LncRNA RPL29P2 promotes peritoneal fibrosis and impairs peritoneal transport function via miR-1184 in peritoneal dialysis.

Peritoneal dialysis (PD), hemodialysis and kidney transplantation are the three therapies to treat uremia. However, PD is discontinued for peritoneal membrane fibrosis (PMF) and loss of peritoneal transport function (PTF) due to damage from high concentrations of glucose in PD fluids (PDFs). The mechanism behind PMF is unclear, and there are no available biomarkers for the evaluation of PMF and PTF. Using microarray screening, we found that a new long noncoding RNA (lncRNA), RPL29P2, was upregulated in the PM (peritoneal membrane) of long-term PD patients, and its expression level was correlated with PMF severity and the PTF loss. In vitro and rat model assays suggested that lncRNA RPL29P2 targets miR-1184 and induces the expression of collagen type I alpha 1 chain (COL1A1). Silencing RPL29P2 in the PD rat model might suppress the HG-induced phenotypic transition of Human peritoneal mesothelial cells (HPMCs), alleviate HG-induced fibrosis and prevent the loss of PTF. Overall, our findings revealed that lncRNA RPL29P2, which targets miR-1184 and collagen, may represent a useful marker and therapeutic target of PMF in PD patients.

The design of small-molecule prodrugs and activatable phototherapeutics for cancer therapy.

Cancer remains as one of the most significant health problems, with approximately 19 million people diagnosed worldwide each year. Chemotherapy is a routinely used method to treat cancer patients. However, current treatment options lack the appropriate selectivity for cancer cells, are prone to resistance mechanisms, and are plagued with dose-limiting toxicities. As such, researchers have devoted their attention to developing prodrug-based strategies that have the potential to overcome these limitations. This tutorial review highlights recently developed prodrug strategies for cancer therapy. Prodrug examples that provide an integrated diagnostic (fluorescent, photoacoustic, and magnetic resonance imaging) response, which are referred to as theranostics, are also discussed. Owing to the non-invasive nature of light (and X-rays), we have discussed external excitation prodrug strategies as well as examples of activatable photosensitizers that enhance the precision of photodynamic therapy/photothermal therapy. Activatable photosensitizers/photothermal agents can be seen as analogous to prodrugs, with their phototherapeutic properties at a specific wavelength activated in the presence of disease-related biomarkers. We discuss each design strategy and illustrate the importance of targeting biomarkers specific to the tumour microenvironment and biomarkers that are known to be overexpressed within cancer cells. Moreover, we discuss the advantages of each approach and highlight their inherent limitations. We hope in doing so, the reader will appreciate the current challenges and available opportunities in the field and inspire subsequent generations to pursue this crucial area of cancer research.

Malnutrition and cerebral intraparenchymal damage in patients with thrombosis of dural sinuses and/or cerebral veins.

BACKGROUNDS: Thrombosis of dural sinuses and/or cerebral veins (CVT) is an uncommon form of cerebrovascular disease. Malnutrition is common in patients with cerebrovascular disease, and early assessment of malnutrition and individualized nutritional treatment have been reported to improve functional outcomes of these patients. As for CVT patients, little is known about whether these patients would suffer from malnutrition. Also, the correlation between malnutrition and cerebral intraparenchymal damage (CID) in CVT patients was rarely studied. METHODS: Patients with CVT were retrospectively included in this observational study. Multivariate logistic regressions were used to investigate the effects of nutritional indexes on the risk of CID. Subsequently, we used the independent risk factors to construct the nomogram model, and the consistency index (C-index), calibration curve and decision curve analysis (DCA) to assess the reliability and applicability of the model. RESULTS: A total of 165 patients were included in the final analysis. Approximately 72.7% of CVT patients were regarded as malnourished by our malnutrition screening tools, and malnutrition is associated with an increased risk of CID. Prognostic Nutritional Index (PNI) (OR = 0.873; CI: 0.791, 0.963, p = 0.007) remained as an independent predictor for CID after adjustment for other risk factors. The nomogram model showed that PNI and gender have a great contribution to prediction. Besides, the nomogram model was consistent with the actual observations of CID risk (C-index = 0.65) and was of clinical significance. CONCLUSIONS: We reported that malnutrition, as indicated by PNI, was associated with a higher incidence of CID in CVT patients. Also, we have constructed a nomogram for predicting the risk of CID in these patients.

The subacute toxicity and underlying mechanisms of biomimetic mesoporous polydopamine nanoparticles.

Recently, mesoporous nanomaterials with widespread applications have attracted great interest in the field of drug delivery due to their unique structure and good physiochemical properties. As a biomimetic nanomaterial, mesoporous polydopamine (MPDA) possesses both a superior nature and good compatibility, endowing it with good clinical transformation prospects compared with other inorganic mesoporous nanocarriers. However, the subacute toxicity and underlying mechanisms of biomimetic mesoporous polydopamine nanoparticles remain uncertain. Herein, we prepared MPDAs by a soft template method and evaluated their primary physiochemical properties and metabolite toxicity, as well as potential mechanisms. The results demonstrated that MPDA injection at low (3.61 mg/kg) and medium doses (10.87 mg/kg) did not significantly change the body weight, organ index or routine blood parameters. In contrast, high-dose MPDA injection (78.57 mg/kg) is associated with disturbances in the gut microbiota, activation of inflammatory pathways through the abnormal metabolism of bile acids and unsaturated fatty acids, and potential oxidative stress injury. In sum, the MPDA dose applied should be controlled during the treatment. This study first provides a systematic evaluation of metabolite toxicity and related mechanisms for MPDA-based nanoparticles, filling the gap between their research and clinical transformation as a drug delivery nanoplatform.

Dual-Channel Fluorescent Probe for the Simultaneous Monitoring of Peroxynitrite and Adenosine-5'-triphosphate in Cellular Applications.

Changes in adenosine triphosphate (ATP) and peroxynitrite (ONOO-) concentrations have been correlated in a number of diseases including ischemia-reperfusion injury and drug-induced liver injury. Herein, we report the development of a fluorescent probe ATP-LW, which enables the simultaneous detection of ONOO- and ATP. ONOO- selectively oxidizes the boronate pinacol ester of ATP-LW to afford the fluorescent 4-hydroxy-1,8-naphthalimide product NA-OH (λex = 450 nm, λem = 562 nm or λex = 488 nm, λem = 568 nm). In contrast, the binding of ATP to ATP-LW induces the spirolactam ring opening of rhodamine to afford a highly emissive product (λex = 520 nm, λem = 587 nm). Due to the differences in emission between the ONOO- and ATP products, ATP-LW allows ONOO- levels to be monitored in the green channel (λex = 488 nm, λem = 500-575 nm) and ATP concentrations in the red channel (λex = 514 nm, λem = 575-650 nm). The use of ATP-LW as a combined ONOO- and ATP probe was demonstrated using hepatocytes (HL-7702 cells) in cellular imaging experiments. Treatment of HL-7702 cells with oligomycin A (an inhibitor of ATP synthase) resulted in a reduction of signal intensity in the red channel and an increase in that of the green channel as expected for a reduction in ATP concentrations. Similar fluorescence changes were seen in the presence of SIN-1 (an exogenous ONOO- donor).

Hematuria was a high risk for renal progression and ESRD in immunoglobulin a nephropathy: a systematic review and meta-analysis.

Background: The relationship between hematuria, a typical presentation of immunoglobulin A nephropathy (IgAN), and long-term adverse prognosis of these patients is still controversial. This meta-analysis aims to clarify the effect of hematuria on renal outcomes in IgAN.Methods: Observational cohort studies reporting associations between various forms of hematuria and renal outcomes among IgAN patients were identified from the PubMed and Embase databases. The pooled adjusted risk ratios (RRs) were computed with random effects models.Results: Thirteen studies encompassing 5660 patients with IgAN were included. Patients with initial hematuria did not have a significantly increased risk of developing end-stage renal disease (ESRD) compared with those without hematuria (RR, 1.32; 95% CI, 0.87-2.00; p = .19). However, initial microscopic hematuria was associated with an 87% increase in the risk of ESRD (RR, 1.87; 95% CI, 1.40-2.50; p < .001), while macroscopic hematuria was associated with a 32% decrease in the risk of ESRD (RR, 0.68; 95% CI, 0.58-0.79; p < .001). Additionally, persistent hematuria might be an independent risk factor for ESRD or a 50% decline in eGFR.Conclusions: Among IgAN patients, hematuria, including initial microscopic hematuria and even persistent hematuria, was possibly associated with renal progression and ESRD. However, independent of other classical predictors, initial macroscopic hematuria might be a protective factor for IgAN.

Epithelial-mesenchymal Transition and Cancer Stem Cells: At the Crossroads of Differentiation and Dedifferentiation.

In this review, we explore the connections between epithelial-mesenchymal transition (EMT) and differentiation status. EMTs in development have been described as differentiation events, while in most cases EMTs in cancer have been depicted as dedifferentiation events. We will briefly summarize both embryo development and cancer progression with regard to the involvement of EMT and cell differentiation status. We further present the studies that provide evidence that EMT results in both differentiation and dedifferentiation. Finally, we present our resolution to this dilemma by suggesting that EMT brings about dedifferentiation that enables subsequent differentiation. In normal development, EMT events may cause a partial reversal of differentiation to overcome differentiation barriers. When EMT is aberrantly activated in cancer, cells gain attributes of stem cells that contribute to self-renewal capabilities and are able to differentiate to all cell types represented in the tumor. The resulting cancer stem cells attain hallmarks of cancer, including replicative immortality, resistance to cell death, and invasiveness. Developmental Dynamics 248:10-20, 2019. © 2018 Wiley Periodicals, Inc.

The landscape and diagnostic potential of T and B cell repertoire in Immunoglobulin A Nephropathy.

Immunoglobulin A Nephropathy (IgAN) is the most common glomerulonephritis worldwide. The pathologic hallmark of IgAN is immune complex deposited in glomerular mesangium, which induces inflammation and affects the kidney's normal functions. The exact pathogenesis of IgAN, however, remains obscure. Further, in current clinical practice, the diagnosis relies on needle biopsy of renal tissue. Therefore, a non-invasive method for diagnosis and prognosis surveillance of the disease is highly desirable. To this end, we investigated the T cell receptor beta chain (TCRB) and immunoglobulin heavy chain (IGH) repertoire in circulating lymphocytes and compared them with kidney infiltrating lymphocytes using immune repertoire high throughput sequencing. We found that some features of TCRB and IGH in renal tissues were remarkably different from that in the blood, including decreased repertoire diversity, increased IgA and IgG frequency, and more antigen-experienced B cells. The complementarity-determining region 3 (CDR3) length of circulating TCRB and IGH in IgAN patients was significantly shorter than that in healthy controls, which is the result of both VDJ rearrangement and clonal selection. The IgA1 frequency in the blood of IgAN patients is significantly higher than that in other Nephropathy (NIgAN) patients and healthy control. Importantly we identified a set of TCRB and IGH clones, which can be used to distinguish IgAN from NIgAN and healthy controls with high accuracy. These results indicated that the TCRB and IGH repertoire can potentially serve as non-invasive biomarkers for the diagnosis of IgAN. The characteristics of the kidney infiltrating and circulating lymphocytes repertoires shed light on IgAN detection, treatment and surveillance.

The associations of Bmi-1 with progression of glomerular chronic kidney disease
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BACKGROUND: Our previous studies indicated that Bmi-1 plays an important role in hypoxia-induced tubular epithelial-mesenchymal transition and the development of kidney fibrosis in cellular and animal models. However, circulating Bmi-1 levels in human chronic kidney disease (CKD) and their relation to progression remains unknown. MATERIALS AND METHODS: We conducted a post-hoc analysis of a prospective cohort study. The blood samples and clinical data of 230 patients with glomerular CKD and 67 healthy adults were prospectively collected between January 2010 and June 2012. Serum Bmi-1 was measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: CKD patients had significantly higher serum Bmi-1 concentrations than the healthy controls (496.4 (363.1 - 675.4) pg/mL compared with 257.3 (235.4 - 303.8) pg/mL, p < 0.001). Serum Bmi-1 level inversely correlated with the estimated glomerular filtration rate (eGFR) (r = -0.346, p < 0.001). In addition, positive correlations were identified between serum Bmi-1 levels and serum creatinine, blood urea nitrogen, cystatin C concentration, and the severity of tubulointerstitial fibrosis (r = 0.248, p < 0.001; r = 0.245, p < 0.001; r = 0.273, p < 0.001; r = 0.536, p < 0.001, respectively). Kaplan-Meier survival curves showed that a higher serum Bmi-1 level was associated with a shorter duration of renal survival. Cox multivariate analyses further demonstrated that serum Bmi-1 concentration was an independent prognostic factor for CKD patients (HR = 6.48, p < 0.001). CONCLUSION: Our study showed that high circulating Bmi-1 levels were associated with adverse kidney disease outcome, suggesting that Bmi-1 is a novel biomarker for glomerular CKD progression. More data from larger longitudinal studies are required to validate our findings.
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The MicroRNA-199a/214 Cluster Targets E-Cadherin and Claudin-2 and Promotes High Glucose-Induced Peritoneal Fibrosis.

Serum response factor (SRF) was found to be involved in the phenotypic transition and fibrosis of the peritoneal membrane during treatment with peritoneal dialysis (PD), but the exact mechanism remains unclear. SRF regulates microRNAs (miRNAs) that contain the SRF-binding consensus (CArG) element in the promoter region. Therefore, we investigated whether the miR-199a/214 gene cluster, which contains a CArG element in its promoter, is directly regulated by SRF. High-glucose (HG) treatment significantly unregulated the expression of the miR-199a-5p/214-3p gene cluster in human peritoneal mesothelial cells (HPMCs). By chromatin immunoprecipitation and reporter assays, we found that SRF binds to the miR-199a-5p/214-3p gene cluster promoter after HG stimulation. In vitro, in HPMCs, silencing of miR-199a-5p or miR-214-3p inhibited the HG-induced phenotypic transition and cell migration but enhanced cell adhesion, whereas ectopic expression of mimic oligonucleotides had the opposite effects. Both miR-199a-5p and miR-214-3p targeted claudin-2 and E-cadherin mRNAs. In a PD rat model, treatment with an SRF inhibitor silenced miR-199a-5p and miR-214-3p and alleviated HG-PD fluid-induced damage and fibrosis. Overall, this study reveals a novel SRF-miR-199a/miR-214-E-cadherin/claudin-2 axis that mediates damage and fibrosis in PD.

Twist contributes to proliferation and epithelial-to-mesenchymal transition-induced fibrosis by regulating YB-1 in human peritoneal mesothelial cells.

Twist is overexpressed in high glucose (HG) damage of human peritoneal mesothelial cells (HPMCs) in vitro. Herein, we further identified its precise function related to fibrosis of peritoneal membranes (PMs). The overexpression and activation of Twist and YB-1 (official name, YBX1) and a transformed fibroblastic phenotype of HPMCs were found to be positively related to epithelial-mesenchymal transition progress and PM fibrosis ex vivo in 93 patients who underwent continuous ambulatory peritoneal dialysis (PD), and also in HG-induced immortal HPMCs and an animal model of PD. Evidence from chromatin immunoprecipitation and luciferase reporter assays supported that YBX1 is transcriptionally regulated by the direct binding of Twist to E-box. Overexpression of Twist and YB-1 led to an increase in epithelial-mesenchymal transition, proliferation, and cell cycle progress of HPMCs, which might contribute to PM fibrosis. In contrast, the silencing of Twist or YB-1 inhibited HG-induced growth and cell cycle progression of HPMCs; this led to a down-regulation in the expression of cyclin Ds and cyclin-dependent kinases, finally inhibiting PM fibrosis. Twist contributes to PM fibrosis during PD treatment, mainly through regulation of YB-1.

Obesity and risk of thyroid cancer: evidence from a meta-analysis of 21 observational studies.

BACKGROUND: Several studies have evaluated the association between obesity and thyroid cancer risk. However, the results remain uncertain. In this study, we conducted a meta-analysis to assess the association between obesity and thyroid cancer risk. MATERIAL/METHODS: Published literature from PubMed, EMBASE, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) were retrieved before 10 August 2014. We included all studies that reported adjusted risk ratios (RRs), hazard ratios (HRs) or odds ratios (ORs), and 95% confidence intervals (CIs) of thyroid cancer risk. RESULTS: Thirty-two studies (n=12 620 676) were included in this meta-analysis. Obesity was associated with a significantly increased risk of thyroid cancer (adjusted RR=1.33; 95% CI, 1.24-1.42; I2=25%). In the subgroup analysis by study type, increased risk of thyroid cancer was found in cohort studies and case-control studies. In subgroup analysis by sex, both obese men and women were at significantly greater risk of thyroid cancer than non-obese subjects. When stratified by ethnicity, significantly elevated risk was observed in Caucasians and in Asians. In the age subgroup analysis, both young and old populations showed increased thyroid cancer risk. Subgroup analysis on smoking status showed that increased thyroid cancer risks were found in smokers and in non-smokers. In the histology subgroup analyses, increased risks of papillary thyroid cancer, follicular thyroid cancer, and anaplastic thyroid cancer were observed. However, obesity was associated with decreased risk of medullary thyroid cancer. CONCLUSIONS: Our results indicate that obesity is associated with an increased thyroid cancer risk, except medullary thyroid cancer.

Egr-1 mediates chronic hypoxia-induced renal interstitial fibrosis via the PKC/ERK pathway.

BACKGROUND: Chronic hypoxia-induced epithelial-to-mesenchymal transition (EMT) is a crucial process in renal fibrogenesis. Egr-1, as a transcription factor, has been proven to be important in promoting EMT. However, whether it functions in hypoxia-induced renal tubular EMT has not been fully elucidated. METHODS: Egr-1 were detected at mRNA and protein levels by qPCR and Western blot analysis respectively after renal epithelial cells were subjected to hypoxia treatment. Meanwhile, EMT phenotype was also observed through identification of relevant EMT-specific markers. siRNA was used to knock down Egr-1 expression and subsequent changes were observed. Specific PKC and MAPK/ERK inhibitors were employed to determine the molecular signaling pathway involved in Egr-1-mediated EMT phenotype. In vivo assays using rat remnant kidney model were used to validate the in vitro results. Furthermore, Egr-1 expression was examined in the samples of CKD patients with the clinical relevance revealed. RESULTS: Hypoxia treatment enhanced the mRNA and protein levels of Egr-1 in HK-2 cells, which was accompanied by a reduced expression of the epithelial marker E-cadherin and an enhanced expression of the mesenchymal marker Fsp-1. Downregulation of Egr-1 with siRNA reversed hypoxia-induced EMT. Using the specific inhibitors to protein kinase C (calphostin C) or MAPK/ERK (PD98059), we identified that hypoxia induced Egr-1 expression through the PKC/ERK pathway. In addition, the upregulation of Egr-1 raised endogenous Snail levels, and the downregulation of Snail inhibited Egr-1-mediated EMT in HK-2 cells. Through in vivo assays using rat remnant kidney and CKD patients' kidney tissues, we found that Egr-1 and Snail were overexpressed in tubular epithelial cells with EMT. CONCLUSION: Egr-1 may be an important regulator of the development of renal tubular EMT induced by hypoxia through the PKC/ERK pathway and the activation of Snail. Targeting Egr-1 expression or activity might be a novel therapeutic strategy to control renal fibrosis.

The T-box transcription factor Brachyury promotes renal interstitial fibrosis by repressing E-cadherin expression.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) induced by TGF-ß1 is one of well-recognized factors contributing to renal fibrosis. However, the underlying molecular mechanisms of EMT are not fully understood. Brachyury, an evolutionarily conserved transcription factor, was recently identified as an important factor promoting EMT in human carcinoma cell lines. There is no evidence that Brachyury is involved in renal tubular EMT. RESULTS: Our results demonstrated that Brachyury was prominently induced in TGF-ß1-treated human proximal tubular epithelial (HK-2) cells and that this induction was accompanied by changes characteristic of EMT. Blockage of Brachyury expression by short interfering RNA (siRNA) in HK-2 cells effectively reversed the TGF-ß1-induced EMT phenotype. Brachyury induction repressed E-cadherin transcription; the E-cadherin promoter contains a Brachyury binding site, and decreased expression of E-cadherin occurred in Brachyury-overexpressing cells when they were transfected with reporter constructs using the promoter. This effect was partially mediated by Slug and Snail, as knockdown of Snail and Slug by siRNA effectively reversed Brachyury-mediated EMT and partially restored E-cadherin expression. The expression of Brachyury also presented in a rat model of obstructive nephropathy and in tubulointerstitial fibrosis tissues of IgA nephropathy, suggesting that it may have a role in EMT and renal fibrosis in vivo. CONCLUSION: Our results demonstrate for the first time that Brachyury plays an important role in regulating TGF-ß1-mediated renal EMT and could be an attractive target for progression of renal disease therapies.

Fahr's syndrome as the initial imaging characteristics of MELAS syndrome with a possible seizure activity and cardiac arrest: a case report.

This study reported a case of MELAS syndrome presenting as the initial imaging characteristics of Fahr's syndrome with "near" sudden unexpected death in epilepsy (SUDEP) and lateralized periodic discharges (LPD). The patient, a young boy, experienced loss of consciousness 2 days prior, which was followed by two limb and facial convulsions. He was later found in cardiac arrest during hospitalization, but regained consciousness gradually after receiving cardiopulmonary resuscitation and tracheal intubation. The patient exhibited short stature, intellectual disability, poor sports abilities, and academic performance since childhood, but had no family history. Emergency head computed tomography (CT) revealed high density calcification in bilateral caudate nucleus, lentiform nucleus, thalamus, and dentate nucleus with evidence of an acute process. The patient was transferred to the neurology department where he continued to recover consciousness, though he experienced dysarthria, left limb hemiplegia, and hemiparesthesia. Changes in head magnetic resonance imaging (MRI) findings were noted at admission, 1 month later, and 6 months later. LPD were observed in his video electroencephalogram. The CT urography indicated a narrow left ureteropelvic junction with left hydronephrosis, which was suggestive of ureteropelvic junction obstruction. Ultimately, a diagnosis of near-SUDEP was suspected in this patient, indicating a rare case of MELAS syndrome with near-SUDEP and LPD. The gene tests results revealed the presence of the mitochondrial DNA A3243G mutation, leading to the final diagnosis of MELAS syndrome. This case expands the clinical disease spectrum of the MELAS syndrome.

Effects of health-related dispositions on citizens' appraisals toward the COVID-19 pandemic and protective behavior.

In this study, health risk attitude and health locus of control were included as dispositional factors in the Protection Motivation Theory (PMT) to explain people's protective behavior in the context of COVID-19 pandemic. Empirical data involved two waves of data with a sample of 526 adults with full-time jobs from Beijing, China, and structural equation model results confirmed a partial successful extension of the PMT. Specifically, health risk attitude had a direct effect on citizens' protective behavior, but without an indirect effect mediated by threat appraisal toward the COVID-19 pandemic; health locus of control did not directly associate with citizens' protective behavior, but had an indirect effect on it fully via coping appraisal toward the COVID-19 pandemic. Thus, the PMT has been extended by adding a distal dispositional factor on the impact of coping appraisal on protective behavior. Implications for advancing the government's anti-epidemic strategy are discussed.

Effects of Dietary Supplementation with Tea Residue on Growth Performance, Digestibility, and Diarrhea in Piglets.

Thirty-six healthy 21-day-old weaned ternary piglets (Duroc × Landrace × Yorkshire) were randomly divided into two treatments with 18 replicates per treatment and one pig per replicate. The control group was fed with a basal diet and the test group was fed with diets supplemented with 1 kg/t tea residue. The test period was 28 days. The results are as follows: The addition of tea residue in the diet had no significant effect on the growth performance of weaned piglets (p > 0.05), but it could significantly reduce the diarrhea rate of piglets from 1 to 7 days and 1 to 28 days (p < 0.05). Compared with the control group, the dietary supplementation of tea residue had no significant effect on nutrient apparent digestibility, plasma biochemical indexes and plasma immune indexes (p > 0.05) but increased the content of glutathione in plasma (p < 0.05). Tea residue had no significant effect on the morphology of the jejunum and ileum of piglets (p > 0.05), but it could significantly reduce the content of chloride ions in feces (p < 0.05). Compared with the basal diet group, there was no significant difference in the relative expression of TMEM16A and CFTR mRNA in the colon of weaned piglets (p > 0.05). The whole-cell patch clamp recording showed that the TMEM16A and CFTR ion channels could be activated by ionomycin and forskolin, respectively. However, when HT-29 cells transfected with TMEM16A and CFTR channels were treated with tea residue extract, it could significantly inhibit the chloride current of the TMEM16A and CFTR ion channels (p < 0.05).

Structural characterization of lignin from the green pretreatments for co-producing xylo-oligosaccharides and glucose: Toward full biomass utilization.

Three green non-enzymatic catalysis pretreatments (NECPs) including autohydrolysis, subcritical CO2-assisted seawater autohydrolysis, and inorganic salt catalysis were utilized to simultaneously produce xylo-oligosaccharides (XOS), glucose, and cellulolytic enzyme lignin (CEL) from sugarcane bagasse (SCB). The yield of XOS in all three NECPs was over 50 % with a competitive glucose yield of enzymatic hydrolysis. And the effects of different pretreatments on the chemical structure and composition of CEL samples were also investigated. The pretreatments significantly increased the thermal stability, yield, and purity of the CEL samples. Moreover, the net yield of lignin was 58.3 % with lignin purity was 98.9 % in the autohydrolysis system. Furthermore, there was a decrease in the molecular weight of CEL samples as the pretreatment intensity increased. And the original lignin structural units sustained less damage during the NECPs, due to the cleavage of the ß-O-4 bonds dominating lignin degradation. Meanwhile, these pretreatments increased the phenolic-OH in CEL samples, making the lignin more reactive, and enhancing its subsequent modification and utilization. Collectively, the described techniques have demonstrated practical significance for the coproduction of XOS and glucose, and lignin, providing a promising strategy for full utilization of biomass.

Sirtuin 1/sirtuin 3 are robust lysine delactylases and sirtuin 1-mediated delactylation regulates glycolysis.

Lysine lactylation (Kla), an epigenetic mark triggered by lactate during glycolysis, including the Warburg effect, bridges metabolism and gene regulation. Enzymes such as p300 and HDAC1/3 have been pivotal in deciphering the regulatory dynamics of Kla, though questions about additional regulatory enzymes, their specific Kla substrates, and the underlying functional mechanisms persist. Here, we identify SIRT1 and SIRT3 as key "erasers" of Kla, shedding light on their selective regulation of both histone and non-histone proteins. Proteomic analysis in SIRT1/SIRT3 knockout HepG2 cells reveals distinct substrate specificities toward Kla, highlighting their unique roles in cellular signaling. Notably, we highlight the role of specific Kla modifications, such as those on the M2 splice isoform of pyruvate kinase (PKM2), in modulating metabolic pathways and cell proliferation, thereby expanding Kla's recognized functions beyond epigenetics. Therefore, this study deepens our understanding of Kla's functional mechanisms and broadens its biological significance.

Identification of Tau and SOD1 gene mutation in a small Chinese Han pedigree of adult amyotrophic lateral sclerosis.

We report the clinical profile, and a brief investigation of SOD1 and Tau gene mutation from a small Chinese Han pedigree of adults with amyotrophic lateral sclerosis (ALS), which consisted of 32 familial members with 6 affected individuals spanning five generations, and presenting autosomal dominant genetic mode. The mean age of onset was 36.6 ± 15.9 years, and disease duration was 6 months to more than 5 years, the average survival was 16.1 ± 8.2 months. There were 5 patients with an early disease onset, rapid progressive course and short survival, and 1 patient with late onset, slow progressive course and long survival in the kindred. ALS patients began to suffer with weakness and muscle atrophy in one side of a lower extremity, which then spread to the upper extremity, the opposite side and bulbar muscles. All patients had spinal onset type. Muscle stretch reflexes were absent or weak in the upper limbs and accentuation in the lower limbs; pathological signs in the lower limbs were positive. Electromyography disclosed ongoing denervation muscle potentials in the four extremities. Brain and spinal MRI did not show any abnormal signal. A 5 exons mutation of SOD1 in all affected individuals was identified using SSCP. Polymorphisms of partial risk regions in 3',5' UTR, and in introns 9, 10, 11, 12 of the Tau gene in the affected and normal family members and in 70 healthy controls were examined by DNA sequencing. Routine exons mutation of SOD1 was not detected, but one single nucleotide polymorphism of A to G at 138278 at 3' UTR of the Tau gene was shown to significantly over-express in fALS familial members.