Screening for ferroptosis genes related to endometrial carcinoma and predicting of targeted drugs based on bioinformatics.

Endometrial carcinoma is one of most common malignant tumors in women, and ferroptosis is closely related to the development and treatment of endometrial carcinoma. The aim of this study was to screen ferroptosis-related genes associated with endometrial carcinoma and predict targeted drugs through bioinformatics. 761 differentially expressed genes were obtained by the dataset GSE63678 from the GEO database, and most of the genes were enriched in the KEGG_CELL_CYCLE and KEGG_OOCYTE_MEIOSIS signaling pathways. 22 ferroptosis-differentially expressed genes were obtained by intersection with the FerrDb database. These genes were involved in biological processes including macromolecular complex assembly and others, and involved in signal pathways including glutathione metabolism, p53 signaling pathway and others. CDKN2A, IDH1, NRAS, TFRC and GOT1 were obtained as hub genes by PPI network analysis. GEPIA showed that CDKN2A, IDH1, NRAS and TFRC were significantly expressed in endometrial carcinoma. Immunohistochemical results showed that CDKN2A, NRAS and TFRC were significantly expressed in endometrial carcinoma clinical tissue samples. The ROC constructed by TCGA database showed that CDKN2A, NRAS and TFRC had significant value in the diagnosis of endometrial carcinoma, and all had prognostic efficacy. 136,572-09-3 BOSS and others were identified as potential targeted drugs for endometrial carcinoma targeting ferroptosis. Our study has shown that ferroptosis-related genes CDKN2A, NRAS and TFRC are diagnostic markers of endometrial carcinoma, and 136,572-09-3 BOSS, methyprylon BOSS, daunorubicin CTD 00005752, nitroglycerin BOSS and dUTP BOSS, IRON BOSS, Imatinib mesylate BOSS, 2-Butanone BOSS, water BOSS, and L-thyroxine BOSS may be potential therapeutic drugs.

Different evasion strategies in multiple myeloma.

Multiple myeloma is the second most common malignant hematologic malignancy which evolved different strategies for immune escape from the host immune surveillance and drug resistance, including uncontrolled proliferation of malignant plasma cells in the bone marrow, genetic mutations, or deletion of tumor antigens to escape from special targets and so. Therefore, it is a big challenge to efficiently treat multiple myeloma patients. Despite recent applications of immunomodulatory drugs (IMiDS), protease inhibitors (PI), targeted monoclonal antibodies (mAb), and even hematopoietic stem cell transplantation (HSCT), it remains hardly curable. Summarizing the possible evasion strategies can help design specific drugs for multiple myeloma treatment. This review aims to provide an integrative overview of the intrinsic and extrinsic evasion mechanisms as well as recently discovered microbiota utilized by multiple myeloma for immune evasion and drug resistance, hopefully providing a theoretical basis for the rational design of specific immunotherapies or drug combinations to prevent the uncontrolled proliferation of MM, overcome drug resistance and improve patient survival.

B-Type Natriuretic Peptide Inhibits the Expression and Function of SERCA2a in Heart Failure.

B-type natriuretic peptide (BNP) possesses protective cardiovascular properties; however, there has not been sufficient serious consideration of the side effects of BNP. As for sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), it was once considered a new target for the treatment of heart failure (HF). Nevertheless, clinical trials of SERCA2a gene therapy in HF have finally become unsuccessful. Research has found that elevated BNP levels and decreased SERCA2a expression are two important HF characteristics, which are always negatively correlated. We hypothesize that BNP inhibits SERCA2a expression and, therefore, exerts negative effects on SERCA2a expression and function.The effects of BNP on endogenous SERCA2a expression and function were tested in mice with HF induced by transverse aortic constriction and neonatal rat cardiomyocytes (NRCM). Furthermore, to verify the effects of BNP on exogenous SERCA2a gene transduction efficacy, BNP was added to the myocardium and cardiomyocytes infected with an adenovirus overexpressing SERCA2a.In vivo, BNP levels were increased, SERCA2a expression was reduced in both the BNP intervention and HF groups, and BNP reduced the overexpressed exogenous SERCA2a protein in the myocardium. Our in vitro data showed that BNP dose-dependently inhibited the total and exogenous SERCA2a expression in NRCM by activating the cGMP-dependent protein kinase G. BNP also inhibited the effects of SERCA2a overexpression on Ca2+ transience in NRCM.The expression and function of endogenous and exogenous SERCA2a are inhibited by BNP. The opposite relationship between BNP and SERCA2a should be given serious attention in the treatment of HF via BNP or SERCA2a gene therapy.

Rhizoma Paridis saponins attenuate Gram-negative bacteria-induced inflammatory acne by binding to KEAP1 and modulating Nrf2 and MAPK pathways.

Acne vulgaris represents a chronic inflammatory condition, the pathogenesis of which is closely associated with the altered skin microbiome. Recent studies have implicated a profound role of Gram-negative bacteria in acne development, but there is a lack of antiacne agents targeting these bacteria. Polyphyllins are major components of Rhizoma Paridis with great anti-inflammatory potential. In this study, we aimed to evaluate the antiacne effects and the underlying mechanisms of PPH and a PPH-enriched Rhizoma Paridis extract (RPE) in treating the Gram-negative bacteria-induced acne. PPH and RPE treatments significantly suppressed the mRNA and protein expressions of interleukin (IL)-1ß and IL-6 in lipopolysaccharide (LPS)-induced RAW 264.7 and HaCaT cells, along with the intracellular reactive oxygen species (ROS) generation. Furthermore, PPH and RPE inhibited the nuclear translocation of nuclear factor kappa-B (NF-κB) P65 in LPS-induced RAW 264.7 cells. Based on molecular docking, PPH could bind to kelch-like ECH-associated protein 1 (KEAP1) protein. PPH and RPE treatments could activate nuclear factor erythroid 2-related factor 2 (NRF2) and upregulate haem oxygenase-1 (HO-1). Moreover, RPE suppressed the mitogen-activated protein kinase (MAPK) pathway. Therefore, PPH-enriched RPE showed anti-inflammatory and antioxidative effects in vitro, which is promising for alternative antiacne therapeutic.

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice.

Spermatogonial stem cells (SSCs) are essential for continuous spermatogenesis and male fertility. The underlying mechanisms of alternative splicing (AS) in mouse SSCs are still largely unclear. We demonstrated that SRSF1 is essential for gene expression and splicing in mouse SSCs. Crosslinking immunoprecipitation and sequencing data revealed that spermatogonia-related genes (e.g. Plzf, Id4, Setdb1, Stra8, Tial1/Tiar, Bcas2, Ddx5, Srsf10, Uhrf1, and Bud31) were bound by SRSF1 in the mouse testes. Specific deletion of Srsf1 in mouse germ cells impairs homing of precursor SSCs leading to male infertility. Whole-mount staining data showed the absence of germ cells in the testes of adult conditional knockout (cKO) mice, which indicates Sertoli cell-only syndrome in cKO mice. The expression of spermatogonia-related genes (e.g. Gfra1, Pou5f1, Plzf, Dnd1, Stra8, and Taf4b) was significantly reduced in the testes of cKO mice. Moreover, multiomics analysis suggests that SRSF1 may affect survival of spermatogonia by directly binding and regulating Tial1/Tiar expression through AS. In addition, immunoprecipitation mass spectrometry and co-immunoprecipitation data showed that SRSF1 interacts with RNA splicing-related proteins (e.g. SART1, RBM15, and SRSF10). Collectively, our data reveal the critical role of SRSF1 in spermatogonia survival, which may provide a framework to elucidate the molecular mechanisms of the posttranscriptional network underlying homing of precursor SSCs.

BCAS2 regulates oocyte meiotic prophase I by participating in mRNA alternative splicing.

Oocyte meiotic prophase I (MI) is an important event in female reproduction. Breast cancer amplified sequence 2 (BCAS2) is a component of the spliceosome. Previous reports have shown that BCAS2 is critical in male germ cell meiosis, oocyte development, and early embryo genome integrity. However, the role of BCAS2 in oocyte meiosis has not been reported. We used Stra8-GFPCre mice to knock out Bcas2 in oocytes during the pachytene phase. The results of fertility tests showed that Bcas2 conditional knockout (cKO) in oocytes results in infertility in female mice. Morphological analysis showed that the number of primordial follicles in the ovaries of 2-month-old (M) mice was significantly reduced and that follicle development was blocked. Further analysis showed that the number of primordial follicles decreased and that follicle development was slowed in 7-day postpartum (dpp) ovaries. Moreover, primordial follicles undergo apoptosis, and DNA damage cannot be repaired in primary follicle oocytes. Meiosis was abnormal; some oocytes could not reach the diplotene stage, and more oocytes could not develop to the dictyotene stage. Alternative splicing (AS) analysis revealed abnormal AS of deleted in azoospermia like (Dazl) and diaphanous related formin 2 (Diaph2) oogenesis-related genes in cKO mouse ovaries, and the process of AS was involved by CDC5L and PRP19.

Association between sun-protective behaviors and hypertension: a cross-sectional study from National Health and Nutrition Examination Survey 2009 to 2014.

BACKGROUND: In previous studies, sun-protective behaviors increased cardiovascular incidence. Our present article is to further analyze the potential relationship between sun-protective behaviors (staying in the shade, wearing long-sleeved clothing, and applying sunscreen) and hypertension. METHOD: The present cross-sectional study evaluated 8,613 participants (aged 20-60 years) from the National Health and Nutrition Examination Survey (NHANES) obtained between 2009 and 2014. We performed multiple logistic regression analysis to examine the relationship between sun-protective behaviors and hypertension. Subgroup analysis was then performed. Multiple linear regression analysis was utilized to examine the relationship of sun-protective behaviors and each sun-protective behavior with systolic and diastolic blood pressure, stratified by sex and race. RESULTS: A total of 8,613 participants (weighted n = 127,909,475) were applied in our study, including 1,694 hypertensive subjects. Our study demonstrated that sun-protective behaviors of the 2-3 category were associated with increased risk of hypertension, but not with higher systolic and diastolic blood pressure. In subgroup analysis, men, Mexican American, and 25 < BMI ≤ 30 who reported sun-protective behaviors (2-3) were prone to hypertension. Multiple linear regression models showed that non-Hispanic white men with sun-protective behaviors (2-3) were positively associated with systolic and diastolic blood pressure. The association between other-Hispanic men with frequent wearing long-sleeved clothing and diastolic blood pressure was positively correlated. CONCLUSION: Sun-protective behaviors of the 2-3 category could increase the incidence of hypertension, but not increase systolic and diastolic blood pressure. We only found that non-Hispanic white men who reported sun-protective behaviors (2-3) were positively associated with systolic and diastolic blood pressure. These findings suggested that excessive sun-protective behaviors should be avoided.

The role of telomerase in hair growth and relevant disorders: A review.

BACKGROUND: Hair diseases may present with hair loss, hirsutism, hair melanin abnormalities and other manifestations. Hair follicles are known as mini-organs that undergo periodic remodeling, and their constant regeneration in vivo reflects interesting anti-aging functions. Telomerase prevents cellular senescence by maintaining telomere length, but its excessive proliferation in cancer cells may also induce cancer. However, the effects of telomerase in hair growth have rarely been reported. METHODS: In this study, we reviewed the role of telomerase in hair growth and the effects of hair disorders through literature search and analysis. RESULTS: There is growing evidence that telomerase plays an important role in maintaining hair follicle function and proliferation. Changes in telomerase levels in hair follicles have also been found in a variety of hair disorders. CONCLUSION: Telomerase plays a positive role in hair growth and is expected to become a new target for the treatment of alopecia or other hair diseases in the future.

Targeting MET: Discovery of Small Molecule Inhibitors as Non-Small Cell Lung Cancer Therapy.

MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.

The role of inflammatory biomarkers in the development and progression of pre-eclampsia: a systematic review and meta-analysis.

Background: Pre-eclampsia (PE) is a pregnancy complication associated with maternal and fetal morbidity and mortality. Among the potential pathogenesis discussed, inflammation is considered an essential initiator of PE. Previous studies have compared the levels of various inflammatory biomarkers that indicate the existence of PE; however, the relative levels of pro-inflammatory and anti-inflammatory biomarkers and their dynamic changes during PE progression remain unclear. This knowledge is essential to explain the occurrence and progression of the disease. Objective: We aimed to identify the relationship between inflammatory status and PE using inflammatory biomarkers as indicators. We also discussed the underlying mechanism by which inflammatory imbalance contributes to PE by comparing the relative levels of pro-inflammatory and anti-inflammatory biomarkers. Furthermore, we identified additional risk factors for PE. Methods: We reviewed PubMed, Embase, and the Cochrane Library for articles published until 15th September 2022. Original articles that investigated inflammatory biomarkers in PE and normal pregnancy were included. We selected healthy pregnant women as controls. The inflammatory biomarkers in the case and control groups were expressed as standardized mean differences and 95% confidence intervals using a random-effects model. Study quality was assessed using the Newcastle-Ottawa Scale. Publication bias was assessed using Egger's test. Results: Thirteen articles that investigated 2,549 participants were included in this meta-analysis. Patients with PE had significantly higher levels of C-reactive protein (CRP), interleukin (IL)-4, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF) than the controls. CRP and pro-inflammatory cytokine levels were higher than those of anti-inflammatory cytokines. Patients with gestational age > 34 weeks had significantly higher IL-6 and TNF levels. Patients with higher systolic blood pressure had significantly higher IL-8, IL-10, and CRP levels. Conclusion: Inflammatory imbalance is an independent risk factor for PE development. Impairment of the anti-inflammatory system is a crucial initiating factor for PE development. Failed autoregulation, manifested as prolonged exposure to pro-inflammatory cytokines, leads to PE progression. Higher levels of inflammatory biomarkers suggest more severe symptoms, and pregnant women after 34 weeks of gestation are more susceptible to PE.

BCAS2 regulates granulosa cell survival by participating in mRNA alternative splicing.

BACKGROUND: Granulosa cell proliferation and differentiation are essential for follicle development. Breast cancer amplified sequence 2 (BCAS2) is necessary for spermatogenesis, oocyte development, and maintaining the genome integrity of early embryos in mice. However, the function of BCAS2 in granulosa cells is still unknown. RESULTS: We show that conditional disruption of Bcas2 in granulosa cells caused follicle development failure; the ratio of the positive cells of the cell proliferation markers PCNA and Ki67 were unchanged in granulosa cells. Specific deletion of Bcas2 caused a decrease in the BrdU-positive cell ratio, cell cycle arrest, DNA damage, and an increase in apoptosis in granulosa cells, and RPA1 was abnormally stained in granulosa cells. RNA-seq results revealed that knockout of Bcas2 results in unusual expression of cellular senescence genes. BCAS2 participated in the PRP19 complex to mediate alternative splicing (AS) of E2f3 and Flt3l mRNA to inhibit the cell cycle. Knockout of Bcas2 resulted in a significant decrease in the ratio of BrdU-positive cells in the human granulosa-like tumour (KGN) cell line. CONCLUSIONS: Our results suggest that BCAS2 may influence the proliferation and survival of granulosa cells through regulating pre-mRNA splicing of E2f3 and Flt3l by forming the splicing complex with CDC5L and PRP19.

SRSF2 in Sertoli cells is essential for testicular development and spermatogenesis in mice.

Sertoli cells are essential for testis development and normal spermatogenesis by providing support and nutrients. Pre-messenger RNA (pre-mRNA) processing is the basic mechanism required for gene expression, and members of the serine/arginine-rich protein (SR) family are key components of the machines that perform these basic processing events. Serine/arginine-rich splicing factor 2 (SRSF2) is an important member of the SR family; however, the physiological functions of SRSF2 in Sertoli cells are still unclear. Here, we found that SRSF2 was localized in the nuclei of Sertoli and germ cells in male mice at all stages by breeding Amh-Cre mice obtained with Srsf2-specific knockout in Sertoli cells to define the function of SRSF2 in Sertoli cells. The experimental results showed that specific deletion of SRSF2 impaired fetal Sertoli cell proliferation and induced abnormal apoptosis and severe DNA damage in seminiferous tubules, resulting in severe testicular dysplasia, seminiferous tubule atrophy, and almost no normal seminiferous tubules at postnatal day 14. Eventually, these changes resulted in failure to produce normal sperm and infertility. Further RNA-seq results showed that many key genes related to proliferation and apoptosis were downregulated; Racgap1 mRNA undergoes exon skipping. Thus, SRSF2-dependent Sertoli cells are essential for testicular development and male reproduction.

Discovery of D6808, a Highly Selective and Potent Macrocyclic c-Met Inhibitor for Gastric Cancer Harboring MET Gene Alteration Treatment.

MET alterations have been validated as a driven factor in NSCLC and gastric cancers. The c-Met inhibitors, capmatinib, tepotinib, and savolitinib, are only approved for the treatment of NSCLC harboring exon 14 skipping mutant MET. We used a molecular hybridization in conjunction with macrocyclization strategy for structural optimization to obtain a series of 2-(2-(quinolin-6-yl)ethyl)pyridazin-3(2H)-one derivatives as new c-Met inhibitors. One of the macrocyclic compounds, D6808, potently inhibited c-Met kinase and MET-amplified Hs746T gastric cancer cells with IC50 values of 2.9 and 0.7 nM, respectively. It also strongly suppressed Ba/F3-Tpr-Met cells harboring resistance-relevant mutations (F1200L/M1250T/H1094Y/F1200I/L1195V) with IC50 values of 4.2, 3.2, 1.0, 39.0, and 33.4 nM, respectively. Furthermore, D6808 exhibited extraordinary target specificity in a Kinome profiling against 373 wild-type kinases and served as a promising macrocycle-based compound for further anticancer drug development.

The effects of bariatric surgery on cognition in patients with obesity: a systematic review and meta-analysis.

Obesity impairs cognition. Bariatric surgery can result in substantial weight loss in patients with severe obesity; however, the impact of bariatric surgery on cognitive function remains controversial. To quantify the effect of bariatric surgery on cognition in patients with severe obesity, we performed a meta-analysis of 20 studies retrieved from PubMed, Cochrane, and Embase. Of these, 6 cohort studies found that Roux-en-Y gastric bypass leads to better performance for immediate verbal memory function (standardized mean difference [SMD] = .56; 95% confidence interval [CI]: .30-.82, P < .0001; I2 = 0%) and delayed memory function (SMD = .64; 95% CI: .38-.90, P < .00001; I2 = 0%) during in the short term. Similarly, positive impacts on immediate verbal memory function (SMD = .46; 95% CI: .09-.83, P < .00001) and delayed memory function (SMD = .84; 95% CI: .46-1.22, P < .0001) were identified during a long-term follow-up. The Roux-en-Y gastric bypass group showed no improvements in attention, cognitive speed, and executive function compared with the control obese group. In 14 longitudinal studies (12 single-arm pre-post comparison studies and 2 cohort studies whose control group had no follow-up cognitive data), patients performed better postoperatively than preoperatively in all cognitive domains during repeated assessments. The analysis for the 20 operative groups showed that individuals treated with bariatric surgery had higher scores after repeated assessment of most neuropsychological tests except for animal fluency and letter fluency than baseline scores. These findings suggest that patients with severe obesity may obtain immediate verbal and delayed memory function benefits from Roux-en-Y gastric bypass.

Glycosylation modification identifies novel molecular phenotypes and prognostic stratifications of glioma.

Glycosylation modification plays a vital role in tumor progression and is highly associated with glioma prognosis. However, the influence of glycosylation modification on the tumor microenvironment (TME) and omic features of glioma remains unclear. Differentially expressed glycosylation-related genes between adjacent and tumor tissues of The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets were identified. We performed unsupervised clustering to classify patients into different molecular phenotypes, and analyzed their TME heterogeneity, including immunocyte infiltration, immune pathways and tumor purity. Subsequently, we developed a prognostic predicting system named GlycoScore by stepwise least absolute shrinkage and selection operator-Cox regression to evaluate the modification pattern and its association with somatic mutation, clinical significance, immune fractions and drug resistance. Two clustering clusters were identified and presented distinct clinical outcomes and biological functions characterized by hotand cold tumors respectively. Patients with higher GlycoScores exhibited poor prognosis, less mutation counts, and were more sensitive to chemotherapeutics. We also confirmed that the GlycoScore severed as an independent risk factor. Cancer hallmarks such as cell cycle, hippo, and TGFß were active in the high-GlycoScore group. The combination of tumor mutation burden and the GlycoScore presented an excellent performance in prognostic stratification. Our study suggests that glycosylation is essential for modeling TME of glioma and the GlycoScore is a promising prognostic signature and indicator of immunotherapeutic efficacy.

Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC.

KRAS is the most frequently mutated oncogene and plays a predominant role in driving initiation and progression of multiple cancers. Attempts to degrade the oncogene KRASG12C with PROTAC strategy have been considered as an alternative strategy to combate cancers. However, the irreversible PROTACs may compromise the substoichiometric activity to decrease the potency. Herein, we report the development of YF135, the first reversible-covalent PROTAC capable of recruiting VHL mediated proteasomal degradation of KRASG12C. YF135 induces the rapid and sustained degradation of endogenous KRASG12C and attenuates pERK signaling in H358 and H23 cells in a reversible manner.

Improving the bioavailability and bioactivity of garlic bioactive compounds via nanotechnology.

This review highlights main bioactive compounds and important biological functions especially anticancer effects of the garlic. In addition, we review current literature on the stability and bioavailability of garlic components. Finally, this review aims to provide a potential strategy for using nanotechnology to increase the stability and solubility of garlic components, providing guidelines for the qualities of garlic products to improve their absorption and prevent their early degradation, and extend their circulation time in the body. The application of nanotechnology to improve the bioavailability and targeting of garlic compounds are expected to provide a theoretical basis for the functional components of garlic to treat human health. We review the improvement of bioavailability and bioactivity of garlic bioactive compounds via nanotechnology, which could promisingly overcome the limitations of conventional garlic products, and would be used to prevent and treat cancer and other diseases in the near future.

Effect of Defocused Nanosecond Laser Paint Removal on Mild Steel Substrate in Ambient Atmosphere.

The obvious advantages of laser paint removal technology make it a viable alternative to traditional paint removal methods. Infrared nanosecond laser was used to remove paint from car body. The microstructure, composition, surface roughness, hardness and ablative products of the samples were analyzed. The effect of the process combination of laser defocus distance and ambient atmosphere (ambient air, compressed air and inert atmosphere) on the substrate damage and the paint removal effectiveness was explored, and the related mechanism was discussed. Defocus not only changed the fluence of laser spot but also increased the spot diameter. The effect of defocused laser paint removal on the paint and substrate was caused by the superposition of these two factors. The results show that the laser with defocus distance of +4 mm effectively removed the paint in inert atmosphere and has the least adverse effect on the substrate. The content of C element and organic components on the substrate surface was the lowest, and its surface roughness and hardness was very close to the uncoated substrate. Focused laser paint removal in ambient air caused the most serious damage to the substrate. Its surface microhardness increased by 11 HV, and the influence depth reached 37 µm. The mechanism of laser paint removal without auxiliary gas is the superposition of laser plasma effect, laser gasification effect and thermal stress effect. In open atmosphere (compressed air and inert atmosphere), the mechanism of laser paint removal is laser gasification effect and thermal stress effect. This research can provide practical references and theoretical basis for the large-scale industrial application of low/non-damage laser paint removal technology.

Combination pharmacotherapies for cardiac reverse remodeling in heart failure patients with reduced ejection fraction: A systematic review and network meta-analysis of randomized clinical trials.

Pharmacotherapies, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor II blockers (ARBs), ß-blockers (BBs), mineralocorticoid receptor antagonists (MRAs) and angiotensin receptor blocker-neprilysin inhibitor (ARNI), have played a pivotal role in reducing in-hospital and mortality in heart failure patients with reduced ejection fraction (HFrEF). However, effects of the five drug categories used alone or in combination for cardiac reverse remodeling (CRR) in these patients have not been systematically evaluated. A Bayesian network meta-analysis was conducted based on 55 randomized controlled trials published between 1989 and 2019 involving 12,727 patients from PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov. The study is registered with PROSPERO (CRD42020170457). Our primary outcomes were CRR indicators, including changes of left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV), indexed LVEDV (LVEDVI) and LVESV (LVESVI), and left ventricular end-diastolic dimension (LVEDD) and end-systolic dimension (LVESD); Secondary outcomes were functional capacity comprising New York Heart Association (NYHA) class and 6-min walking distance (6MWD); cardiac biomarkers involving B type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP). The effect sizes were presented as the mean difference with 95% credible intervals. According to the results, all dual-combination therapies except ACEI+ARB were significantly more associated with LVEF or NYHA improvement than placebo, ARB+BB and ARNI+BB were the top two effective dual-combinations in LVEF improvement (+7.59% [+4.27, +11.25] and +7.31% [+3.93, +10.97] respectively); ACEI+BB was shown to be superior to ACEI in reducing LVEDVI and LVESVI (-6.88 mL/m2 [-13.18, -1.89] and -10.64 mL/m2 [-18.73, -3.54] respectively); ARNI+BB showed superiority over ACEI+BB in decreasing the level of NT-proBNP (-240.11 pg/mL [-456.57, -6.73]). All tri-combinations were significantly more effective than placebo in LVEF improvement, and ARNI+BB+MRA ranked first (+21.13% [+14.34, +28.13]); ACEI+BB+MRA was significantly more associated with a decrease in LVEDD than ACEI (-6.57 mm [-13.10, -0.84]). A sensitivity analysis ignoring concomitant therapies for LVEF illustrated that all the five drug types except ARB were shown to be superior to placebo, and ARNI ranked first (+4.83% [+1.75, +7.99]). In conclusion, combination therapies exert more benefits on CRR for patients with HFrEF. Among them, ARNI+BB, ARB+BB, ARNI+BB+MRA and ARB+BB+MRA were the top two effective dual and triple combinations in LVEF improvement, respectively; The new "Golden Triangle" of ARNI+BB+MRA was shown to be superior to ACEI+BB+MRA or ARB+BB+MRA in LVEF improvement.

Enhancing stability and anti-inflammatory properties of curcumin in ulcerative colitis therapy using liposomes mediated colon-specific drug delivery system.

Curcumin liposomes (CUR-LPs) was identified by evaluating morphology, appearance, zeta potential, particle diameter, and drug encapsulation efficiency. The results indicated that particle diameter, surface charge and polydispersity index (PDI) of curcumin (CUR)-loaded anionic liposomes were 167 nm, -34 mV and 0.09, respectively. CUR-LPs is high stable pseudo-pH-sensitive nanoparticles system which has a favorable stability in simulated gastric fluid and slower degradation rate allowing CUR sustained release for prolonged times in simulated intestinal fluid. Within 1 h, the CUR consumption was 21.82% in simulated gastric fluid (SGF) and 27.32% in simulated intestinal fluid (SIF), respectively. CUR-LPs could attenuate clinical symptoms including weight loss, diarrhea and fecal bleeding. Especially, it could also prevent dextran sulfate sodium salt (DSS)-inducedcolon tissue damage and colon shortening, and reduce the production of malondialdehyde (MDA), colonic myeloperoxidase (MPO), Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in animal model. Our study illustrated that liposomes (LPs) was a potential carrier to develop the colon-specific drug delivery system incorporating CUR for treating ulcerative colitis.