Hexokinase II promotes the Warburg effect by phosphorylating alpha subunit of pyruvate dehydrogenase

Objective: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II(HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells.Methods: HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase(PDHA1) was tested in HEK293 T cells and clear cell renal cell carcinoma(cc RCC) specimens using gene knockdown, western blotting,immunohistochemistry, and immunofluorescence.Results: It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase(PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in cc RCC.Conclusions: The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.

HBXIP blocks myosin-ⅡA assembly by phosphorylating and interacting with NMHC-ⅡA in breast cancer metastasis

Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain(ACD) of non-muscle heavy chain myosin-ⅡA(NMHC-ⅡA).The interaction was enhanced by NMHC-ⅡA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβⅡ.Moreover,HBXIP induced the transcription of PRKCB,encoding PKCβⅡ,by coactivating Sp1,and triggered PKCβⅡ kinase activity.Interestingly,RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate(BZF) suppressed breast cancer metastasis via inhibiting PKCβⅡ-mediated NMHC-ⅡA phosphorylation in vitro and in vivo.We reveal a novel mechanism by which HBXIP promotes myosin-ⅡA disassembly via interacting and phosphorylating NMHC-ⅡA,and BZF can serve as an effective anti-metastatic drug in breast cancer.

Targeting tau in Alzheimer's disease:from mechanisms to clinical therapy

Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.

Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.

Comparative analysis of primate and pig cells reveals primate-specific PINK1 expression and phosphorylation

PTEN-induced putative kinase 1(PINK1),a mitochondrial kinase that phosphorylates Parkin and other proteins,plays a crucial role in mitophagy and protection against neurodegeneration.Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson's disease.However,there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration.Additionally,PINK1 knockout pigs(Sus scrofa)do not appear to exhibit neurodegeneration.In our recent work involving non-human primates,we found that PINK1 is selectively expressed in primate brains,while absent in rodent brains.To extend this to other species,we used multiple antibodies to examine the expression of PINK1 in pig tissues.In contrast to tissues from cynomolgus monkeys(Macaca fascicularis),our data did not convincingly demonstrate detectable PINK1expression in pig tissues.Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation,as observed in cultured monkey cells.A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain.Consistently,PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD.These findings provide new evidence that PINK1expression is specific to primates,underscoring the importance of non-human primates in investigating PINK1function and pathology related to PINK1 deficiency.

Comprehensive analysis of the gut microbiome and posttranslational modifications elucidates the route involved in microbiota-host interactions

The gut microbiome interacts with the host to maintain body homeostasis,with gut microbial dysbiosis implicated in many diseases.However,the underlying mechanisms of gut microbe regulation of host behavior and brain functions remain unclear.This study aimed to elucidate the influence of gut microbiota on brain functions via post-translational modification mechanisms in the presence or absence of bacteria without any stimulation.We conducted succinylome analysis of hippocampal proteins in germ-free(GF)and specific pathogen-free(SPF)mice and metagenomic analysis of feces from SPF mice.These results were integrated with previously reported hippocampal acetylome and phosphorylome data from the same batch of mice.Subsequent bioinformatics analyses revealed 584 succinylation sites on 455 proteins,including 54 up-regulated succinylation sites on 91 proteins and 99 down-regulated sites on 51 proteins in the GF mice compared to the SPF mice.We constructed a panoramic map of gut microbiota-regulated succinylation,acetylation,and phosphorylation,and identified cross-talk and relative independence between the different types of post-translational modifications in modulating complicated intracellular pathways.Pearson correlation analysis indicated that 13 taxa,predominantly belonging to the Bacteroidetes phylum,were correlated with the biological functions of post-translational modifications.Positive correlations between these taxa and succinylation and negative correlations between these taxa and acetylation were identified in the modulation of intracellular pathways.This study highlights the hippocampal physiological changes induced by the absence of gut microbiota,and proteomic quantification of succinylation,phosphorylation,and acetylation,contributing to our understanding of the role of the gut microbiome in brain function and behavioral phenotypes.

Aspartoacylase suppresses prostate cancer progression by blocking LYN activation

Background:Globally,despite prostate cancer(PCa)representing second most prevalent malignancy in male,the precise molecular mechanisms implicated in its pathogenesis remain unclear.Consequently,elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies,ultimately advancing the management of PCa.Methods:A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University.The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa.The expression of aspartoacylase(ASPA)in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques.To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis,a comprehensive set of in vitro and in vivo assays were conducted,including orthotopic and tumor-bearing mouse models(n=8 for each group).A combination of experimental approaches,such as Western blotting,luciferase assays,immunoprecipitation assays,mass spectrometry,glutathione S-transferase pulldown experiments,and rescue studies,were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa.The Student‘s t-test was employed to assess the statistical significance between two distinct groups,while one-way analysis of variance was utilized for comparisons involving more than two groups.A two-sided P<0.05 was deemed to indicate statistical significance.Results:ASPA was identified as a novel inhibitor of PCa progression.The expression of ASPA was found to be significantly down-regulated in PCa tissue samples,and its decreased expression was independently associated with patients’prognosis(HR=0.60,95%CI 0.40–0.92,P=0.018).Our experiments demonstrated that modulation of ASPA activity,either through gain-or loss-of-function,led to the suppression or enhancement of PCa cell proliferation,migration,and invasion,respectively.The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models.Mechanistically,ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets,JNK1/2 and C-Jun,in both PCa cells and mouse models,in an enzyme-independent manner.Importantly,the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models.Moreover,we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples,suggesting a potential regulatory role of ASPA in modulating LYN signaling.Conclusions:Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy.

Phosphorylated cellulose nanofibers establishing reliable ion-sieving barriers for durable lithium-sulfur batteries

The shuttle effect is among the most characteristic and formidable challenges in the pursuit of high-performance lithium-sulfur(Li-S)batteries.Herein,phosphorylated cellulose nanofibers(pCNF)are intentionally engineered to establish an ion-sieving barrier against polysulfide shuttling and thereby improve battery performance.The phosphorylation,involving the grafting of phosphate groups onto the cellulose backbone,imparts an exceptional electronegativity that repels the polysulfide anions from penetrating through the separator.Moreover,the electrolyte wettability and Li^(+)transfer can be significantly promoted by the polar nature of pCNF and the facile Li^(+)disassociation.As such,rational ion management is realized,contributing to enhanced reversibility in both sulfur and lithium electrochemistry.As a result,Li-S cells equipped with the self-standing pCNF separator demonstrate outstanding long-term cyclability with a minimum fading rate of 0.013%per cycle over 1000 cycles at 1 C,and a decent areal capacity of 5.37 mA h cm^(-2) even under elevated sulfur loading of 5.0 mg cm^(-2) and limited electrolyte of 6.0 mL g^(-1).This work provides a facile and effective pathway toward the well-tamed shuttle effect and highly durable Li-S batteries.

Brønsted-acid sites induced photocatalytic cracking of low-polarity polyethylene plastics

Polyolefins such as polyethylene(PE)are one of the largest-scale synthetic plastics and play a key role in modern society.However,polyethylene is extremely inert to chemical recycling owing to its lack of chemical functionality and low polarity,making it one of the most challenging environmental hazards globally.Herein,we developed a phosphorylated CeO_(2)catalyst by an organophosphate precursor and featured efficient photocatalysis of low-density polyethylene(LDPE)without the acid or alkaline pre-treatment.Compared to pristine CeO_(2),the surface phosphorylation allows to introduce Brønsted acid sites,which facilitate to form carbonium ions on LDPE via protonation.In addition,the suitable band structure of the phosphorylated CeO_(2)catalyst enables efficient photoabsorption and generates reactive oxygen species,leading to the C–C bond cleavage of LDPE.As a result,the phosphorylated CeO_(2)catalyst exhibited an outstanding carbon conversion rate of>94%after 48 h of photocatalysis under 50 mW/cm^(2)of simulated sunlight,with a high CO_(2)product selectivity of>99%.Furthermore,the PE microparticles with sizes larger than 10μm released from LDPE plastic wrap were directly and completely degraded by photocatalysis within 12 h,suggesting an attractive and environmentally benign strategy of utilizing solar energy-based photocatalysis for reducing potential hazards of LDPE plastic trashes.

Metabolic reprogramming of the inflammatory response in the nervous system:the crossover between inflammation and metabolism

Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.

Surviving winter on the Qinghai-Xizang Plateau:Extensive reversible protein phosphorylation plays a dominant role in regulating hypometabolism in hibernating Nanorana parkeri

Changes in protein abundance and reversible protein phosphorylation(RPP)play important roles in regulating hypometabolism but have never been documented in overwintering frogs at high altitudes.To test the hypothesis that protein abundance and phosphorylation change in response to winter hibernation,we conducted a comprehensive and quantitative proteomic and phosphoproteomic analysis of the liver of the Xizang plateau frog,Nanorana parkeri,living on the Qinghai-Xizang Plateau.In total,5170 proteins and 5695 phosphorylation sites in 1938 proteins were quantified.Based on proteomic analysis,674 differentially expressed proteins(438 up-regulated,236 down-regulated)were screened in hibernating N.parkeri versus summer individuals.Functional enrichment analysis revealed that higher expressed proteins in winter were significantly enriched in immune-related signaling pathways,whereas lower expressed proteins were mainly involved in metabolic processes.A total of 4251 modified sites(4147 up-regulated,104 down-regulated)belonging to 1638 phosphoproteins(1555 up-regulated,83 down-regulated)were significantly changed in the liver.During hibernation,RPP regulated a diverse array of proteins involved in multiple functions,including metabolic enzymatic activity,ion transport,protein turnover,signal transduction,and alternative splicing.These changes contribute to enhancing protection,suppressing energy-consuming processes,and inducing metabolic depression.Moreover,the activities of phosphofructokinase,glutamate dehydrogenase,and ATPase were all significantly lower in winter compared to summer.In conclusion,our results support the hypothesis and demonstrate the importance of RPP as a regulatory mechanism when animals transition into a hypometabolic state.

In vivo measurement of NADH fluorescence lifetime in skeletal muscle via -ber-coupled time-correlated single photon counting

Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluorescent,and itsfluorescence lifetime can be used to infer metabolic dynamics in living cells.Fiber-coupled time-correlated single photon counting(TCSPC)equipped with an implantable needle probe can be used to measure NADH lifetime in vivo,enabling investigation of changing metabolic demand during muscle contraction or tissue regeneration.This study illustrates a proof of concept for point-based,minimally-invasive NADHfluorescence lifetime measurement in vivo.Volumetric muscle loss(VML)injuries were created in the left tibialis anterior(TA)muscle of male Sprague Dawley rats.NADH lifetime measurements were collected before,during,and after a 30 s tetanic contraction in the injured and uninjured TA muscles,which was subsequently-t to a biexponential decay model to yield a metric of NADH utilization(cytoplasmic vs protein-bound NADH,the A11/A22 ratio).On average,this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest,suggesting higher levels of free NADH in contracting and recovering muscle,indicating increased rates of glycolysis.In injured muscle,this ratio was higher than uninjured muscle overall but decreased over time,which is consistent with current knowledge of inflammatory response to injury,suggesting tissue regeneration has occurred.These data suggest that-ber-coupled TCSPC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.

Metabolic reprogramming: a new option for the treatment of spinal cord injury

Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.

LATS1 Promotes B-ALL Tumorigenesis by Regulating YAP1 Phosphorylation and Subcellular Localization

Objective YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors;differentiating between these roles may depend on the YAP1 phosphorylation pattern.The specific function of YAP1 in B cell acute lymphoblastic leukemia(B-ALL),however,is currently unclear.Thus,in the present study,the role of YAP1 in B-ALL was investigated using relevant cell lines and patient datasets.Methods The effects of shRNA-mediated knockdown on YAP1 and LATS1 levels in the NALM6 and MOLT-4 cell lines were examined using Western blotting,quantitative real-time polymerase chain reaction,flow cytometry,immunostaining,and nude mouse subcutaneous tumorigenesis experiments.Gene expression levels of Hippo pathway-related molecules before and after verteporfin(VP)treatment were compared using RNA-Seq to identify significant Hippo pathway-related genes in NALM6 cells.Results Patients with ALL showing high YAP1 expression and low YAP1-Ser127 phosphorylation levels had worse prognoses than those with low YAP1 protein expression and high YAP1-Ser127 phosphorylation levels.YAP1-Ser127 phosphorylation levels were lower in NALM6 cells than in MOLT-4 and control cells;YAP1 was distributed in the nuclei in NALM6 cells.Knockdown of YAP1 inhibited MOLT-4 and NALM6 cell proliferation and arrested the NALM6 cell cycle in the G0/G1 phase.Before and after VP treatment,the expression of the upstream gene LATS1 was upregulated;its overexpression promoted YAP1-Ser127 phosphorylation.Further,YAP1 was distributed in the plasma.Conclusion LATS1 may downregulate YAP1-Ser127 phosphorylation and maintain B-ALL cell function;thus,VP,which targets this axis,may serve as a new therapeutic method for improving the outcomes for B-ALL patients.

α-Synuclein pathology from the body to the brain:so many seeds so close to the central soil

α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and highly phospho rylated a-synuclein constitutes the main component of Lewy bodies in the brain,the pathological hallmark of Parkinson s disease.For decades,much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson s disease as a systemic disease.Recent evidence demonstrates that,at least in some patients,the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain.Injection of α-synuclein preformed fibrils into the gastrointestinal tra ct trigge rs the gutto-brain propagation of α-synuclein pathology.However,whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation.In this review,we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson’s disease.We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.

Cardioprotective Potential of Cymbopogon citratus Essential Oil against Isoproterenol-induced Cardiomyocyte Hypertrophy:Possible Involvement of NLRP3 Inflammasome and Oxidative Phosphorylation Complex Subunits

Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.

IL-17 induces NSCLC cell migration and invasion by elevating MMP19 gene transcription and expression through the interaction of p300-dependent STAT3-K631 acetylation and its Y705-phosphorylation

The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.

Metformin-associated lactic acidosis:A mini review of pathophysiology,diagnosis and management in critically ill patients

Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation,leading to metforminassociated lactic acidosis(MALA).As diabetes mellitus is a common chronic metabolic condition found in critically ill patients,pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit.The aim of this narrative mini review is therefore to update clinicians about MALA,and to provide a practical approach to its diagnosis and treatment.MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis,and confirmed when lactate exceeds 5 mmol/L.Risk factors include those that reduce renal elimination of metformin(renal impairment from any cause,histamine-2 receptor antagonists,ribociclib)and excessive alcohol consumption(as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism).Treatment of MALA involves immediate cessation of metformin,supportive management,treating other concurrent causes of lactic acidosis like sepsis,and treating any coexisting diabetic ketoacidosis.Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy.The optimal time to restart metformin has not been well-studied.It is nonetheless reasonable to first ensure that lactic acidosis has resolved,and then recheck the kidney function post-recovery from critical illness,ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m^(2) or better before restarting metformin.

Combined Oxidative Phosphorylation Deficiency-20-Exome as a Diagnostic Implement

Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.

EL1-like Casein Kinases Suppress ABA Signaling and Responses by Phosphorylating and Destabilizing the ABA Receptors PYR/PYLs in Arabidopsis

Unveiling the signal transduction of phytohormone abscisic acid （ABA） and its regulatory mechanisms is critical for developing the strategies toward improving plant responses to stressful environments. ABA signaling is perceived and mediated by multiple PYR/PYL receptors, whose post-translational modifications, especially phosphorylation, remain largely unknown. In this study, we demonstrate thatArabidopsis ELl-like （AEL） protein, a casein kinase that regulates various physiological processes, phosphorylate PYR/PYLs to promote their ubiquitination and degradation, resulting in suppressed ABA responses. Arabidopsis ael triple mutants display hypersensitive responses to ABA treatment, which is consistent with the suppressed degradation of PYR/PYL proteins. PYR/PYLs are phosphorylated in vivo and mutation of the conserved AEL phosphorylation sites results in reduced phosphorylation, ubiquitination, and degradation of PYR/PYLs, and hence enhanced ABA responses. Taken together, these results demonstrate that AEL-mediated phosphorylation plays crucial roles in regulating the stability and function of PYR/ PYLs, providing significant insights into the post-translational regulation of PYR/PYL receptors and ABA signaling.