In the film, we found that the spleens of the Zn-deficient group had high levels of proteinaceous material exudation, interstitial broadening, and lymphocyte reduction, with increased collagen, α-SMA expression, antioxidants, and oxygen free radicals. Zn deficiency inhibited the expression of antioxidants in mice, and the activity of oxygen free radicals in Zn-deficient mice was increased. The detection of α-SMA, collagen 1, and TGF-ß by fluorescence quantitative PCR revealed that the expression index increased in Zn-deficient mice. In addition, to verify the effect of Zn deficiency on the extracellular matrix (ECM) regulatory system, MMPs were determined by real-time PCR, and the expression in the Zn deficiency group was lower than that in the normal group and high-Zn group. The MMP-2 and MMP-13 analyses showed that the expression of the high-Zn group was significantly higher than that of the normal group, indicating that Zn plays an important role in its expression. The above experimental analysis showed that Zn deficiency induces oxygen free radical damage, which further leads to spleen fibrosis.

2-Aminoadipic acid protects against obesity and diabetes.

Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorders. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreased fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1-/- mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to DIO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by ß3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating ß3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes.