Synthesis of scaberol C amino acid ester derivatives with anti-cancer activity.

A series of amino acid ester trifluoroacetate derivatives was synthesized from scaberol C. They were screened for their inhibitory activity against Non-Small Cell Lung Cancer (NSCLC) cells. Among them, compound 2 l showed significant cytotoxicity against A549 and H460 cells (IC50), and was more active than cisplatin (DDP). The epidermal growth factor receptor (EGFR) was overexpressed in NSCLC, which was the target of multiple cancer therapies and a strong prognostic indicator. Our previous studies reported that the target of scaberol C derivatives against NSCLC cells was EGFR. And then molecular docking analysis and molecular dynamics (MD) simulations indicated that 2 l can stably and covalently bind to the EGFR target protein.

Portal Venous and Hepatic Arterial Coefficients Predict Post-Hepatectomy Overall and Recurrence-Free Survival in Patients with Hepatocellular Carcinoma: A Retrospective Study.

Background: The dominant artery blood supply is a characteristic of hepatocellular carcinoma (HCC). However, it is not known whether the blood supply can predict the post-hepatectomy prognosis of patients with HCC. This retrospective study investigated the prognostic value of the portal venous and arterial blood supply estimated on triphasic liver CT (as a portal venous coefficient, PVC, and hepatic arterial coefficient, HAC, respectively) in patients with HCC following hepatectomy. Methods: HCC patients who were tested by triphasic liver CT 2 weeks before hepatectomy and received R0 hepatectomy at the Second Affiliated Hospital, Kunming Medical University between January 1, 2016 and December 31, 2020, were retrospectively screened. Their PVC and HAC, and other variables were analyzed for the prediction of overall survival (OS) and recurrence-free survival (RFS) using the least absolute shrinkage and selection operator and Cox proportional hazard regression models. Results: Four hundred and nineteen patients (53.2 ± 10.6 years of age and 370 men) were evaluated. A shorter OS was independently associated with higher blood albumin and total bilirubin grade [hazard ratio (HR) 2.020, 95% confidence interval (CI) 1.534-2.660], higher Barcelona Clinic Liver Cancer (BCLC) stage (HR 1.514, 95% CI 1.290-1.777), PVC ≤ 0.386 (HR 1.628, 95% CI 1.149-2.305), and HAC > 0.029 (HR 1.969, 95% CI 1.380-2.809). A shorter RFS was independently associated with male (HR 1.652, 95% CI 1.005-2.716), higher serum α-fetoprotein ≥ 400 ng/mL (HR 1.672, 95% CI 1.236-2.263), higher BCLC stage (HR 1.516, 95% CI 1.300-1.768), tumor PVC ≤ 0.386 (HR 1.641, 95% CI 1.198-2.249), and tumor HAC > 0.029 (HR 1.455, 95% CI 1.060-1.997). Conclusion: Tumor PVC or HAC before hepatectomy is valuable for independently predicting postoperative survival of HCC patients.

Tip60-FOXO regulates JNK signaling mediated apoptosis in Drosophila.

The JNK signaling pathway plays crucial roles in various physiological processes, including cell proliferation, differentiation, migration, apoptosis, and stress response. Dysregulation of this pathway is closely linked to the onset and progression of numerous major diseases, such as developmental defects and tumors. Identifying and characterizing novel components of the JNK signaling pathway to enhance and refine its network hold significant scientific and clinical importance for the prevention and treatment of associated cancers. This study utilized the model organism Drosophila and employed multidisciplinary approaches encompassing genetics, developmental biology, biochemistry, and molecular biology to investigate the interplay between Tip60 and the JNK signaling pathway, and elucidated its regulatory mechanisms. Our findings suggest that loss of Tip60 acetyltransferase activity results in JNK signaling pathway activation and subsequent induction of JNK-dependent apoptosis. Genetic epistasis analysis reveals that Tip60 acts downstream of JNK, paralleling with the transcription factor FOXO. The biochemical results confirm that Tip60 can bind to FOXO and acetylate it. Introduction of human Tip60 into Drosophila effectively mitigates apoptosis induced by JNK signaling activation, underscoring conserved regulatory role of Tip60 in the JNK signaling pathway from Drosophila to humans. This study further enhances our understanding of the regulatory network of the JNK signaling pathway. By revealing the role and mechanism of Tip60 in JNK-dependent apoptosis, it unveils new insights and potential therapeutic avenues for preventing and treating associated cancers.

The predictive value of γ-glutamyl transferase to serum albumin ratio in hepatocellular carcinoma patients after liver transplantation.

Background: Elevated preoperative γ-glutamyl transferase (GGT) levels or reduced serum albumin levels have been established as negative prognostic factors for patients with hepatocellular carcinoma (HCC) and various other tumors. Nonetheless, the prognostic significance of the GGT to serum albumin ratio (GAR) in liver transplantation (LT) therapy for HCC is still not well-defined. Methods: A retrospective analysis was conducted on the clinical data of 141 HCC patients who underwent LT at Shulan (Hangzhou) Hospital from June 2017 to November 2020. Using the receiver operating characteristic (ROC) curve, the optimal GAR cutoff value to predict outcomes following LT was assessed. Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent risk factors associated with both overall survival (OS) and recurrence-free survival (RFS). Results: A GAR value of 2.04 was identified as the optimal cutoff for predicting both OS and RFS, with a sensitivity of 63.2% and a specificity of 74.8%. Among these patients, 80 (56.7%) and 90 (63.8%) met the Milan and the University of California San Francisco (UCSF) criteria, respectively. Univariate Cox regression analysis showed that microvascular invasion (MVI), maximum tumor size (>5 cm), total tumor size (>8 cm), liver cirrhosis, TNM stage (III), and GAR (≥2.04) were significantly associated with both postoperative OS and RFS in patients with HCC (all p < 0.05). Multivariate Cox regression analysis indicated that GAR (≥2.04) was independently linked with RFS and OS. Conclusion: Pre-transplant GAR ≥2.04 is an independent correlate of prognosis and survival outcomes after LT for HCC and can be used as a prognostic indicator for both mortality and tumor recurrence following LT.

Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization.

Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.

PSMA7 promotes the malignant proliferation of esophageal cancer.

Background: It is important to explore novel molecules that play a key role in esophageal cancer (ESCA) progression. Methods: Two ESCA tissue expression profile microarrays (GSE92396 and GSE17351) data from GEO were downloaded, and differentially expressed genes (DEGs) were analyzed using GEO2R. The DEGs common to both microarrays were analyzed for protein-protein interactions, KEGG and GO. The altered expression of proteasome 20S subunit α 7 (PSMA7) in ESCA tissues was analyzed using information from publicly available databases (GEO, TCGA, TNMplot). PSMA7 was overexpressed or knocked down in Eca109 and KYSE150 cells using transfection, and the effects on cell proliferation, migration, invasion and apoptosis were examined using CCK-8, Transwell, and flow cytometry experiments. Results: 284 common DEGs were identified, and 10 core proteins, HSP90AA1, AURKA, CDC6, PCNA, MCM5, KAT2B, GRB2, MYBL2, PSMA7, and CKAP5, involved in ESCA progression were identified. PSMA7 mRNA level was significantly increased in ESCA tissues. PSMA7 overexpression significantly promoted the proliferation, migration and invasion of Eca109 and KYSE150 cells, and significantly promoted apoptosis. In contrast, PSMA7 knockdown inhibited their proliferation and motility, and significantly suppressed apoptosis. Conclusion: This study analyzed multiple proteins that may play a key role in ESCA progression, and identified the pro-cancer role of PSMA7.

[Improved unilateral puncture PVP based on 3D printing technology for the treatment of osteoporotic vertebral compression fracture].

OBJECTIVE: To investigate the clinical effect of unilateral percutaneous vertebroplasty (PVP) combined with 3D printing technology for the treatment of thoracolumbar osteoporotic compression fracture. METHODS: A total of 77 patients with thoracolumbar osteoporotic compression fractures from October 2020 to April 2022 were included in the study, all of which were vertebral body compression fractures caused by trauma. According to different treatment methods, they were divided into experimental group and control group. Thirty-two patients used 3D printing technology to improve unilateral transpedicle puncture vertebroplasty in the experimental group, there were 5 males and 27 females, aged from 63 to 91 years old with an average of (77.59±8.75) years old. Forty-five patients were treated with traditional bilateral pedicle puncture vertebroplasty, including 7 males and 38 females, aged from 60 to 88 years old with an average of(74.89±7.37) years old. Operation time, intraoperative C-arm X-ray times, anesthetic dosage, bone cement injection amount, bone cement diffusion good and good rate, complications, vertebral height, kyphotic angle (Cobb angle), visual analogue scale(VAS), Oswestry disability index (ODI) and other indicators were recorded before and after surgery, and statistically analyzed. RESULTS: All patients were followed up for 6 to 23 months, with preoperative imaging studies, confirmed for thoracolumbar osteoporosis compression fractures, two groups of patients with postoperative complications, no special two groups of patients' age, gender, body mass index (BMI), time were injured, the injured vertebral distribution had no statistical difference(P>0.05), comparable data. Two groups of patients with bone cement injection, bone cement dispersion rate, preoperative and postoperative vertebral body height, protruding after spine angle(Cobb angle), VAS, ODI had no statistical difference(P>0.05). The operative time, intraoperative fluoroscopy times and anesthetic dosage were statistically different between the two groups(P<0.05). Compared with the traditional bilateral puncture group, the modified unilateral puncture group combined with 3D printing technology had shorter operation time, fewer intraoperative fluoroscopy times and less anesthetic dosage. The height of anterior vertebral edge, kyphosis angle (Cobb angle), VAS score and ODI of the affected vertebrae were statistically different between two groups at each time point after surgery(P<0.05). CONCLUSION: In the treatment of thoracolumbar osteoporotic compression fractures, 3D printing technology is used to improve unilateral puncture PVP, which is convenient and simple, less trauma, short operation time, fewer fluoroscopy times, satisfactory distribution of bone cement, vertebral height recovery and kyphotic Angle correction, and good functional improvement.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Design of Recyclable Carboxylic Metal-Organic Framework/Chitosan Aerogels for Oil Bleaching.

Novel hierarchical metal-organic framework/chitosan aerogel composites were developed for oil bleaching. UiO-66-COOH-type metal organic frameworks (Zr-MOFs) were synthesized and integrated onto a chitosan matrix with different contents and named MOF-aerogel-1 and MOF-aerogel-2. Due to the compatibility of chitosan, the carboxylic zirconium MOF-aerogels not only maintained the inherent chemical accessibility of UiO-66-COOH, but the unique crystallization and structural characteristics of these MOF nanoparticles were also preserved. Through 3-dimensional reconstructed images, aggregation of the UiO-66-COOH particles was observed in MOF-aerogel-1, while the MOF was homogeneously distributed on the surface of the chitosan lamellae in MOF-aerogel-2. All aerogels, with or without immobilized MOF nanoparticles, were capable of removing carotenoids during oil bleaching. MOF-aerogel-2 showed the most satisfying removal proportions of 26.6%, 36.5%, and 47.2% at 50 °C, 75 °C, and 100 °C, respectively, and its performance was very similar to that of commercial activated clay. The reuse performance of MOF-aerogel-2 was tested, and the results showed its exceptional sustainability for carotenoid removal. These findings suggested the effectiveness of the MOFaerogel for potential utilization in oil bleaching treatments.

Brucine suppresses proliferation and promotes apoptosis of human cholangiacarcinoma cells via the inhibition of COX2 expression.

Aims The aim of this study was to investigate the anti-tumor efficacy of brucine on intrahepatic cholangiocarcinoma (ICC). Methods ICC QBC939 cells were treated with brucine, cell viability, cell cycle and apoptosis were analyzed using CCK-8 and flow cytometry. The expression of COX-2 and apoptosis related proteins Casp3, Bax and Bcl-2 were detected by Western blot analysis. QBC939 cells were subcutaneously transplanted into nude mice and the mice were injected with brucine intraperitoneally. The expression of Ki67, COX-2 and apoptosis related proteins were detected by immunohistochemical staining and Western blot analysis. Results Brucine significantly inhibited the proliferation and cell cycle progression while promoted the apoptosis of QBC939 cells. The expression of the apoptotic proteins Casp3 and Bax was upregulated, while the expression of Bcl-2 and COX-2 was downregulated in QBC939 cells with brucine treatment. Moreover, the overexpression of COX-2 could antagonize the effects of brucine on QBC939 cells. In vivo, brucine inhibited subcutaneous tumor formation in nude mice, and the expression of Ki67, COX-2 and Bcl-2 decreased while the expression of Casp3 and Bax increased in tumor tissues from nude mice with brucine treatment. Conclusions Brucine can significantly inhibit the progression of cholangiocarcinoma in vitro and in vivo, and the mechanism may be related to the inhibition of COX-2 expression.

Low-temperature 3D-printed collagen/chitosan scaffolds loaded with exosomes derived from neural stem cells pretreated with insulin growth factor-1 enhance neural regeneration after traumatic brain injury.

There are various clinical treatments for traumatic brain injury, including surgery, drug therapy, and rehabilitation therapy; however, the therapeutic effects are limited. Scaffolds combined with exosomes represent a promising but challenging method for improving the repair of traumatic brain injury. In this study, we determined the ability of a novel 3D-printed collagen/chitosan scaffold loaded with exosomes derived from neural stem cells pretreated with insulin-like growth factor-1 (3D-CC-INExos) to improve traumatic brain injury repair and functional recovery after traumatic brain injury in rats. Composite scaffolds comprising collagen, chitosan, and exosomes derived from neural stem cells pretreated with insulin-like growth factor-1 (INExos) continuously released exosomes for 2 weeks. Transplantation of 3D-CC-INExos scaffolds significantly improved motor and cognitive functions in a rat traumatic brain injury model, as assessed by the Morris water maze test and modified neurological severity scores. In addition, immunofluorescence staining and transmission electron microscopy showed that 3D-CC-INExos implantation significantly improved the recovery of damaged nerve tissue in the injured area. In conclusion, this study suggests that transplanted 3D-CC-INExos scaffolds might provide a potential strategy for the treatment of traumatic brain injury and lay a solid foundation for clinical translation.

Hydrogen sulfide in health and diseases: cross talk with noncoding RNAs.

Hydrogen sulfide (H2S) is previously described as a potentially lethal toxic gas. However, this gasotransmitter is also endogenously generated by the actions of cystathionine-ß-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in mammalian systems, thus belonging to the family of gasotransmitters after nitric oxide (NO) and carbon monoxide (CO). The physiological or pathological significance of H2S has been extensively expanded for decades. Growing evidence has revealed that H2S exerts cytoprotective functions in the cardiovascular, nervous, and gastrointestinal systems by modulating numerous signaling pathways. With the continuous advancement of microarray and next-generation sequencing technologies, noncoding RNAs (ncRNAs) have gained recognition as key players in human health and diseases due to their considerable potential as predictive biomarkers and therapeutic targets. Coincidentally, H2S and ncRNAs are not independent regulators but interact with each other during the development and progression of human diseases. Specifically, ncRNAs might serve as downstream mediators of H2S or act on H2S-generating enzymes to govern endogenous H2S production. The purpose of this review is to summarize the interactive regulatory roles of H2S and ncRNAs in the initiation and development of various diseases and explore their potential health and therapeutic benefits. This review will also highlight the importance of cross talk between H2S and ncRNAs in disease therapy.

Comparison of lateral transperitoneal versus retroperitoneal laparoscopic adrenalectomy for pheochromocytoma: a single-centre retrospective study.

Laparoscopic adrenalectomy (LA) has became the standardized treatment for pheochromocytoma. The aim of this study was to evaluate outcomes of lateral transperitoneal and retroperitoneal LA for pheochromocytoma. Between January 2011 and December 2021, 142 patients with pheochromocytoma underwent LA via lateral transperitoneal (123 patients) or retroperitoneal (19 patients) approaches. Data of these patients were assessed to investigate the differences in perioperative outcomes and intraoperative haemodynamic parameters between the two procedures. Clinical parameters at presentation were comparable between the two groups, except for tumour size, which was larger in the transperitoneal group (50 [10-115] mm vs 35 [7-110] mm, P = 0.012). There were no significant differences between the two groups in terms of operation time, estimated blood loss, intraoperative transfusion rate, incidence of complications, conversion to open surgery, postoperative analgesic requirement, time to first oral intake, or mean hospital stay. Intraoperative haemodynamic parameters of the two groups were similar. After adjusting for tumour size using propensity score matching, both perioperative outcomes and haemodynamic parameters were still comparable. Lateral transperitoneal and retroperitoneal laparoscopic adrenalectomies provide similar perioperative and haemodynamic outcomes for surgical resection of pheochromocytoma.

Multi-omics profiling of cholangiocytes reveals sex-specific chromatin state dynamics during hepatic cystogenesis in polycystic liver disease.

BACKGROUND & AIMS: Cholangiocytes transit from quiescence to hyperproliferation during cystogenesis in polycystic liver disease (PLD), the severity of which displays prominent sex differences. Epigenetic regulation plays important roles in cell state transition. We aimed to investigate the sex-specific epigenetic basis of hepatic cystogenesis and to develop therapeutic strategies targeting epigenetic modifications for PLD treatment. METHODS: Normal and cystic primary cholangiocytes were isolated from wild-type and PLD mice of both sexes. Chromatin states were characterized by analyzing chromatin accessibility (ATAC sequencing) and multiple histone modifications (chromatin immunoprecipitation sequencing). Differential gene expression was determined by transcriptomic analysis (RNA sequencing). Pharmacologic inhibition of epigenetic modifying enzymes was undertaken in PLD model mice. RESULTS: Through genome-wide profiling of chromatin dynamics, we revealed a profound increase of global chromatin accessibility during cystogenesis in both male and female PLD cholangiocytes. We identified a switch from H3K9me3 to H3K9ac on cis-regulatory DNA elements of cyst-associated genes and showed that inhibition of H3K9ac acetyltransferase or H3K9me3 demethylase slowed cyst growth in male, but not female, PLD mice. In contrast, we found that H3K27ac was specifically increased in female PLD mice and that genes associated with H3K27ac-gained regions were enriched for cyst-related pathways. In an integrated epigenomic and transcriptomic analysis, we identified an estrogen receptor alpha-centered transcription factor network associated with the H3K27ac-regulated cystogenic gene expression program in female PLD mice. CONCLUSIONS: Our findings highlight the multi-layered sex-specific epigenetic dynamics underlying cholangiocyte state transition and reveal a potential epigenetic therapeutic strategy for male PLD patients. IMPACT AND IMPLICATIONS: In the present study, we elucidate a sex-specific epigenetic mechanism underlying the cholangiocyte state transition during hepatic cystogenesis and identify epigenetic drugs that effectively slow cyst growth in male PLD mice. These findings underscore the importance of sex difference in the pathogenesis of PLD and may guide researchers and physicians to develop sex-specific personalized approaches for PLD treatment.

Flavonoid-Rich Extract of Oldenlandia diffusa (Willd.) Roxb. Inhibits Gastric Cancer by Activation of Caspase-Dependent Mitochondrial Apoptosis.

OBJECTIVE: To evaluate the apoptosis and cycle arrest effects of Oldenlandia diffusa flavonoids on human gastric cancer cells, determine the action mechanisms in association with the mitochondrial dependent signal transduction pathway that controls production of reactive oxygen species (ROS), and evaluate the pharmacodynamics of a mouse xenotransplantation model to provide a reference for the use of flavonoids in prevention and treatment of gastric cancer. METHODS: Flavonoids were extracted by an enzymatic-ultrasonic assisted method and purified with D-101 resin. Bioactive components were characterized by high-performance liquid chromatography. Cell lines MKN-45, AGS, and GES-1 were treated with different concentrations of flavonoids (64, 96, 128, 160 µg/mL). The effect of flavonoids on cell viability was evaluated by MTT method, and cell nuclear morphology was observed by Hoechst staining. The apoptosis rate and cell cycle phases were measured by flow cytometry, the production of ROS was detected by laser confocal microscope, the mitochondrial membrane potential (MMP) were observed by fluorescence microscope, and the expression of apoptotic proteins related to activation of mitochondrial pathway were measured by immunoblotting. MKN-45 cells were transplanted into BALB/c nude mice to establish a xenograft tumor model. Hematoxylin and eosin staining was used to reveal the subcutaneous tumor tissue. The tumor volume and tumor weight were measured, the expression levels of proliferation markers proliferating cell nuclear antigen (PCNA) and Ki-67 were detected by immunohistochemistry, and the expression levels of CA72-4 were measured by enzyme linked immunosorbent assay. RESULTS: Oldenlandia diffusa flavonoids inhibited proliferation of MKN-45 and AGS human gastric cancer cells, arrested the cell cycle in G1/S phase, induced accumulation of ROS in the process of apoptosis, and altered MMP. In addition, flavonoids increased Apaf-1, Cleaved-Caspase-3, and Bax, and decreased Cyclin A, Cdk2, Bcl-2, Pro-Caspase-9, and Mitochondrial Cytochrome C (P<0.05). The MKN-45 cell mouse xenotransplantation model further clarified the growth inhibitory effect of flavonoids towards tumors. The expression levels of PCNA and Ki-67 decreased in each flavonoid dose group, the expression level of CA72-4 decreased (P<0.05). CONCLUSION: Flavonoids derived from Oldenlandia diffusa can inhibit proliferation and induce apoptosis of human gastric cancer cells by activating the mitochondrial controlled signal transduction pathway.

Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy.

INTRODUCTION: Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation. Metrnl is found to protect against cardiac hypertrophy and doxorubicin-induced cardiotoxicity. However, its role in diabetic cardiomyopathy (DCM) is undefined. OBJECTIVES: We aimed to elucidate the potential roles of Metrnl in DCM. METHODS: Gain- andloss-of-function experimentswere utilized to determine the roles of Metrnl in the pathological processes of DCM. RESULTS: We found that plasma Metrnl levels, myocardial Metrnl protein and mRNA expressions were significantly downregulated in both streptozotocin (STZ)-induced (T1D) mice and leptin receptor deficiency (db/db) (T2D) mice. Cardiac-specific overexpression (OE) of Metrnl markedly ameliorated cardiac injury and dysfunction in both T1D and T2D mice. In sharp contrast, specific deletion of Metrnl in the heart had the opposite phenotypes. In parallel, Metrnl OE ameliorated, whereas Metrnl downregulation exacerbated high glucose (HG)-elicited hypertrophy, apoptosis and oxidative damage in primary neonatal rat cardiomyocytes. Antibody-induced blockade of Metrnl eliminated the effects of benefits of Metrnl in vitro and in vivo. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism in cardiomyocytes. Besides, Metrnl-induced ULK1 phosphorylation facilitated the dephosphorylation and mitochondrial translocation of STING where it interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase that was responsible for ubiquitination and degradation of STING, rendering cardiomyocytes sensitive to autophagy activation. CONCLUSION: Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.

First-Principles Study on Mechanical and Optical Behavior of Plutonium Oxide under Typical Structural Phases and Vacancy Defects.

The chemical corrosion aging of plutonium is a very important topic. It is easy to be corroded and produces oxidation products of various valence states because of its 5f electron orbit between local and non-local. On the one hand, the phase diagram of plutonium and oxygen is complex, so there is still not enough research on typical structural phases. On the other hand, most of the studies on plutonium oxide focus on PuO2 and Pu2O3 with stoichiometric ratio, while the understanding of non-stoichiometric ratio, especially for Pu2O3-x, is not deep enough. Based on this, using the DFT + U theoretical scheme of density functional theory, we have systematically studied the structural stability, lattice parameters, electronic structure, mechanical and optical properties of six typical high temperature phases of ß-Pu2O3, α-Pu2O3,γ-Pu2O3, PuO, α-PuO2,γ-PuO2. Further, the mechanical properties and optical behavior of Pu2O3-x under different oxygen vacancy concentrations are analyzed and discussed in detail. The result shows that the elasticity modulus of single crystal in mechanical properties is directly related to the oxygen/plutonium ratio and crystal system. As the number of oxygen vacancies increases, the mechanical constants continue to increase. In terms of optical properties, PuO has the best optical properties, and the light absorption rate decreases with the increase of oxygen vacancy concentration.

Benefits of Curcumin in the Vasculature: A Therapeutic Candidate for Vascular Remodeling in Arterial Hypertension and Pulmonary Arterial Hypertension?

Growing evidence suggests that hypertension is one of the leading causes of cardiovascular morbidity and mortality since uncontrolled high blood pressure increases the risk of myocardial infarction, aortic dissection, hemorrhagic stroke, and chronic kidney disease. Impaired vascular homeostasis plays a critical role in the development of hypertension-induced vascular remodeling. Abnormal behaviors of vascular cells are not only a pathological hallmark of hypertensive vascular remodeling, but also an important pathological basis for maintaining reduced vascular compliance in hypertension. Targeting vascular remodeling represents a novel therapeutic approach in hypertension and its cardiovascular complications. Phytochemicals are emerging as candidates with therapeutic effects on numerous pathologies, including hypertension. An increasing number of studies have found that curcumin, a polyphenolic compound derived from dietary spice turmeric, holds a broad spectrum of pharmacological actions, such as antiplatelet, anticancer, anti-inflammatory, antioxidant, and antiangiogenic effects. Curcumin has been shown to prevent or treat vascular remodeling in hypertensive rodents by modulating various signaling pathways. In the present review, we attempt to focus on the current findings and molecular mechanisms of curcumin in the treatment of hypertensive vascular remodeling. In particular, adverse and inconsistent effects of curcumin, as well as some favorable pharmacokinetics or pharmacodynamics profiles in arterial hypertension will be discussed. Moreover, the recent progress in the preparation of nano-curcumins and their therapeutic potential in hypertension will be briefly recapped. The future research directions and challenges of curcumin in hypertension-related vascular remodeling are also proposed. It is foreseeable that curcumin is likely to be a therapeutic agent for hypertension and vascular remodeling going forwards.

AtRsmD Is Required for Chloroplast Development and Chloroplast Function in Arabidopsis thaliana.

AtRsmD was recently demonstrated to be a chloroplast 16S rRNA methyltransferase (MTase) for the m2G915 modification in Arabidopsis. Here, its function of AtRsmD for chloroplast development and photosynthesis was further analyzed. The AtRsmD gene is highly expressed in green photosynthetic tissues. AtRsmD is associated with the thylakoid in chloroplasts. The atrsmd-2 mutant exhibited impaired photosynthetic efficiency in emerging leaves under normal growth conditions. A few thylakoid lamellas could be observed in the chloroplast from the atrsmd-2 mutant, and these thylakoids were loosely organized. Knockout of the AtRsmD gene had minor effects on chloroplast ribosome biogenesis and RNA loading on chloroplast ribosomes, but it reduced the amounts of chloroplast-encoded photosynthesis-related proteins in the emerging leaves, for example, D1, D2, CP43, and CP47, which reduced the accumulation of the photosynthetic complex. Nevertheless, knockout of the AtRsmD gene did not cause a general reduction in chloroplast-encoded proteins in Arabidopsis grown under normal growth conditions. Additionally, the atrsmd-2 mutant exhibited more sensitivity to lincomycin, which specifically inhibits the elongation of nascent polypeptide chains. Cold stress exacerbated the effect on chloroplast ribosome biogenesis in the atrsmd-2 mutant. All these data suggest that the AtRsmD protein plays distinct regulatory roles in chloroplast translation, which is required for chloroplast development and chloroplast function.

Giant retroperitoneal lipoma presenting with abdominal distention: A case report and review of the literature.

BACKGROUND: Retroperitoneal lipomas are extremely rare tumors and tend to be large in size (> 10 cm) when diagnosed, causing various clinical manifestations. Preoperative diagnosis of retroperitoneal lipomas is difficult. There is a lack of relevant information about the management and prognosis of these benign tumors due to limited reports. CASE SUMMARY: A 53-year-old woman who complained about progressive abdominal distention and aggravating satiety was referred to the gynecological outpatient department of Peking Union Medical College Hospital. Computerized tomography (CT) revealed an immense mass with fat density, measuring 28.6 cm× 16.6 cm in size. Adjacent organs, including the intestinal tract and uterus, were squeezed to the right side of the abdomen. An exploratory laparotomy was performed with suspicion of liposarcoma. Intraoperatively, a giant yellowish lobulated mass was found occupying the retroperitoneum and it was removed by tumor debulking. Postoperative histopathological results confirmed the diagnosis of retroperitoneal lipoma. CONCLUSION: Retroperitoneal lipoma is a very rare condition and is difficult to differentiate from well-differentiated liposarcoma. Radiographic investigations, especially CT and magnetic resonance imaging, are important for preoperative diagnosis. Surgical resection is the fundamental treatment, which is difficult due to its size and relation to neighboring structures.