Retracted: The Effects of Hesperidin on Neuronal Apoptosis and Cognitive Impairment in the Sevoflurane Anesthetized Rat are Mediated Through the PI3/Akt/PTEN and Nuclear Factor-κB (NF-κB) Signaling Pathways.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Haijin Huang, Cuicui Hu, Lin Xu, Xiaoping Zhu, Lili Zhao, Jia Min. The Effects of Hesperidin on Neuronal Apoptosis and Cognitive Impairment in the Sevoflurane Anesthetized Rat are Mediated Through the PI3/Akt/PTEN and Nuclear Factor-kappaB (NF-kappaB) Signaling Pathways. Med Sci Monit, 2020; 26: e920522. DOI: 10.12659/MSM.920522.

Nuclear Factor Erythroid 2-Related Factor 2 as a Potential Therapeutic Target in Neonatal Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a prominent cause of neonatal mortality and neurodevelopmental disorders; however, effective therapeutic interventions remain limited. During neonatal hypoxic-ischemic injury events, increased reactive oxygen species (ROS) production and decreased antioxidant levels lead to the induction of oxidative stress, which plays a pivotal role in the pathological process of neonatal HIE. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key endogenous antioxidant transcription factor that protects against oxidative stress by promoting the transcription of various antioxidant genes. It has been demonstrated that Nrf2 signaling pathway activation by different compounds may protect against neonatal HIE. This review outlines the role of oxidative stress in neonatal HIE and summarizes the impact of antioxidants on neonatal HIE via activation of the Nrf2 signaling pathway. In conclusion, Nrf2 signaling pathway potentially exerts antioxidant, anti-inflammatory, antiapoptotic and antiferroptotic effects, thereby emerging as a focal point for future neonatal HIE treatment strategies.

Effect of mutation at c.493T>C locus of transcription factor HNF1α gene on its protein level.

Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor that is crucial for the regulation to maintain the function of pancreatic ß-cell, hepatic lipid metabolism, and other processes. Mature-onset diabetes of the young type 3 is a monogenic form of diabetes caused by HNF1α mutations. Although several mutation sites have been reported, the specific mechanisms remain unclear, such hot-spot mutation as the P291fsinsC mutation and the P112L mutation and so on. In preliminary studies, we discovered one MODY3 patient carrying a mutation at the c.493T>C locus of the HNF1α gene. In this study, we analyzed the pathogenic of the mutation sites by using the Mutation Surveyor software and constructed the eukaryotic expression plasmids of the wild-type and mutant type of HNF1α to detect variations in the expression levels and stability of HNF1α protein by using Western blot. The analyses of the Mutation Surveyor software showed that the c.493T>C site mutation may be pathogenic gene and the results of Western blot showed that both the amount and stability of HNF1α protein expressed by the mutation type plasmid were reduced significantly compared to those by the wild type plasmid (P<0.05). This study suggests that the c.493T>C (p.Trp165Arg) mutation dramatically impacts HNF1α expression, which might be responsible for the development of the disease and offers fresh perspectives for the following in-depth exploration of MODY3's molecular pathogenic process.

Dexmedetomidine improves lung injury after one-lung ventilation in esophageal cancer patients by inhibiting inflammatory response and oxidative stress.

Aim: To explore the effect of Dexmedetomidine (DEX) on lung injury in patients undergoing One-lung ventilation (OLV). Methods: Esophageal cancer patients undergoing general anesthesia with OLV were randomly divided into the DEX group and control group, with 30 cases in each group. Mean arterial pressure (MAP), heart rate (HR), arterial partial pressure of oxygen (PO2), and arterial partial pressure of nitrogen dioxide (PCO2) were recorded at the time points after anesthesia induction and before OLV (T1), OLV 30 min (T2), OLV 60 min (T3), OLV 120 min (T4), OLV end before (T5) and before leaving the room (T6) in both groups. Reverse Transcription-Polymerase Chain Reaction (RT-qPCR) was applied to detect the levels of CC16 mRNA. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum CC16 protein levels. The content of malondialdehyde (MDA) in serum was determined by thio barbituric acid (TBA) method. ELISA was used to measure the concentrations of TNF-α (tumor necrosis factor-alpha)/and IL-6 (interleukin 6). Results: DEX treatment slowed down HR at time points T1-T6 and increased PO2 and PCO2 at time points T2-T5 compared with the control group. Moreover, at time points T2-T6, DEX treatment reduced the levels of club cell secretory protein-16 (CC16) mRNA and serum CC16 protein levels. Furthermore, DEX treatment caused the reduction of MDA, TNF-α and IL-6 concentrations in serum of patients. Conclusion: During the OLV process, DEX could reduce serum CC16 protein levels, inhibit inflammatory reactions and oxidative stress, and improve oxygenation index, indicating a protective effect on lung injury during OLV.

RNA-seq transcriptome and pathway analysis of the medicinal mushroom Lignosus tigris (Polyporaceae) offer insights into its bioactive compounds with anticancer and antioxidant potential.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal mushrooms belonging to the Lignosus spp., colloquially known as Tiger Milk mushrooms (TMMs), are used as traditional medicine by communities across various regions of China and Southeast Asia to enhance immunity and to treat various diseases. At present, three Lignosus species have been identified in Malaysia: L. rhinocerus, L. tigris, and L. cameronensis. Similarities in their macroscopic morphologies and the nearly indistinguishable appearance of their sclerotia often lead to interchangeability between them. Hence, substantiation of their traditional applications via identification of their individual bioactive properties is imperative in ensuring that they are safe for consumption. L. tigris was first identified in 2013. Thus far, studies on L. tigris cultivar sclerotia (Ligno TG-K) have shown that it possesses significant antioxidant activities and has greater antiproliferative action against selected cancer cells in vitro compared to its sister species, L. rhinocerus TM02®. Our previous genomics study also revealed significant genetic dissimilarities between them. Further omics investigations on Ligno TG-K hold immense potential in facilitating the identification of its bioactive compounds and their associated bioactivities. AIM OF STUDY: The overall aim of this study was to investigate the gene expression profile of Ligno TG-K via de novo RNA-seq and pathway analysis. We also aimed to identify highly expressed genes encoding compounds that contribute to its cytotoxic and antioxidant properties, as well as perform a comparative transcriptomics analysis between Ligno TG-K and its sister species, L. rhinocerus TM02®. MATERIALS AND METHODS: Total RNA from fresh 3-month-old cultivated L. tigris sclerotia (Ligno TG-K) was extracted and analyzed via de novo RNA sequencing. Expressed genes were analyzed using InterPro and NCBI-Nr databases for domain identification and homology search. Functional categorization based on gene functions and pathways was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Clusters of Orthologous Genes (COG) databases. Selected genes were subsequently subjected to phylogenetic analysis. RESULTS: Our transcriptomics analysis of Ligno TG-K revealed that 68.06% of its genes are expressed in the sclerotium; 80.38% of these were coding transcripts. Our analysis identified highly expressed transcripts encoding proteins with prospective medicinal properties. These included serine proteases (FPKM = 7356.68), deoxyribonucleases (FPKM = 3777.98), lectins (FPKM = 3690.87), and fungal immunomodulatory proteins (FPKM = 2337.84), all of which have known associations with anticancer activities. Transcripts linked to proteins with antioxidant activities, such as superoxide dismutase (FPKM = 1161.69) and catalase (FPKM = 1905.83), were also highly expressed. Results of our sequence alignments revealed that these genes and their orthologs can be found in other mushrooms. They exhibit significant sequence similarities, suggesting possible parallels in their anticancer and antioxidant bioactivities. CONCLUSION: This study is the first to provide a reference transcriptome profile of genes expressed in the sclerotia of L. tigris. The current study also presents distinct COG profiles of highly expressed genes in Ligno TG-K and L. rhinocerus TM02®, highlighting that any distinctions uncovered may be attributed to their interspecies variations and inherent characteristics that are unique to each species. Our findings suggest that Ligno TG-K contains bioactive compounds with prospective medicinal properties that warrant further investigations. CLASSIFICATION: Systems biology and omics.

Proteomics analysis of histone deacetylase inhibitor-resistant solid tumors reveals resistant signatures and potential drug combinations.

Histone deacetylase inhibitors (HDACis) are important drugs for cancer therapy, but the indistinct resistant mechanisms of solid tumor therapy greatly limit their clinical application. In this study we conducted HDACi-perturbated proteomics and phosphoproteomics analyses in HDACi-sensitive and -resistant cell lines using a tandem mass tag (TMT)-based quantitative proteomic strategy. We found that the ribosome biogenesis proteins MRTO4, PES1, WDR74 and NOP16 vital to tumorigenesis might regulate the tumor sensitivity to HDACi. By integrating HDACi-perturbated protein signature with previously reported proteomics and drug sensitivity data, we predicted and validated a series of drug combination pairs potentially to enhance the sensitivity of HDACi in diverse solid tumor. Functional phosphoproteomic analysis further identified the kinase PDK1 and ROCK as potential HDACi-resistant signatures. Overall, this study reveals the potential HDACi-resistant signatures and may provide promising drug combination strategies to attenuate the resistance of solid tumor to HDACi.

Exercise, Spinal Microglia and Neuropathic Pain: Potential Molecular Mechanisms.

As one of the most common neuropathic disorders, neuropathic pain often has a negative impact on patients with persistent pain, mood disorders and sleep disturbances. Currently, neuropathic pain is not treated with any specific drug, instead, drugs for other diseases are used as replacements in clinics, but most have adverse effects. In recent years, the role of spinal cord microglia in the pathogenesis of neuropathic pain has been widely recognized, and they are being explored as potential therapeutic targets. Spinal microglia are known to be involved in the pathogenic mechanisms of neuropathic pain through purine signaling, fractalkine signaling, and p38 MAPK signaling. Exercise is a safe and effective treatment, and numerous studies have demonstrated its effectiveness in improving neurological symptoms. Nevertheless, it remains unclear what the exact molecular mechanism is. This review summarized the specific molecular mechanisms of exercise in alleviating neuropathic pain by mediating the activity of spinal microglia and maintaining the phenotypic homeostasis of spinal microglia through purine signaling, fractalkine signaling and p38 MAPK signaling. In addition, it has been proposed that different intensities and types of exercise affect the regulation of the above-mentioned signaling pathways differently, providing a theoretical basis for the improvement of neuropathic pain through exercise.

Effects of light regulation on the synthesis of secondary metabolites in medicinal plants / 药学实践杂志

Secondary metabolites of medicinal plants are extremely important to human health because of their special pharmacological activities or efficacy. They are the main source of drugs, health care products, and cosmetics. As human beings continue to pursue health and longevity, the demand in the pharmaceutical market continues to grow. It becomes especially important to improve the production and quality of secondary metabolites of medicinal plants. Plant secondary metabolites are a kind of adaptation of plants to their environment and are the result of the interaction between plants and biotic and abiotic factors during the long-term evolution process. The production and accumulation of secondary metabolites in medicinal plants are mainly affected by plant genetic factors and environmental factors. Among them, light environment is extremely important for their synthesis. Therefore, light regulation has long been a research focus for many scholars in China and abroad. In this article, we the recent research progress on the effects of light regulation on the secondary metabolites of medicinal plants were reviewed, mainly focusing on the effects of light quality, light intensity and photoperiod, in order to provide theoretical basis and practical guidance for the efficient production of secondary metabolites with important pharmacological activities.

Activation of cerebral Ras-related C3 botulinum toxin substrate (Rac) 1 promotes post-ischemic stroke functional recovery in aged mice.

Brain functional impairment after stroke is common; however, the molecular mechanisms of post-stroke recovery remain unclear. It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke. Mounting evidence suggests that axonal regeneration and angiogenesis, the major forms of brain plasticity responsible for post-stroke recovery, diminished with advanced age. Previous studies suggest that Ras-related C3 botulinum toxin substrate (Rac) 1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model. Here, we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged (male, 18 to 22 months old C57BL/6J) brain after ischemic stroke. We found that as mice aged, Rac1 expression declined in the brain. Delayed overexpression of Rac1, using lentivirus encoding Rac1 injected day 1 after ischemic stroke, promoted cognitive (assessed using novel object recognition test) and sensorimotor (assessed using adhesive removal tests) recovery on days 14-28. This was accompanied by the increase of neurite and proliferative endothelial cells in the peri-infarct zone assessed by immunostaining. In a reverse approach, pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells. Furthermore, Rac1 inhibition reduced the activation of p21-activated kinase 1, the protein level of brain-derived neurotrophic factor, and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke. Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

Structural and functional analyses of Burkholderia pseudomallei BPSL1038 reveal a Cas-2/VapD nuclease sub-family.

Burkholderia pseudomallei is a highly versatile pathogen with ~25% of its genome annotated to encode hypothetical proteins. One such hypothetical protein, BPSL1038, is conserved across seven bacterial genera and 654 Burkholderia spp. Here, we present a 1.55 Å resolution crystal structure of BPSL1038. The overall structure folded into a modified ßαßßαßα ferredoxin fold similar to known Cas2 nucleases. The Cas2 equivalent catalytic aspartate (D11) pairs are conserved in BPSL1038 although B. pseudomallei has no known CRISPR associated system. Functional analysis revealed that BPSL1038 is a nuclease with endonuclease activity towards double-stranded DNA. The DNase activity is divalent ion independent and optimum at pH 6. The concentration of monovalent ions (Na+ and K+) is crucial for nuclease activity. An active site with a unique D11(X20)SST motif was identified and proposed for BPSL1038 and its orthologs. Structure modelling indicates the catalytic role of the D11(X20)SST motif and that the arginine residues R10 and R30 may interact with the nucleic acid backbone. The structural similarity of BPSL1038 to Cas2 proteins suggests that BPSL1038 may represent a sub-family of nucleases that share a common ancestor with Cas2.

Influence and mechanism of sodium-glucose cotransporter-2 inhibitors on the cardiac function: study protocol for a prospective cohort study.

Background: Acute myocardial infarction (AMI) poses a significant threat to cardiovascular diseases (CVDs), leading to a high risk of heart failure (HF) and cardiovascular death. Growing evidence has unveiled the potential of sodium-glucose cotransporter-2 (SGLT2) inhibitors to improve cardiovascular outcomes in patients with CVD regardless of diabetes, but there is limited evidence in AMI patients. Furthermore, it is controversial whether the effects can be ascribed to the amelioration of left ventricular (LV) function, which further complicates the understanding of their underlying mechanism. Methods: This study is a prospective, phase IV, open-label, parallel group, single-center trial conducted in a large tertiary teaching hospital in China. A total of 120 patients with AMI and type 2 diabetes mellitus (T2DM) will be included. Those who received SGLT2 inhibitors are considered as the experimental group, and those taking other antidiabetic agents are considered as the control group. The primary outcome is change in LV end-systolic volume index (LVESVi) measured by cardiac magnetic resonance (CMR) imaging from baseline during 1-year follow-up period. Secondary outcomes include other LV parameters such as LV mass, LV volume, and LV ejection fraction (EF); quality of life and functional capacity such as Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OS) and EuroQol-5 dimension (EQ-5D); biomarkers associated with diagnostic parameters of AMI and possible mechanisms on cardiovascular protection, such as creatine kinase, troponin T (TnT) level, troponin I (TnI) level, soluble suppression of tumorigenicity-2 (sST2), galectin-3 (Gal-3), fibroblast growth factor 21 (FGF21), and microRNA (miRNA) level. Discussion: This study aims to investigate whether SGLT2 inhibitors could improve LV function by measuring CMR, quality of life, and functional capacity in patients with AMI in real-world settings, providing evidence on the underlying mechanism of SGLT2 inhibitors on cardioprotection. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=173672, identifier ChiCTR2200065792.

Poly(butylene adipate-co-terephthalate) biodegradation by Purpureocillium lilacinum strain BA1S.

Poly(butylene adipate-co-terephthalate) (PBAT), a promising biodegradable aliphatic-aromatic copolyester material, can be applied as an alternative material to reduce the adverse effects of conventional plastics. However, the degradation of PBAT plastics in soil is time-consuming, and effective PBAT-degrading microorganisms have rarely been reported. In this study, the biodegradation properties of PBAT by an elite fungal strain and related mechanisms were elucidated. Four PBAT-degrading fungal strains were isolated from farmland soils, and Purpureocillium lilacinum strain BA1S showed a prominent degradation rate. It decomposed approximately 15 wt.% of the PBAT films 30 days after inoculation. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and Liquid chromatography mass spectrometry (LC‒MS) were conducted to analyze the physicochemical properties and composition of the byproducts after biodegradation. In the presence of PBAT, the lipolytic enzyme activities of BA1S were remarkably induced, and its cutinase gene was also significantly upregulated. Of note, the utilization of PBAT in BA1S cells was closely correlated with intracellular cytochrome P450 (CYP) monooxygenase. Furthermore, CreA-mediated carbon catabolite repression was confirmed to be involved in regulating PBAT-degrading hydrolases and affected the degradation efficiency. This study provides new insight into the degradation of PBAT by elite fungal strains and increases knowledge on the mechanism, which can be applied to control the biodegradability of PBAT films in the future. KEY POINTS: • Purpureocillium lilacinum strain BA1S was isolated from farmland soils and degraded PBAT plastic films at a prominent rate. • The lipolytic enzyme activities of strain BA1S were induced during coculture with PBAT, and the cutinase gene was significantly upregulated during PBAT degradation. • CreA-mediated carbon catabolite repression of BA1S plays an essential role in regulating the expression of PBAT-degrading hydrolases.

Getting a Foothold on Diabetic Foot Disease-Outcomes of a Multidisciplinary Clinical Pathway for Inpatient Diabetic Foot Care: A 17-Year Institutional Review.

INTRODUCTION: Diabetes foot disease (DFD) contributes to poor quality of life, clinical and economic burden. Multidisciplinary diabetes foot teams provide prompt access to specialist teams thereby improving limb salvage. We present a 17-year review of an inpatient multidisciplinary clinical care path (MCCP) for DFD in Singapore. METHODS: This was a retrospective cohort study of patients admitted for DFD and enrolled in our MCCP to a 1700-bed university hospital from 2005 to 2021. RESULTS: There were 9279 patients admitted with DFD with a mean of 545 (±119) admissions per year. The mean age was 64 (±13.3) years, 61% were Chinese, 18% Malay and 17% Indian. There was a higher proportion of Malay (18%) and Indian (17%) patients compared to the country's ethnic composition. A third of the patients had end stage renal disease and prior contralateral minor amputation. There was a reduction in inpatient major lower extremity amputation (LEA) from 18.2% in 2005 to 5.4% in 2021 (odds ratio 0.26, 95% confidence interval 0.16-0.40, P < .001) which was the lowest since pathway inception. Mean time from admission to first surgical intervention was 2.8 days and mean time from decision for revascularization to procedure was 4.8 days. The major-to-minor amputation rate reduced from 1.09 in 2005 to 0.18 in 2021, reflecting diabetic limb salvage efforts. Mean and median length of stay (LOS) for patients in the pathway was 8.2 (±14.9) and 5 (IQR = 3) days, respectively. There was a gradual trend of increase in the mean LOS from 2005 to 2021. Inpatient mortality and readmission rate was stable at 1% and 11%. CONCLUSION: Since the institution of a MCCP, there was a significant improvement in major LEA rate. An inpatient multidisciplinary diabetic foot care path helped to improve care for patients with DFD.

Comparison of the effects of remimazolam and dexmedetomidine on early postoperative cognitive function in elderly patients with gastric cancer.

Purpose: To compare the effects of remimazolam and dexmedetomidine on early postoperative cognitive dysfunction (POCD) in aged gastric cancer patients. Methods: From June to December 2022, 104 elderly patients (aged 65-80 years) received laparoscopic radical resection of gastric cancer at the First Affiliated Hospital of Nanchang University. Using the random number table approach, the patients were separated into three groups: remimazolam (Group R), dexmedetomidine (Group D), and saline (Group C). The primary outcome was the incidence of POCD, and secondary outcomes included TNF-α and S-100ß protein concentrations, hemodynamics, VAS scores, anesthesia recovery indicators, and the occurrence of adverse events within 48 h postoperatively. Results: At 3 and 7 days after surgery, there were no statistically significant differences in the incidence of POCD, the MMSE and MoCA scores between groups R and D (p > 0.05). However, compared to the saline group, both groups had higher MMSE and MoCA scores and decreased incidences of POCD. These differences were statistically significant (p < 0.05). Between group R and group D, there were no statistically significant changes (p > 0.05) in the levels of TNF-α and S-100ß protein at the three time points (at the end of the surgery, 1 day later, and 3 days later). Even though neither group's concentration of the two factors was as high as that of the saline group, the differences were statistically significant (p < 0.05). At all three time points-following induction (T2), 30 min into the operation (T3), and at the conclusion of the surgery (T4)-the heart rate and blood pressure in group R were greater than those in groups D and C. Statistics showed that the differences were significant (p < 0.05). The incidence of intraoperative hypotension was highest in group D and lowest in group R (p < 0.05). The dose of propofol and remifentanil, group C > group R > group D. Extubation and PACU residence times did not differ statistically significantly (p > 0.05) between the three groups. There was no significant difference in VAS scores between groups R and D after 24 h postoperatively (p > 0.05), although both had lower scores than group C, and the difference was statistically significant (p < 0.05). The VAS scores between the three groups at 72 h (T6) and 7 days (T7) were not statistically significant (p > 0.05). Adverse reactions such as respiratory depression, hypotension, bradycardia, agitation, drowsiness, and nausea and vomiting had the lowest incidence in group R and the highest incidence in group C (p < 0.05). Conclusion: Remimazolam is similarly beneficial as dexmedetomidine in lowering the incidence of early POCD in aged patients after radical gastric cancer resection, probably due to reduced inflammatory response.

Effects of millimeter-wave for preventing joint stiffness in the immobilized knee rat model.

AIM: To explore the effects and mechanism of millimeter-wave treatment on the development of joint stiffness in the immobilized knee rat model. METHODS: Twenty-four Sprague-Dawley (SD) rats were randomly divided into the control group (O, n = 8), the surgical control group (OC, n = 8), and the millimeter-wave treatment group (MO, n = 8). After immobilized knee modeling, the knee mobility and quadriceps diameter was measured at the 6th week. Hematoxylin and eosin and Masson staining were performed to detect the pathology and fibrous lesions of the knee joint. Furthermore, the expression of TGF-ß1 and Collagen I was quantified by immunohistochemical assay in the knee capsule, and Western blotting was performed to quantify the protein expression of NF-κB and MuRF1 in skeletal muscle. RESULTS: Compared with the O group, knee mobility, and quadriceps diameter was decreased (P < 0.01), and articular capsule fibrosis and quadriceps atrophy occurred in all rats with fixed knee joints. Compared with the OC group, millimeter-wave treatment significantly increased articular mobility and the quadriceps diameter; and improved the fibrotic lesions of the joint capsule and quadriceps atrophy. Moreover, levels of TGF-ß1, Collagen I, and MuRF1 were upregulated (P < 0.01) by knee immobilization, and collagen fiber content in the articular capsule was also increased (P < 0.01). However, millimeter-wave treatment reversed it. The most noteworthy result was that NF-κB expression was not significantly different in all groups. CONCLUSION: Millimeter-wave treatment reversed joint contracture and quadriceps atrophy caused by joint fixation, inhibited TGF-ß1 and Collagen I protein expression of the joint capsule and reduced MuRF1 expression of the quadriceps muscle, thereby inhibiting the development of joint stiffness.

Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis.

Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes. AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although a few studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein we show that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1) during EMT processes and inhibits lung cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2. Genetic deletion of PHF2 aggravates lung cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effect of metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering the transcription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reduces H3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the anti-metastasis effect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higher phosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis via PHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as the potential epigenetic target in cancer metastasis.

CCL17 drives fibroblast activation in the progression of pulmonary fibrosis by enhancing the TGF-ß/Smad signaling.

Pulmonary fibrosis (PF) is a type of fatal respiratory diseases with limited therapeutic options and poor prognosis. The chemokine CCL17 plays crucial roles in the pathogenesis of immune diseases. Bronchoalveolar lavage fluid (BALF) CCL17 levels are significantly higher in patients with idiopathic PF (IPF) than in healthy volunteers. However, the source and function of CCL17 in PF remain unclear. Here, we demonstrated that the levels of CCL17 were increased in the lungs of IPF patients and mice with bleomycin (BLM)-induced PF. In particular, CCL17 were upregulated in alveolar macrophages (AMs) and antibody blockade of CCL17 protected mice against BLM-induced fibrosis and significantly reduced fibroblast activation. Mechanistic studies revealed that CCL17 interacted with its receptor CCR4 on fibroblasts, thereby activating the TGF-ß/Smad signaling pathway to promote fibroblast activation and tissue fibrosis. Moreover, the knockdown of CCR4 by CCR4-siRNA or blockade by CCR4 antagonist C-021 was able to ameliorate PF pathology in mice. In summary, the CCL17-CCR4 axis is involved in the progression of PF, and targeting of CCL17 or CCR4 inhibits fibroblast activation and tissue fibrosis and may benefit patients with fibroproliferative lung diseases.

Investigation of targets and anticancer mechanisms of covalently acting natural products by functional proteomics.

Eriocalyxin B (EB), 17-hydroxy-jolkinolide B (HJB), parthenolide (PN), xanthatin (XT) and andrographolide (AG) are terpenoid natural products with a variety of promising antitumor activities, which commonly bear electrophilic groups (α,ß-unsaturated carbonyl groups and/or epoxides) capable of covalently modifying protein cysteine residues. However, their direct targets and underlying molecular mechanisms are still largely unclear, which limits the development of these compounds. In this study, we integrated activity-based protein profiling (ABPP) and quantitative proteomics approach to systematically characterize the covalent targets of these natural products and their involved cellular pathways. We first demonstrated the anti-proliferation activities of these five compounds in triple-negative breast cancer cell MDA-MB-231. Tandem mass tag (TMT)-based quantitative proteomics showed all five compounds commonly affected the ubiquitin mediated proteolysis pathways. ABPP platform identified the preferentially modified targets of EB and PN, two natural products with high anti-proliferation activity. Biochemical experiments showed that PN inhibited the cell proliferation through targeting ubiquitin carboxyl-terminal hydrolase 10 (USP10). Together, this study uncovered the covalently modified targets of these natural products and potential molecular mechanisms of their antitumor activities.

Antioxidants attenuate mitochondrial oxidative damage through the Nrf2 pathway: A promising therapeutic strategy for stroke.

Stroke represents one of the leading causes of disability and death worldwide. Reactive oxygen species overproduction-induced oxidative stress in mitochondria results in mitochondrial DNA damage, mitochondrial autophagy (mitophagy), inflammation, and apoptosis during the pathologic progression of stroke. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator that induces the transcription of a wide range of antioxidant genes to attenuate mitochondrial oxidative stress. Different antioxidative compounds, including polyphenols, mitochondrial antioxidants, triterpenoids, and others, have been shown to be able to activate Nrf2 and, thus, exert neuroprotective effects on stroke by ameliorating mitochondrial oxidative damage. In this review, we briefly discussed the role of mitochondrial oxidative stress in the pathophysiology of stroke and focused on the protective effects of antioxidative compounds through attenuating mitochondrial oxidative damage by activating Nrf2 in stroke. In conclusion, these antioxidants may represent novel therapeutic strategies against stroke.