Exercise Attenuate Diaphragm Atrophy in COPD Mice via Inhibiting the RhoA/ROCK Signaling.

Background: Exercise is an indispensable component of pulmonary rehabilitation with strong anti-inflammatory effects. However, the mechanisms by which exercise prevents diaphragmatic atrophy in COPD (chronic obstructive pulmonary disease) remain unclear. Methods: Forty male C57BL/6 mice were assigned to the control (n=16) and smoke (n=24) groups. Mice in the smoke group were exposed to the cigarette smoke (CS) for six months. They were then divided into model and exercise training groups for 2 months. Histological changes were observed in lung and diaphragms. Subsequently, agonist U46639 and antagonist Y27632 of RhoA/ROCK were subjected to mechanical stretching in LPS-treated C2C12 myoblasts. The expression levels of Atrogin-1, MuRF-1, MyoD, Myf5, IL-1ß, TNF-α, and RhoA/ROCK were determined by Western blotting. Results: Diaphragmatic atrophy and increased RhoA/ROCK expression were observed in COPD mice. Exercise training attenuated diaphragmatic atrophy, decreased the expression of MuRF-1, and increased MyoD expression in COPD diaphragms. Exercise also affects the upregulation of RhoA/ROCK and inflammation-related proteins. In in vitro experiments with C2C12 myoblasts, LPS remarkably increased the level of inflammation and protein degradation, whereas Y27632 or combined with mechanical stretching prevented this phenomenon considerably. Conclusion: RhoA/ROCK plays an important role in the prevention of diaphragmatic atrophy in COPD.

Effect of Rectus Sheath Block on Postoperative Quality of Recovery After Transabdominal Midline Gynecological Surgery: A Randomized Controlled Trial.

Introduction: Rectus sheath block is an emerging technique that provide effective perioperative analgesia and is related to lower perioperative opioid consumption and decrease opioid-related adverse effects. The present research is designed to explore the effect of rectus sheath block on recovery quality in patients following transabdominal midline gynecological surgery. Methods: Ninety female patients following elective transabdominal midline gynecological surgery were enrolled. Patients were randomized to group R (n = 45) which receive preoperative ultrasound-guided RSB with 0.4% ropivacaine or group C which is control group (n = 45). The primary outcome was the quality of recovery on the first postoperative day. The quality of recovery was assessed by the 40-item Quality of Recovery questionnaire (QoR-40). Secondary outcomes included the intraoperative opioid consumption, time to first flatus and time to first discharging from bed, postoperative nausea and vomiting, and patient satisfaction. Results: The patients in two groups had comparable baseline characteristics. Postoperative global QoR-40 scores were significantly better in group R than in group C (165.0[159.5-170.0] vs 155.0[150.0-157.0], respectively; median difference 12[95% confidence interval: 8-15, P<0.001]). Preoperative RSB reduced intraoperative opioid consumption, reduced the time to first flatus, time to first discharging from bed and the post anaesthesia care unit discharge time. Furthermore, group R showed greater patient satisfaction. Conclusion: A single preoperative administration of RSB with ropivacaine improved the quality of recovery in patients following transabdominal midline gynecological surgery.

Although laparoscopic surgery accounts for a higher proportion of gynecological procedures, open gynecological surgery remains irreplaceable for some patients. Recovery from open gynecological surgery is a combination of physical injuries and psychological challenges. Consequently, accelerating functional recovery, alleviating discomfort and improving the quality of recovery in such patients is a clinical issue that we need to focus on. The QoR 40 scale is a patient-reported assessment tool which evaluates the quality of recovery in five dimensions. Ultrasound-guided rectus sheath block is a safe and effective abdominal wall nerve block for anesthesia and analgesia of umbilical and median abdominal longitudinal incisions. This study investigated the impact of rectus sheath block on the quality of postoperative recovery after open gynecological surgery using the QoR40 scale. Participants were randomized to two groups: rectus sheath block treatments and a control group receiving standard care only. Rectus sheath block improves the quality of recovery in patients undergoing open gynecological surgery one day after surgery without adverse effects, which has successfully made rapid rehabilitation from bench to bedside.

Mitochondrial activity related genes of mast cells identify poor prognosis and metastasis of ovarian cancer.

The pro-tumorigenic or anti-tumorigenic role of tumor infiltrating mast cells (TIMs) in tumors depends not only on the type of cancer and the degree of tumor progression, but also on their location in the tumor bulk. In our investigation, we employed immunohistochemistry to reveal that the mast cells (MCs) in the tumor stroma are positively correlated with metastasis of ovarian cancer (OC), but not in the tumor parenchyma. To delve deeper into the influence of different culture matrix stiffness on MCs' biological functions within the tumor parenchymal and stromal regions, we conducted a transcriptome analysis of the mouse MC line (P815) cultured in two-dimensional (2D) or three-dimensional (3D) culture system. Further research has found that the softer 3D extracellular matrix stiffness could improve the mitochondrial activity of MCs to promote proliferation by increasing the expression levels of mitochondrial activity-related genes, namely Pet100, atp5md, and Cox7a2. Furthermore, employing LASSO regression analysis, we identified that Pet100 and Cox7a2 were closely associated with the prognosis of OC patients. These two genes were subsequently employed to construct a risk score model, which revealed that the high-risk group model as one of the prognostic factors for OC patients. Additionally, the XCell algorithm analysis showed that the high-risk group displayed a broader spectrum of immune cell infiltrations. Our research revealed that TIMs in the tumor stroma could promote the metastasis of OC, and mitochondrial activity-related proteins Pet100/Cox7a2 can serve as biomarkers for prognostic evaluation of OC.

Aerobic exercise training engages the canonical wnt pathway to improve pulmonary function and inflammation in COPD.

BACKGROUND: We studied whether the exercise improves cigarette smoke (CS) induced chronic obstructive pulmonary disease (COPD) in mice through inhibition of inflammation mediated by Wnt/ß-catenin-peroxisome proliferator-activated receptor (PPAR) γ signaling. METHODS: Firstly, we observed the effect of exercise on pulmonary inflammation, lung function, and Wnt/ß-catenin-PPARγ. A total of 30 male C57BL/6J mice were divided into the control group (CG), smoke group (SG), low-intensity exercise group (LEG), moderate-intensity exercise group (MEG), and high-intensity exercise group (HEG). All the groups, except for CG, underwent whole-body progressive exposure to CS for 25 weeks. Then, we assessed the maximal exercise capacity of mice from the LEG, MEG, and HEG, and performed an 8-week treadmill exercise intervention. Then, we used LiCl (Wnt/ß-catenin agonist) and XAV939 (Wnt/ß-catenin antagonist) to investigate whether Wnt/ß-catenin-PPARγ pathway played a role in the improvement of COPD via exercise. Male C57BL/6J mice were randomly divided into six groups (n = 6 per group): CG, SG, LiCl group, LiCl and exercise group, XAV939 group, and XAV939 and exercise group. Mice except those in the CG were exposed to CS, and those in the exercise groups were subjected to moderate-intensity exercise training. All the mice were subjected to lung function test, lung histological assessment, and analysis of inflammatory markers in the bronchoalveolar lavage fluid, as well as detection of Wnt1, ß-catenin and PPARγ proteins in the lung tissue. RESULTS: Exercise of various intensities alleviated lung structural changes, pulmonary function and inflammation in COPD, with moderate-intensity exercise exhibiting significant and comprehensive effects on the alleviation of pulmonary inflammation and improvement of lung function. Low-, moderate-, and high-intensity exercise decreased ß-catenin levels and increased those of PPARγ significantly, and only moderate-intensity exercise reduced the level of Wnt1 protein. Moderate-intensity exercise relieved the inflammation aggravated by Wnt agonist. Wnt antagonist combined with moderate-intensity exercise increased the levels of PPARγ, which may explain the highest improvement of pulmonary function observed in this group. CONCLUSIONS: Exercise effectively decreases COPD pulmonary inflammation and improves pulmonary function. The beneficial role of exercise may be exerted through Wnt/ß-catenin-PPARγ pathway.

Manganese-based nanomaterials promote synergistic photo-immunotherapy: green synthesis, underlying mechanisms, and multiple applications.

Single phototherapy and immunotherapy have individually made great achievements in tumor treatment. However, monotherapy has difficulty in balancing accuracy and efficiency. Combining phototherapy with immunotherapy can realize the growth inhibition of distal metastatic tumors and enable the remote monitoring of tumor treatment. The development of nanomaterials with photo-responsiveness and anti-tumor immunity activation ability is crucial for achieving photo-immunotherapy. As immune adjuvants, photosensitizers and photothermal agents, manganese-based nanoparticles (Mn-based NPs) have become a research hotspot owing to their multiple ways of anti-tumor immunity regulation, photothermal conversion and multimodal imaging. However, systematic studies on the synergistic photo-immunotherapy applications of Mn-based NPs are still limited; especially, the green synthesis and mechanism of Mn-based NPs applied in immunotherapy are rarely comprehensively discussed. In this review, the synthesis strategies and function of Mn-based NPs in immunotherapy are first introduced. Next, the different mechanisms and leading applications of Mn-based NPs in immunotherapy are reviewed. In addition, the advantages of Mn-based NPs in synergistic photo-immunotherapy are highlighted. Finally, the challenges and research focus of Mn-based NPs in combination therapy are discussed, which might provide guidance for future personalized cancer therapy.

Revisiting airway epithelial dysfunction and mechanisms in chronic obstructive pulmonary disease: the role of mitochondrial damage.

Chronic exposure to environmental hazards causes airway epithelial dysfunction, primarily impaired physical barriers, immune dysfunction, and repair or regeneration. Impairment of airway epithelial function subsequently leads to exaggerated airway inflammation and remodeling, the main features of chronic obstructive pulmonary disease (COPD). Mitochondrial damage has been identified as one of the mechanisms of airway abnormalities in COPD, which is closely related to airway inflammation and airflow limitation. In this review, we evaluate updated evidence for airway epithelial mitochondrial damage in COPD and focus on the role of mitochondrial damage in airway epithelial dysfunction. In addition, the possible mechanism of airway epithelial dysfunction mediated by mitochondrial damage is discussed in detail, and recent strategies related to airway epithelial-targeted mitochondrial therapy are summarized. Results have shown that dysregulation of mitochondrial quality and oxidative stress may lead to airway epithelial dysfunction in COPD. This may result from mitochondrial damage as a central organelle mediating abnormalities in cellular metabolism. Mitochondrial damage mediates procellular senescence effects due to mitochondrial reactive oxygen species, which effectively exacerbate different types of programmed cell death, participate in lipid metabolism abnormalities, and ultimately promote airway epithelial dysfunction and trigger COPD airway abnormalities. These can be prevented by targeting mitochondrial damage factors and mitochondrial transfer. Thus, because mitochondrial damage is involved in COPD progression as a central factor of homeostatic imbalance in airway epithelial cells, it may be a novel target for therapeutic intervention to restore airway epithelial integrity and function in COPD.

Cell sheet formation enhances the therapeutic effects of adipose-derived stromal vascular fraction on urethral stricture.

Urethral stricture (US) is a common disease in urology, lacking effective treatment options. Although injecting a stem cells suspension into the affected area has shown therapeutic benefits, challenges such as low retention rate and limited efficacy hinder the clinical application of stem cells. This study evaluates the therapeutic impact and the mechanism of adipose-derived vascular fraction (SVF) combined with cell sheet engineering technique on urethral fibrosis in a rat model of US. The results showed that SVF-cell sheets exhibit positive expression of α-SMA, CD31, CD34, Stro-1, and eNOS. In vivo study showed less collagen deposition, low urethral fibrosis, and minimal tissue alteration in the group receiving cell sheet transplantation. Furthermore, the formation of a three-dimensional (3D) tissue-like structure by the cell sheets enhances the paracrine effect of SVF, facilitates the infiltration of M2 macrophages, and suppresses the TGF-ß/Smad2 pathway through HGF secretion, thereby exerting antifibrotic effects. Small animal in vivo imaging demonstrates improved retention of SVF cells at the damaged urethra site with cell sheet application. Our results suggest that SVF combined with cell sheet technology more efficiently inhibits the early stages of urethral fibrosis.

"Three-in-One" Multifunctional Hollow Nanocages with Colorimetric Photothermal Catalytic Activity for Enhancing Sensitivity in Biosensing.

Immunochromatographic assays (ICAs) have been widely used in the field detection of mycotoxin contaminants. Nevertheless, the lack of multisignal readout capability and the ability of signaling tags to maintain their biological activity while efficiently loading antibodies remain a great challenge in satisfying diverse testing demands. Herein, we proposed a novel three-in-one multifunctional hollow vanadium nanomicrosphere (high brightness-catalytic-photothermal properties)-mediated triple-readout ICA (VHMS-ICA) for sensitive detection of T-2. As the key to this biosensing strategy, vanadium was used as the catalytic-photothermal characterization center, and natural polyphenols were utilized as the bridging ligands for coupling with the antibody while self-assembling with formaldehyde cross-linking into a hollow nanocage-like structure, which offers the possibility of realizing a three-signal readout strategy and improving the coupling efficiency to the antibody while preserving its biological activity. The constructed sensors showed a detection limit (LOD) of 2 pg/mL for T-2, which was about 345-fold higher than that of conventional gold nanoparticle-based ICA (0.596 ng/mL). As anticipated, the detection range of VHMS-ICA was extended about 8-fold compared with the colorimetric signal alone. Ultimately, the proposed immunosensor performed well in maize and oat samples, with satisfactory recoveries. Owing to the synergistic and complementary interactions between distinct signaling modes, the establishment of multimodal immunosensors with multifunctional tags is an efficient strategy to satisfy diversified detection demands.

FSTL3 promotes tumor immune evasion and attenuates response to anti-PD1 therapy by stabilizing c-Myc in colorectal cancer.

Programmed cell death 1 ligand 1 (PDL1)/programmed cell death 1 (PD1) blockade immunotherapy provides a prospective strategy for the treatment of colorectal cancer (CRC), but various constraints on the effectiveness of the treatment are still remaining. As reported in previous studies, follistatin-like 3 (FSTL3) could mediate inflammatory response in macrophages by induction lipid accumulation. Herein, we revealed that FSTL3 were overexpressed in malignant cells in the CRC microenvironment, notably, the expression level of FSTL3 was related to tumor immune evasion and the clinical efficacy of anti-PD1 therapy. Further studies determined that hypoxic tumor microenvironment induced the FSTL3 expression via HIF1α in CRC cells, FSTL3 could bind to the transcription factor c-Myc (354-406 amino acids) to suppress the latter's ubiquitination and increase its stability, thereby to up-regulated the expression of PDL1 and indoleamine 2,3-dioxygenase 1 (IDO1). The results in the immunocompetent tumor models verified that FSLT3 knockout in tumor cells increased the proportion of CD8+ T cells in the tumor microenvironment, reduced the proportion of regulatory T cells (CD25+ Foxp3+) and exhausted T cells (PD1+ CD8+), and synergistically improved the anti-PD1 therapy efficacy. To sum up, FSTL3 enhanced c-Myc-mediated transcriptional regulation to promote immune evasion and attenuates response to anti-PD1 therapy in CRC, suggesting the potential of FSTL3 as a biomarker of immunotherapeutic efficacy as well as a novel immunotherapeutic target in CRC.

Development and validation of a novel nomogram model to assess the risk of gastric contents in outpatients undergoing elective sedative gastrointestinal endoscopy procedures.

BACKGROUND: Gastric contents may contribute to patients' aspiration during anesthesia. Ultrasound can accurately assess the risk of gastric contents in patients undergoing sedative gastrointestinal endoscopy (GIE) procedures, but its efficiency is limited. Therefore, developing an accurate and efficient model to predict gastric contents in outpatients undergoing elective sedative GIE procedures is greatly desirable. METHODS: This study retrospectively analyzed 1501 patients undergoing sedative GIE procedures. Gastric contents were observed under direct gastroscopic vision and suctioned through the endoscope. High-risk gastric contents were defined as having solid content or liquid volume > 25 ml and pH < 2.5; otherwise, they were considered low-risk gastric contents. Univariate analysis and multivariate analysis were used to select the independent risk factors to predict high-risk gastric contents. Based on the selected independent risk factors, we assigned values to each independent risk factor and established a novel nomogram. The performance of the nomogram was verified in the testing cohort by the metrics of discrimination, calibration, and clinical usefulness. In addition, an online accessible web calculator was constructed. RESULTS: We found BMI, cerebral infarction, cirrhosis, male, age, diabetes, and gastroesophageal reflux disease were risk factors for gastric contents. The AUROCs were 0.911 and 0.864 in the development and testing cohort, respectively. Moreover, the nomogram showed good calibration ability. Decision curve analysis and Clinical impact curve demonstrated that the predictive nomogram was clinically useful. The website of the nomogram was https://medication.shinyapps.io/dynnomapp/. CONCLUSIONS: This study demonstrates that clinical variables can be combined with algorithmic techniques to predict gastric contents in outpatients. Nomogram was constructed from routine variables, and the web calculator had excellent clinical applicability to assess the risk of gastric contents accurately and efficiently in outpatients, assist anesthesiologists in assessment and identify the most appropriate patients for ultrasound.

An AMPK agonist suppresses the progress of colorectal cancer by regulating the polarization of TAM to M1 through inhibition of HIF-1α and mTOR signal pathway.

OBJECTIVE: This study aimed to evaluate the impact of an adenosine monophosphate-activated protein kinase (AMPK) agonist, metformin (MET), on the antitumor effects of macrophages and to determine the underlying mechanism involved in the process. MATERIALS AND METHODS: M0 macrophages were derived from phorbol-12-myristate-13-acetate-stimulated THP-1 cells. RESULTS: The levels of tumor necrosis factor-alpha (TNF-α) and human leukocyte antigen-DR (HLA-DR) were decreased in macrophages incubated with HCT116 cells, whereas those of arginase-1 (Arg-1), CD163, and CD206 were elevated; these effects were reversed by MET. The transfection of small interfering (si) RNA abrogated the influence of MET on the expression of the M1/M2 macrophage biomarkers. MET significantly suppressed the proliferation and migration abilities of HCT116 cells incubated with M0 macrophages; these actions were reversed by siRNA transfection against AMPK. The hypoxia-inducible factor 1-alpha (HIF-1α), phosphorylated protein kinase B (p-AKT), and phosphorylated mammalian target of rapamycin (p-mTOR) levels were reduced by the introduction of MET and promoted by siRNA transfection against AMPK. In addition, the levels of HIF-1α, p-AKT, and p-mTOR suppressed by MET were markedly increased following the transfection of siRNA against AMPK. CONCLUSION: These findings indicate that MET can repress the progression of colorectal cancer by transforming tumor-associated macrophages to the M1phenotype via inhibition of the HIF-1α and mTOR signaling pathways.

Small-molecule exhibits anti-tumor activity by targeting the RNA m6A reader IGF2BP3 in ovarian cancer.

Based on its absence in normal tissues and its role in tumorigenesis and tumor progression, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of N6-methyladenosine (M6A) on RNA, represents a putative valuable and specific target for some cancer therapy. In this study, we performed bioinformatic analysis and immunohistochemistry (IHC) to find that IGF2BP3 was highly expressed in tumor epithelial cells and fibroblasts of ovarian cancer (OC), and was associated with poor prognosis, metastasis, and chemosensitivity in OC patients. In particular, we discovered that knockdown IGF2BP3 expression inhibited the malignant phenotype of OC cell lines by decreasing the protein levels of c-MYC, VEGF, CDK2, CDK6, and STAT1. To explore the feasibility of IGF2BP3 as a therapeutic target for OC, a small molecular AE-848 was designed and screened by molecular operating environment (MOE), which not only could duplicate the above results of knockdown assay but also reduced the expression of c-MYC in M2 macrophages and tumor-associated macrophages and promoted the cytokine IFN-γ and TNF-α secretion. The pharmacodynamic models of two kinds of OC bearing animals were suggested that systemic therapy with AE-848 significantly inhibited tumor growth by reducing the expression of tumor-associated antigen (c-MYC/VEGF/Ki67/CDK2) and improving the anti-tumor effect of macrophages. These results suggest that AE-848 can inhibit the growth and progression of OC cells by disrupting the stability of the targeted mRNAs of IGF2BP3 and may be a targeted drug for OC treatment.

LGALS1 regulates cell adhesion to promote the progression of ovarian cancer.

The present study aimed to explore the significance and molecular mechanisms of galectin-1 (LGALS1) in ovarian cancer (OC). Using the Gene Expression Omnibus database and The Cancer Genome Atlas database, the results of the present study demonstrated that LGALS1 mRNA expression was markedly increased in OC and associated with advanced tumor, lymphatic metastasis and residual lesions. In Kaplan-Meier analysis, patients who expressed LGALS1 highly had a poor prognosis. Furthermore, using The Cancer Genome Atlas database, differentially expressed genes that are potentially regulated by LGALS1 in OC were determined. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to build a biological network of upregulated differentially expressed genes. The results of the enrichment analysis revealed that the upregulated differentially expressed genes were primarily associated with 'ECM-receptor interaction', 'cell-matrix adhesion' and 'focal adhesion', which are closely associated with the metastasis of cancer cells. Subsequently, cell adhesion was selected for further analysis. The results demonstrated that LGALS1 was co-expressed with the candidate genes. Subsequently, the elevated expression levels of candidate genes were verified in OC tissues, and survival analysis indicated that high expression of candidate genes was associated with shortened overall survival of patients with OC. In the present study, OC samples were also collected to verify the high protein expression levels of LGALS1 and fibronectin 1. The results of the present study highlighted that LGALS1 may regulate cell adhesion and participate in the development of OC. Therefore, LGALS1 exhibits potential as a therapeutic target in OC.

Mature cystic teratoma of the ovary with a grossly visible, completely developed intestinal loop: A case report and review of the literature.

RATIONALE: The mature cystic teratoma of the ovary (MCTO), is composed of mature differentiated elements, thus showing highly differentiated tissue and highly morphological heterogeneity. Although gastrointestinal epithelium can be identified in 7% to 13% of cases of MCTO, the occurrence of visible, functional, and fully developed loop tissue is rare in clinical practice. PATIENT CONCERNS: A 17-year-old female patient presented with persistent abdominal pain. DIAGNOSIS: The patient was diagnosed with MCTO where a visible, functional intestinal loop was observed during laparoscopic surgery. Microscopy of the intestinal structure indicated a well-organized, intact layer of intestinal wall. INTERVENTIONS: An emergency single-port laparoscopic excision of the right ovarian cyst and histopathology were performed. OUTCOMES: After 2 years of follow-up, there were no signs of recurrence in the patient. LESSONS: The immune signature of CK7-/CK20+ is characteristic of tumors of gastrointestinal origin and can be used to distinguish tumors associated with mature cystic teratoma. Besides, gynecologists should keep an eye on the possibility of malignant transformation malignant transformation of MCTO.

Association between one-year exposure to air pollution and the prevalence of pulmonary nodules in China.

PM2.5is a well-known airborne hazard to cause various diseases. Evidence suggests that air pollution exposure contributes to the occurrence of pulmonary nodules. Pulmonary nodules detected on the computed tomography scans can be malignant or progress to malignant during follow-up. But the evidence of the association between PM2.5exposure and pulmonary nodules was limited. To examine potential associations of exposures to PM2.5and its major chemical constituents with the prevalence of pulmonary nodules. A total of 16 865 participants were investigated from eight physical examination centers in China from 2014 to 2017. The daily concentrations of PM2.5and its five components were estimated by high-resolution and high-quality spatiotemporal datasets of ground-level air pollutants in China. The logistic regression and the quantile-based g-computation models were used to assess the single and mixture impact of air pollutant PM2.5and its components on the risk of pulmonary nodules, respectively. Each 1 mg m-3increase in PM2.5(OR 1.011 (95% CI: 1.007-1.014)) was positively associated with pulmonary nodules. Among five PM2.5components, in single-pollutant effect models, every 1µg m-3increase in organic matter (OM), black carbon (BC), and NO3-elevated the risk of pulmonary nodule prevalence by 1.040 (95% CI: 1.025-1.055), 1.314 (95% CI: 1.209-1.407) and 1.021 (95% CI: 1.007-1.035) fold, respectively. In mixture-pollutant effect models, the joint effect of every quintile increase in PM2.5components was 1.076 (95% CI: 1.023-1.133) fold. Notably, NO3-BC and OM contributed higher risks of pulmonary nodules than other PM2.5components. And the NO3-particles were identified to have the highest contribution. The impacts of PM2.5components on pulmonary nodules were consistent across gender and age.These findings provide important evidence for the positive correlation between exposure to PM2.5and pulmonary nodules in China and identify that NO3-particles have the highest contribution to the risk.

Imidazo[1,2-a]pyridine Derivatives as AMPK Activators: Synthesis, Structure-Activity Relationships, and Regulation of Reactive Oxygen Species in Renal Fibroblasts.

Adenosine 5'-monophosphate activated protein kinase (AMPK) has emerged as a promising target for the discovery of drugs to treat diabetic nephropathy (DN). Herein, a series of imidazo[1,2-a]pyridines were designed and synthesized. Among them, the active compound (EC50 =11.0 nM) showed good enzyme activation and molecular docking results showed hydrogen bonding interactions with the key amino acids Asn111 and Lys29 in the active site. Meanwhile, further cellular level experiments revealed that it could reduce reactive oxygen species (ROS) levels in NRK-49F cells induced by high glucose, and Western Blot experiments also demonstrate that it can increase the levels of p-AMPK and p-ACC and decrease the levels of TGF-ß1. The results of this study extend the structural types of AMPK activators and provide novel lead compounds for the subsequent development.

Hypoxia-induced ROS aggravate tumor progression through HIF-1α-SERPINE1 signaling in glioblastoma.

Hypoxia, as an important hallmark of the tumor microenvironment, is a major cause of oxidative stress and plays a central role in various malignant tumors, including glioblastoma. Elevated reactive oxygen species (ROS) in a hypoxic microenvironment promote glioblastoma progression; however, the underlying mechanism has not been clarified. Herein, we found that hypoxia promoted ROS production, and the proliferation, migration, and invasion of glioblastoma cells, while this promotion was restrained by ROS scavengers N-acetyl-L-cysteine (NAC) and diphenyleneiodonium chloride (DPI). Hypoxia-induced ROS activated hypoxia-inducible factor-1α (HIF-1α) signaling, which enhanced cell migration and invasion by epithelial-mesenchymal transition (EMT). Furthermore, the induction of serine protease inhibitor family E member 1 (SERPINE1) was ROS-dependent under hypoxia, and HIF-1α mediated SERPINE1 increase induced by ROS via binding to the SERPINE1 promoter region, thereby facilitating glioblastoma migration and invasion. Taken together, our data revealed that hypoxia-induced ROS reinforce the hypoxic adaptation of glioblastoma by driving the HIF-1α-SERPINE1 signaling pathway, and that targeting ROS may be a promising therapeutic strategy for glioblastoma.

HOXC8 alleviates high glucose-triggered damage of trophoblast cells during gestational diabetes mellitus via activating TGFß1-mediated Notch1 pathway.

Gestational diabetes mellitus (GDM) is an increasingly frequent disease occurred during pregnancy. HOXC8 has been disclosed to take part in the regulation of cancers. Additionally, the HOXC8 expression was dramatically decreased in the placenta of pre-eclampsia patients, but its expression and function have not been investigated in GDM. In this work, it was demonstrated that the mRNA and protein expression of HOXC8 was lower in GDM placenta tissues and GDM cell model. In addition, HOXC8 facilitated trophoblast cell proliferation and weakened trophoblast cell mitochondrial apoptosis. HOXC8 enhanced trophoblast cell migration and angiogenesis. Moreover, HOXC8 activated the TGFß1-mediated Notch1 signaling pathway. Results showed that the mRNA and protein expressions of TGFß1 and Notch1 were both lower in the GDM group than that in the NP group. Besides, there were positive correlations among HOXC8, TGFß1 and Notch1. Inhibition of TGFß1 (SB202190 treatment) reversed the effects of HOXC8 on trophoblast cells through modulating cell proliferation, mitochondrial apoptosis, migration and angiogenesis. At last, through in vivo experiments, it was identified that HOXC8 relieved GDM symptoms in vivo. In conclusion, HOXC8 alleviated HG-stimulated damage of trophoblast cells during GDM through activating TGFß1-mediated Notch1 pathway. This discovery may provide a novel and useful bio-target for GDM treatment.

Dual "Unlocking" Strategy to Overcome Inefficient Nanomedicine Delivery and Tumor Hypoxia for Enhanced Photodynamic-Immunotherapy.

Lacking blood vessels is one of the main characteristics of most solid tumors due to their rapid and unrestricted growth, which thus causes the inefficient delivery efficiency of nanomedicine and tumor hypoxia. Herein, a dual "unlocking" strategy to overcome these obstacles is proposed by combining engineered hybrid nanoparticles (named ZnPc@FOM-Pt) with dexamethasone (DXM). It is verified that pretreatment of tumors with DXM can increase intratumorally micro-vessel density (delivery "unlocking") to enhance the tumor delivery efficiency of ZnPc@FOM-Pt and decrease HIF-1α expression. Correspondingly, more Pt can catalyze tumor-overexpressed H2 O2 to produce oxygen to further cause hypoxia "unlocking," ultimately achieving boosted ZnPc-based photodynamic therapy in vivo (tumor inhibition rate: 99.1%). Moreover, the immunosuppressive tumor microenvironment is efficiently reversed and the therapeutic effect of anti-PD-L1-based immunotherapy is promoted by this newly designed nanomedicine. This dual "unlocking" strategy provides an innovative paradigm on simultaneously enhancing nanomedicine delivery efficacy and hypoxia relief for tumor therapy.

GSH-Responsive Organosilica Hybrid Nanosystem as a Cascade Promoter for Enhanced Starvation and Chemodynamic Therapy.

Glucose oxidase (GOD)-mediated starvation therapy (ST) that causes intratumoral glucose depletion is a promising strategy for tumor treatment. However, the ultimate efficacy is inevitably limited by tumor hypoxia, as oxygen is a key component in the consumption of glucose by GOD. In this study, a kind of glutathione (GSH)-responsive organosilica hybrid micelles loaded with Mn3 O4 and GOD (denoted as Mn3 O4 @PDOMs-GOD) is ingeniously designed for enhanced ST and chemodynamic therapy (CDT). Specifically, the internalized Mn3 O4 @PDOMs-GOD in tumor cells consumes intracellular glucose and oxygen (O2 ) under the catalysis of GOD to generate hydrogen peroxide (H2 O2 ), which is subsequently decomposed by Mn3 O4 to liberate O2 . This cyclically regenerated O2 will form a virtuous cycle of O2 and H2 O2 compensation to enhance the ST outcome. Meanwhile, Mn3 O4 can oxidize and deplete the overexpressed GSH in the tumor microenvironment (TME) to release Mn2+ , which then catalyzes H2 O2 into highly toxic hydroxyl radicals (·OH) to accomplish chemodynamic therapy (CDT). Both in vitro and in vivo experiment results demonstrate the significant antitumor efficacy of Mn3 O4 @PDOMs-GOD by the cooperatively enhanced ST and CDT, suggesting the feasibility to develop promising therapeutic platforms with higher treatment efficacies.