DataSheet_1_Imaging-Based Body Fat Distribution in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.docx

BackgroundWomen with polycystic ovary syndrome (PCOS) are generally considered to be central obese and at higher risks of metabolic disturbances. Imaging methods are the golden standards for detecting body fat distribution. However, evidence based on magnetic resonance imaging (MRI) and computed tomography (CT) is conflicting. This study systematically reviewed the imaging-based body fat distribution in PCOS patients and quantitatively evaluated the difference in body fat distribution between PCOS and BMI-matched controls.MethodsPUBMED, EMBASE, and Web of Science were searched up to December 2019, and studies quantitatively compared body fat distribution by MRI, CT, ultrasound, or X-ray absorptiometry (DXA) between women with PCOS and their BMI-matched controls were included. Two researchers independently reviewed the articles, extract data and evaluated the study quality based on Newcastle-Ottawa Scale (NOS).Results47 studies were included in systematic review and 39 were eligible for meta-analysis. Compared to BMI-matched controls, higher accumulations of visceral fat (SMD 0.41; 95%CI: 0.23-0.59), abdominal subcutaneous fat (SMD 0.31; 95%CI: 0.20-0.41), total body fat (SMD 0.19; 95% CI: 0.06-0.32), trunk fat (SMD 0.47; 95% CI: 0.17-0.77), and android fat (SMD 0. 36; 95% CI: 0.06-0.66) were identified in PCOS group. However, no significant difference was identified in all the above outcomes in subgroups only including studies using golden standards MRI or CT to evaluate body fat distribution (SMD 0.19; 95%CI: -0.04-0.41 for visceral fat; SMD 0.15; 95%CI: -0.01-0.31 for abdominal subcutaneous fat). Moreover, meta-regression and subgroup analyses showed that young and non-obese patients were more likely to accumulate android fat.ConclusionsPCOS women seem to have abdominal fat accumulation when compared with BMI-matched controls. However, MRI- and CT- assessed fat distribution was similar between PCOS and controls, suggesting central obesity may be independent of PCOS. These findings will help us reappraise the relationship between PCOS and abnormal fat deposition and develop specialized lifestyle interventions for PCOS patients.Systematic Review RegistrationPROSPERO, identifier CRD42018102983.</p

Image1_Comparing the efficacy and safety of medications in adults with hypertrophic cardiomyopathy: a systematic review and network meta-analysis.tif

BackgroundHypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. The purpose of this study was to evaluate the efficacy and safety of several medications and recommend better drug treatments for adults with HCM.MethodsA review of PubMed, Embase, the Cochrane Controlled Register of Trials (CENTRAL), ClinicalTrials.gov and CNKI databases was conducted for studies on the efficacy and safety of drugs for adults with HCM. A frequentist random effects model was used in this network analysis.ResultsThis network meta-analysis included 7 studies assessing seven medications, 6 studies evaluating monotherapy and 1 study evaluating combination therapy. Based on the network meta-analysis results, xiaoxinbi formula plus metoprolol (MD −56.50% [−72.43%, −40.57%]), metoprolol (MD −47.00% [−59.07%, −34.93%]) and mavacamten (MD −34.50% [−44.75%, −24.25%]) significantly reduced the resting left ventricular outflow tract gradient (LVOTG) in comparison with placebo. Resting LVOTG could also be reduced with N-acetylcysteine (NAC). The incidence of adverse drug reactions was not significantly different between the placebo group and the treatment group.ConclusionFor adults with HCM, the top 4 treatments included xiaoxinbi formula plus metoprolol, metoprolol, mavacamten and NAC.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=374222], identifier [CRD42022374222].</p

Table1_Scalable expansion of human pluripotent stem cells under suspension culture condition with human platelet lysate supplementation.DOCX

The large-scale production of human pluripotent stem cells (hPSCs), including both embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), shows potential for advancing the translational realization of hPSC technology. Among multiple cell culture methods, suspension culture, also known as three-dimensional (3D) culture, stands out as a promising method to fulfill the large-scale production requirements. Under this 3D culture condition, cell expansion and the preservation of pluripotency and identity during long-term culture heavily relies on the culture medium. However, the xenogeneic supplements in culture medium remains an obstacle for the translation of cell and gene therapy applications from bench to bedside. Here, we tested human platelet lysate (hPL), a xeno-free and serum-free biological material, as a supplement in the 3D culture of hPSCs. We observed reduced intercellular variability and enhanced proliferation in both hESC and hiPSC lines. These cells, after extended culture in the hPL-supplemented system, maintained pluripotency marker expression, the capacity to differentiate into cells of all three germ layers, and normal karyotype, confirming the practicability and safety of hPL supplementation. Furthermore, through RNA-sequencing analysis, we found an upregulation of genes associated with cell cycle regulations in hPL-treated cells, consistent with the improved cellular division efficiency. Taken together, our findings underscore the potential of hPL as a xeno-free and serum-free supplement for the large-scale production of hPSCs, which holds promise for advancing clinical applications of these cells.</p

Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT

Natural Metal Polyphenol Nanozyme: Free Radical Scavenging and Antioxidation for the Treatment of Acute Kidney Injury

Acute kidney injury (AKI) is a severe renal dysfunction syndrome associated with high morbidity and mortality. Excessive production of reactive oxygen/nitrogen species (RONS) is involved in the development and progression of AKI. Therefore, scavenging endogenous RONS and reducing excessive oxidative stress is essential for restoring renal function after AKI. Although nanozyme-mediated antioxidant therapy has been proposed as an effective strategy to prevent AKI, low renal uptake and high organ toxicity hinder its potential for practical applications. To address this problem, we have designed a metal-phenolic nanozyme named RosA-Mn NPs, which possesses cascade antioxidant functionalities. The nanozyme has multienzymatic cascade capacity as well as broad spectrum of ROS and free radical scavenging activities. As expected, RosA-Mn NPs promote the recovery of mitochondrial function and reduce endoplasmic reticulum stress and secondary inflammation through effective ROS scavenging in vitro. Moreover, RosA-Mn NPs overcome the shortcomings of artificial enzymes that failed to rapidly accumulate in kidney tissues. The renal tubular targeting of RosA-Mn NPs could be exploited to mitigate the tubular damage, improve tubular functions, and eventually prevent the progression of AKI. Notably, RosA-Mn NPs also protect kidney from oxidation and inflammation in a cisplatin-induced AKI mouse model. RNA sequencing analysis demonstrated that autophagy, apoptosis, and antioxidation-related pathways were modulated by the treatment with RosA-Mn NPs. In summary, the multienzymatic activities and biocompatibility of RosA-Mn NPs show great potential in the treatment of AKI and other ROS-related diseases

Antitumor Effects of a Distinct Sonodynamic Nanosystem through Enhanced Induction of Immunogenic Cell Death and Ferroptosis with Modulation of Tumor Microenvironment

Sonodynamic therapy (SDT) holds great promise to be applied for cancer therapy in clinical settings. However, its poor therapeutic efficacy has limited its applications owing to the apoptosis-resistant mechanism of cancer cells. Moreover, the hypoxic and immunosuppressive tumor microenvironment (TME) also weakens the efficacy of immunotherapy in solid tumors. Therefore, reversing TME remains a formidable challenge. To circumvent these critical issues, we developed an ultrasound-augmented strategy to regulate the TME by utilizing an HMME-based liposomal nanosystem (HB liposomes), which can synergistically promote the induction of ferroptosis/apoptosis/immunogenic cell death (ICD) and initiate the reprograming of TME. The RNA sequencing analysis demonstrated that apoptosis, hypoxia factors, and redox-related pathways were modulated during the treatment with HB liposomes under ultrasound irradiation. The in vivo photoacoustic imaging experiment showed that HB liposomes enhanced oxygen production in the TME, alleviated TME hypoxia, and helped to overcome the hypoxia of the solid tumors, consequently improving the SDT efficiency. More importantly, HB liposomes extensively induced ICD, resulting in enhanced T-cell recruitment and infiltration, which normalizes the immunosuppressive TME and facilitates antitumor immune responses. Meanwhile, the HB liposomal SDT system combined with PD1 immune checkpoint inhibitor achieves superior synergistic cancer inhibition. Both in vitro and in vivo results indicate that the HB liposomes act as a sonodynamic immune adjuvant that is able to induce ferroptosis/apoptosis/ICD via generated lipid-reactive oxide species during the SDT and reprogram TME due to ICD induction. This sonodynamic nanosystem integrating oxygen supply, reactive oxygen species generation, and induction of ferroptosis/apoptosis/ICD is an excellent strategy for effective TME modulation and efficient tumor therapy

MXene-Based Dual Functional Nanocomposite with Photothermal Nanozyme Catalytic Activity to Fight Bacterial Infections

Bacterial infections are common complications for diabetic wounds and represent a considerable challenge for wound therapy. Diabetic wound infections differ from those of normal wounds. Owing to the special microenvironment around them, diabetic wounds are more susceptible to infection and are difficult to heal. Nanozymes are of great significance to treat diabetic wound bacterial infections through unique catalytic activities, particularly for controlling drug-resistant bacteria. However, their intrinsically low catalytic activity largely restricts their bactericidal function. Therefore, it is crucial to design and develop novel antibacterial modalities with multiple mechanisms of action. In this study, we design and synthesize a CeO2/Nb2C nanocomposite with dual functions of peroxidase activity and an excellent near-infrared (NIR) photothermal property. Under 808 nm laser irradiation, the CeO2/Nb2C nanocomposite produced a photothermal antibacterial effect and simultaneously displayed a synergistic enzyme catalytic property, thereby killing bacteria in a sustained manner with more than 80% sterilization ratio. The CeO2/Nb2C nanocomposite could accelerate the recovery of diabetic wounds when the skin lesions infected with methicillin-resistant Staphylococcus aureus (MRSA) were irradiated with an 808 nm laser in a diabetic mouse model. An RNA sequencing assay was used to profile the dynamic transcriptome of MRSA. The data set reveals that bacteria experience dysfunction in energy metabolism, cell morphology, and oxidative stress systems during the treatment with CeO2/Nb2C nanocomposite under NIR irradiation, which further affects their survival. Moreover, the CeO2/Nb2C nanocomposite exhibits good biosafety in vitro and in vivo, which indicates their potency as antibacterial agents. This study provides a novel antibacterial strategy by the combination of the catalytic sterilization with the NIR photothermal activity of nanozymes for the effective treatment of MRSA-related diabetic wound infection

Nanozymes with Broad-Spectrum Scavenging of Reactive Oxygen Species (ROS) Alleviate Inflammation in Acute Liver Injury

Reactive oxygen species (ROS) related oxidative stress causes an inflammatory storm and massive hepatocyte necrosis in acute liver injury (ALI). Necrotic hepatocytes trigger an irreversible secondary injury mediated by the innate immune system, potentially leading to liver failure or even death. Therefore, antioxidant therapies may be hepatoprotective. Herein, we have reported novel metal–phenolic nanozymes (CA-Mn NPs) with broad-spectrum ROS scavenging ability. CA-Mn NPs inhibited hepatocyte apoptosis and prevented the recruitment of inflammatory monocytes through antioxidant mechanism in vitro. Meanwhile, CA-Mn NPs suppressed cell apoptosis and the levels of inflammatory factors in carbon tetrachloride (CCl4)-induced ALI mice. We further focused on the anti-inflammatory mechanisms of CA-Mn NPs and found that the Nrf2-Keap1 signaling pathway was upregulated and the NF-κB p65 pathway was downregulated. Besides, CA-Mn NPs restored the autophagic function and converted the M1 type macrophages to the M2 type. RNA sequencing also confirmed that CA-Mn NPs regulate the expression of apoptotic, autophagic, and inflammatory genes. Overall, the clearance of ROS by CA-Mn NPs prevented inflammation and apoptosis in ALI mice, providing new insights for the development of therapeutic strategies