Nicotinamide riboside attenuates myocardial ischemia-reperfusion injury via regulating SIRT3/SOD2 signaling pathway.

Ischemic heart disease invariably leads to devastating damage to human health. Nicotinamide ribose (NR), as one of the precursors of NAD+ synthesis, has been discovered to exert a protective role in various neurological and cardiovascular disorders. Our findings demonstrated that pretreatment with 200 mg/kg NR for 3 h significantly reduced myocardial infarct area, decreased levels of CK-MB and LDH in serum, and improved cardiac function in the rats during myocardial ischemia-reperfusion (I/R) injury. Meanwhile, 0.5 mM NR also effectively increased the viability and decreased the LDH release of H9c2 cells during OGD/R. We had provided evidence that NR pretreatment could decrease mitochondrial reactive oxygen species (mtROS) production and MDA content, and enhance SOD activity, thereby mitigating mitochondrial damage and inhibiting apoptosis during myocardial I/R injury. Further investigations revealed that NR increased NAD+ content and upregulated SIRT3 protein expression in myocardium. Through using of SIRT3 small interfering RNA and the SIRT3 deacetylase activity inhibitor 3-TYP, we had confirmed that the cardioprotective effect of NR on cardiomyocytes was largely dependent on the inhibition of mitochondrial oxidative stress via SIRT3-SOD2 axis. Overall, our study suggested that exogenous supplementation with NR mitigated mitochondrial damage and inhibited apoptosis during myocardial I/R injury by reducing mitochondrial oxidative stress via SIRT3-SOD2-mtROS pathway.

Regulation of FSP1 myristoylation by NADPH: A novel mechanism for ferroptosis inhibition.

Excitotoxicity is a prevalent pathological event in neurodegenerative diseases. The involvement of ferroptosis in the pathogenesis of excitotoxicity remains elusive. Transcriptome analysis has revealed that cytoplasmic reduced nicotinamide adenine dinucleotide phosphate (NADPH) levels are associated with susceptibility to ferroptosis-inducing compounds. Here we show that exogenous NADPH, besides being reductant, interacts with N-myristoyltransferase 2 (NMT2) and upregulates the N-myristoylated ferroptosis suppressor protein 1 (FSP1). NADPH increases membrane-localized FSP1 and strengthens resistance to ferroptosis. Arg-291 of NMT2 is critical for the NADPH-NMT2-FSP1 axis-mediated suppression of ferroptosis. This study suggests that NMT2 plays a pivotal role by bridging NADPH levels and neuronal susceptibility to ferroptosis. We propose a mechanism by which the NADPH regulates N-myristoylation, which has important implications for ferroptosis and disease treatment.

Regulation of cardiac fibrosis in mice with TAC/DOCA-induced HFpEF by resistin-like molecule gamma and adenylate cyclase 1.

Heart failure with preserved ejection fraction (HFpEF) is one of the major subtypes of heart failure (HF) and no effective treatments for this common disease exist to date. Cardiac fibrosis is central to the pathology of HF and a potential avenue for the treatment of HFpEF. To explore key fibrosis-related genes and pathways in the pathophysiological process of HFpEF, a mouse model of HFpEF was constructed. The relevant gene expression profiles were downloaded from the Gene Expression Omnibus database, and single-sample Gene Set Enrichment Analysis (ssGSEA) was performed targeting fibrosis-related pathways to explore differentially expressed genes (DEGs) in healthy control and HFpEF heart tissues with cross-tabulation analysis of fibrosis-related genes. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the identified fibrosis-related genes. The two most significant DEGs were selected, and further validation was conducted in HFpEF mice. The results indicated that myocardial fibrosis was significantly upregulated in HFpEF mice compared to healthy controls, while the ssGSEA results revealed significant differences in the enrichment of nine fibrosis-related pathways in HFpEF myocardial tissue, with 112 out of 798 DEGs being related to fibrosis. The in vivo results demonstrated that expression levels of resistin-like molecule gamma (Relmg) and adenylate cyclase 1 (Adcy1) in the heart tissues of HFpEF mice were significantly higher and lower, respectively, compared to healthy controls. Taken together, these results suggest that Relmg and Acdy1 as well as the fibrosis process may be potential targets for HFpEF treatment.

Inflammatory cytokine profiles in erectile dysfunction: a bidirectional Mendelian randomization.

Objectives: Inflammatory cytokines (ICs) play an important role in erectile dysfunction (ED). Previous studies have demonstrated that most ED patients have high levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). The causality between 41 ICs and ED is investigated using the Mendelian randomization (MR) approach. Methods: Single nucleotide polymorphisms (SNPs) exposure data of 41 ICs came from a genome-wide association study (GWAS) of 8293 subjects. At the same time, the FINNGEN R9 database provided the ED outcome data containing 2205 ED patients and 164104 controls. MR-Egger (ME), inverse variance weighting (IVW), and weighted median (WM) were applied to conduct the MR study and IVW was taken as the main criterion. Results: From a genetic perspective, the increase of interferon-inducible protein-10 (IP-10) level significantly increased the risk of ED (P=0.043, odds ratio (OR)=1.269, 95% confidence interval (95%CI): 1.007-1.600), while the increase of interleukin-1 receptor antagonist (IL-1RA) markedly decreased the risk of ED (P=0.037, OR=0.768, 95%CI: 0.600-0.984). Meanwhile, IP-10 (p=0.099) and IL-1RA (p=0.135) failed to demonstrate causality in reverse MR analysis. Conclusions: Changes in ICs levels will significantly affect the risk of ED, especially IP-10 as a risk component for ED and IL-1RA as a protective component for ED. In the future, we can achieve targeted treatment and prevention of ED by intervening with specific inflammatory factors.

TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes.

Obesity is one of the most common metabolic diseases around the world, which is distinguished by the abnormal buildup of triglycerides within adipose cells. Recent research has revealed that autophagy regulates lipid mobilization to maintain energy balance. TIGAR (Trp53 induced glycolysis regulatory phosphatase) has been identified as a glycolysis inhibitor, whether it plays a role in the metabolism of lipids is unknown. Here, we found that TIGAR transgenic (TIGAR+/+) mice exhibited increased fat mass and trended to obesity phenotype. Non-target metabolomics showed that TIGAR caused the dysregulation of the metabolism profile. The quantitative transcriptome sequencing identified an increased levels of LRRK2 and RAB7B in the adipose tissue of TIGAR+/+ mice. It was confirmed in vitro that TIGAR overexpression increased the levels of LRRK2 by inhibiting polyubiquitination degradation, thereby suppressing macroautophagy and chaperone-mediated autophagy (CMA) while increasing lipid accumulation which were reversed by the LRRK2 inhibitor DNL201. Furthermore, TIGAR drove LRRK2 to interact with RAB7B for suppressing lysosomal degradation of lipid droplets, while the increased lipid droplets in adipocytes were blocked by the RAB7B inhibitor ML282. Additionally, fat-specific TIGAR knockdown of TIGAR+/+ mice alleviated the symptoms of obesity, and adipose tissues-targeting superiority DNL201 nano-emulsion counteracted the obesity phenotype in TIGAR+/+ mice. In summary, the current results indicated that TIGAR performed a vital function in the lipid metabolism through LRRK2-mediated negative regulation of macroautophagy and CMA in adipocyte. The findings suggest that TIGAR has the potential to serve as a viable therapeutic target for treating obesity and its associated metabolic dysfunction.

Transcriptomic and physiological analyses of Symphytum officinale L. in response to multiple heavy metal stress.

Soil heavy metal contamination has become a global environmental issue, which threaten soil quality, food security and human health. Symphytum officinale L. have exhibited high tolerance and restoration capacity to heavy metals (HMs) stress. However, little is known about the mechanisms of HMs in S. officinale. In this study, transcriptomic and physiological changes of S. officinale response to different HMs (Pb, Cd and Zn) were analyzed and investigated the key genes and pathways involved in HMs uptake patterns. The results showed that phenotypic effects are not significant, and antioxidant enzyme activities were all upregulated. Transcriptome analysis indicated that 1247 differential genes were up-regulated, and 1963 differential genes were down-regulated under Cd stress, while 3752 differential genes were up-regulated, and 7197 differential genes were down-regulated under Pb stress; and 527 differential genes were up-regulated; and 722 differential genes were down-regulated under Zn stress. Based on their expression, we preliminarily speculate that different HMs resistance of S. officinale may be regulated by the differential expression of key genes. These results provide a theoretical basis for determining the exact expression of genes in plants under different heavy metal stress, the processes involved molecular pathways, and how they can be efficiently utilized to improve plant tolerance to toxic metals and improve phytoremediation efficiency.

Phase Error Reduction for a Structured-Light 3D System Based on a Texture-Modulated Reprojection Method.

Fringe projection profilometry (FPP), with benefits such as high precision and a large depth of field, is a popular 3D optical measurement method widely used in precision reconstruction scenarios. However, the pixel brightness at reflective edges does not satisfy the conditions of the ideal pixel-wise phase-shifting model due to the influence of scene texture and system defocus, resulting in severe phase errors. To address this problem, we theoretically analyze the non-pixel-wise phase propagation model for texture edges and propose a reprojection strategy based on scene texture modulation. The strategy first obtains the reprojection weight mask by projecting typical FPP patterns and calculating the scene texture reflection ratio, then reprojects stripe patterns modulated by the weight mask to eliminate texture edge effects, and finally fuses coarse and refined phase maps to generate an accurate phase map. We validated the proposed method on various texture scenes, including a smooth plane, depth surface, and curved surface. Experimental results show that the root mean square error (RMSE) of the phase at the texture edge decreased by 53.32%, proving the effectiveness of the reprojection strategy in eliminating depth errors at texture edges.

Diffusion-weighted imaging-based radiomics model using automatic machine learning to differentiate cerebral cystic metastases from brain abscesses.

OBJECTIVES: To develop a radiomics model based on diffusion-weighted imaging (DWI) utilizing automated machine learning method to differentiate cerebral cystic metastases from brain abscesses. MATERIALS AND METHODS: A total of 186 patients with cerebral cystic metastases (n = 98) and brain abscesses (n = 88) from two clinical institutions were retrospectively included. The datasets (129 from institution A) were randomly portioned into separate 75% training and 25% internal testing sets. Radiomics features were extracted from DWI images using two subregions of the lesion (cystic core and solid wall). A thorough image preprocessing method was applied to DWI images to ensure the robustness of radiomics features before feature extraction. Then the Tree-based Pipeline Optimization Tool (TPOT) was utilized to search for the best optimized machine learning pipeline, using a fivefold cross-validation in the training set. The external test set (57 from institution B) was used to evaluate the model's performance. RESULTS: Seven distinct TPOT models were optimized to distinguish between cerebral cystic metastases and abscesses either based on different features combination or using wavelet transform. The optimal model demonstrated an AUC of 1.00, an accuracy of 0.97, sensitivity of 1.00, and specificity of 0.93 in the internal test set, based on the combination of cystic core and solid wall radiomics signature using wavelet transform. In the external test set, this model reached 1.00 AUC, 0.96 accuracy, 1.00 sensitivity, and 0.93 specificity. CONCLUSION: The DWI-based radiomics model established by TPOT exhibits a promising predictive capacity in distinguishing cerebral cystic metastases from abscesses.

Effect of robbing intensity on reproductive success of Symphytum officinale (Boraginaceae).

The intervention of nectar robbers in plant pollination systems will cause some pollinators to modify their foraging behavior to act as secondary robbers, consequently adopting a mixed foraging strategy. The influence of nectar robbing on pollinator behavior may be affected by spatio-temporal difference of robbing intensity, and consequently, may have different effects on the pollination of host plants. However, whether and how the nectar robbing might influence pollinators under different robbing intensity still needs further investigation. In this study, Symphytum officinale was used to detect the effect of nectar robbers on pollinators under different robbing intensity as well as their effects on plant reproductive success. Six robbing levels and three bumblebees with mixed foraging behaviors were used to evaluate the effect of different robbing intensity on pollinator behavior, visitation rate, flower longevity and pollen deposition. Our results indicated that the robbing rate increased gradually with the proportion of robbed flowers, but which did not affect the frequency of legitimate visits. The increase of robbing rate promoted the corolla abscission, and then enhanced the self-pollen deposition, but which had no significant effect on cross-pollen deposition. These results indicate that the overall fitness of S. officinale was improved by combined self and cross-pollination modes when visited by both pollinators and nectar robbers simultaneously. Although nectar robbing is not uncommon, its consequences for pollination in the interaction web have not been well studied. Our results emphasize the significance of indirect impacts in mediating the adaptive outcomes of species interactions.

Thermal evaporation-driven fabrication of Ru/RuO2 nanoparticles onto nickel foam for efficient overall water splitting.

Developing high-performance bifunctional electrocatalysts towards the hydrogen evolution reaction/oxygen evolution reaction (HER/OER) holds great significance for efficient water splitting. This work presents a two-stage metal-organic thermal evaporation strategy for the fabrication of Ru-based catalysts (Ru/NF) through growing ruthenium (Ru)/ruthenium dioxide (RuO2) nanoparticles (NPs) on nickel foam (NF). The optimal Ru/NF shows remarkable performance in both the HER (26.1 mV) and the OER (235.4 mV) at 10 mA cm-2 in an alkaline medium. The superior OER performance can be attributed to the synergistic interaction between Ru and RuO2, facilitating fast alkaline water splitting. Density functional theory studies reveal that the resulting Ru/RuO2 with the (110) crystal surface reinforces the adsorption of oxygen on RuO2, while metallic Ru improves water dissociation in alkaline electrolytes. Besides, Ru/NF requires only 1.50 V at 10 mA cm-2 for overall water splitting, surpassing 20 wt% Pt/C/NF||RuO2/NF. This work demonstrates the promising potential of a thermal evaporation approach for designing stable Ru-based nanomaterials loaded onto conductive substrates for high performance overall water splitting.

Identification and validation of a novel signature based on macrophage marker genes for predicting prognosis and drug response in kidney renal clear cell carcinoma by integrated analysis of single cell and bulk RNA sequencing.

Macrophages are found in a variety of tumors and play a critical role in shaping the tumor microenvironment, affecting tumor progression, metastasis, and drug resistance. However, the clinical relevance of marker genes associated with macrophage in kidney renal clear cell carcinoma (KIRC) has yet to be documented. In this study, we initiated a thorough examination of single-cell RNA sequencing (scRNA-seq) data for KIRC retrieved from the Gene Expression Omnibus (GEO) database and determined 244 macrophage marker genes (MMGs). Univariate analysis, LASSO regression, and multivariate regression analysis were performed to develop a five-gene prognostic signature in The Cancer Genome Atlas (TCGA) database, which could divide KIRC patients into low-risk (L-R) and high-risk (H-R) groups. Then, a nomogram was constructed to predict the survival rate of KIRC patients at 1, 3, and 5 years, which was well assessed by receiver operating characteristic curve (ROC), calibration curve, and decision curve analyses (DCA). Functional enrichment analysis showed that immune-related pathways (such as immunoglobulin complex, immunoglobulin receptor binding, and cytokine-cytokine receptor interaction) were mainly enriched in the H-R group. Additionally, in comparison to the L-R cohort, patients belonging to the H-R cohort exhibited increased immune cell infiltration, elevated expression of immune checkpoint genes (ICGs), and a higher tumor immune dysfunction and exclusion (TIDE) score. This means that patients in the H-R group may be less sensitive to immunotherapy than those in the L-R group. Finally, IFI30 was validated to increase the ability of KIRC cells to proliferate, invade and migrate in vitro. In summary, our team has for the first time developed and validated a predictive model based on macrophage marker genes to accurately predict overall survival (OS), immune characteristics, and treatment benefit in KIRC patients.

RIGA: Rotation-Invariant and Globally-Aware Descriptors for Point Cloud Registration.

Successful point cloud registration relies on accurate correspondences established upon powerful descriptors. However, existing neural descriptors either leverage a rotation-variant backbone whose performance declines under large rotations, or encode local geometry that is less distinctive. To address this issue, we introduce RIGA to learn descriptors that are Rotation-Invariant by design and Globally-Aware. From the Point Pair Features (PPFs) of sparse local regions, rotation-invariant local geometry is encoded into geometric descriptors. Global awareness of 3D structures and geometric context is subsequently incorporated, both in a rotation-invariant fashion. More specifically, 3D structures of the whole frame are first represented by our global PPF signatures, from which structural descriptors are learned to help geometric descriptors sense the 3D world beyond local regions. Geometric context from the whole scene is then globally aggregated into descriptors. Finally, the description of sparse regions is interpolated to dense point descriptors, from which correspondences are extracted for registration. To validate our approach, we conduct extensive experiments on both object- and scene-level data. With large rotations, RIGA surpasses the state-of-the-art methods by a margin of 8 ° in terms of the Relative Rotation Error on ModelNet40 and improves the Feature Matching Recall by at least 5 percentage points on 3DLoMatch.

The high-quality genome of Cryptotaenia japonica and comparative genomics analysis reveals anthocyanin biosynthesis in Apiaceae.

Cryptotaenia japonica, a traditional medicinal and edible vegetable crops, is well-known for its attractive flavors and health care functions. As a member of the Apiaceae family, the evolutionary trajectory and biological properties of C. japonica are not clearly understood. Here, we first reported a high-quality genome of C. japonica with a total length of 427 Mb and N50 length 50.76 Mb, was anchored into 10 chromosomes, which confirmed by chromosome (cytogenetic) analysis. Comparative genomic analysis revealed C. japonica exhibited low genetic redundancy, contained a higher percentage of single-cope gene families. The homoeologous blocks, Ks, and collinearity were analyzed among Apiaceae species contributed to the evidence that C. japonica lacked recent species-specific WGD. Through comparative genomic and transcriptomic analyses of Apiaceae species, we revealed the genetic basis of the production of anthocyanins. Several structural genes encoding enzymes and transcription factor genes of the anthocyanin biosynthesis pathway in different species were also identified. The CjANSa, CjDFRb, and CjF3H gene might be the target of Cjaponica_2.2062 (bHLH) and Cjaponica_1.3743 (MYB). Our findings provided a high-quality reference genome of C. japonica and offered new insights into Apiaceae evolution and biology.

The Multiple Roles of Autophagy in Neural Function and Diseases.

Autophagy involves the sequestration and delivery of cytoplasmic materials to lysosomes, where proteins, lipids, and organelles are degraded and recycled. According to the way the cytoplasmic components are engulfed, autophagy can be divided into macroautophagy, microautophagy, and chaperone-mediated autophagy. Recently, many studies have found that autophagy plays an important role in neurological diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, neuronal excitotoxicity, and cerebral ischemia. Autophagy maintains cell homeostasis in the nervous system via degradation of misfolded proteins, elimination of damaged organelles, and regulation of apoptosis and inflammation. AMPK-mTOR, Beclin 1, TP53, endoplasmic reticulum stress, and other signal pathways are involved in the regulation of autophagy and can be used as potential therapeutic targets for neurological diseases. Here, we discuss the role, functions, and signal pathways of autophagy in neurological diseases, which will shed light on the pathogenic mechanisms of neurological diseases and suggest novel targets for therapies.

Lateral Dorsal Basal Lung Resection Based on Functional Preserving Sublobectomy Method: Single-Center Experience.

PURPOSE: Functional preserving sublobectomy (FPSL), a novel balancing strategy for segmentectomy and wedge resection, allows rapid and accurate removal of invisible nodules without the use of any preoperative localization markers. This study aimed to share single-center experience of lateral dorsal basal lung resection based on FPSL, so as to provide new surgical options for thoracic surgeons. METHODS: A retrospective analysis was performed on 13 patients who underwent thoracoscopic basal lung resection after FPSL at XX hospital from January 2021 to August 2022. RESULTS: The operation was successfully performed in 13 patients by using FPSL, including 12 patients with malignant tumors. The mean operating time was 107.5 ± 25.6 min. The mean postoperative hospital stay was 3.7 ± 2.4 days. None of the patients needed extended excision, such as an entire basal or inferior lobectomy. CONCLUSION: Our single-center experience showed that the FPSL method only dealt with the target vessels, which greatly reduced the technical difficulty of surgery. In addition, both arteries and veins could be used as target vessels, and in particular cases such as undeveloped interlobar fissure, the operation could still be completed successfully. Lateral dorsal basal lung resection based on FPSL may be a new surgical option for surgeons.

Identification and validation of telomerase related lncRNAs signature to predict prognosis and tumor immunotherapy response in bladder cancer.

Telomerase allows eukaryotic cells to proliferate indefinitely, an important characteristic of tumor cells. Telomerase-related long no coding RNAs (TERLs) are involved in prognosis and drug sensitivity prediction; however, their association with bladder cancer (BLCA) is still unreported. The objective of this research is to determine a predictive prognostic TERL signature for OS and to provide an efficient treatment option for BLCA. The RNA sequence, clinical information, and mutational data of BLCA patients were acquired from The Cancer Genome Atlas (TCGA) database. With the help of the data from least absolute shrinkage and selection operator (LASSO) regression and Cox regression, a prognostic signature was established including 14 TERLs, which could divide BLCA patients into low-risk (L-R) and high-risk (H-R) cohorts. The time-dependent receiver operating characteristic (ROC) curve demonstrated the greater predictive power of the model. By combing the TERLs-based signature and clinical risk factors (age, sex, grade, and stage), a prognostic nomogram was constructed to forecast the survival rates of patients with BLCA at 1-, 3-, and 5-years, which was well matched by calibration plots C-index and Decision curve analysis (DCA). Furthermore, the L-R cohort showed higher tumor mutation burden (TMB) and lower tumor immune dysfunction and exclusion (TIDE) than the H-R cohort, as well as substantial variability in immune cell infiltration and immune function between the two cohorts was elucidated. As for external validation, LINC01711 and RAP2C-AS1 were identified as poor prognostic factors by survival analysis from the Kaplan-Meier Plotter database, which were validated in BLCA cell lines (EJ, 253J, T24, and 5637) and SV-HUC-1 cells as the control group using qRT-PCR. In addition, interference with the expression of RAP2C-AS1 suppresses the proliferation and migration of BLCA cells, and RAP2C-AS1 could affect the expression of CD274 and CTLA4, which could serve as prognostic markers and characterize the tumor microenvironment in BLCA. Overall, the model based on the 14-TERLs signature can efficiently predict the prognosis and drug treatment response in individuals with bladder cancer.

Experimental validation and pan-cancer analysis identified COL10A1 as a novel oncogene and potential therapeutic target in prostate cancer.

BACKGROUND: Type X collagen (COL10) is a homologous trimeric non-fibrillar collagen found in the extracellular matrix of human tissues, and it exhibits a distinctive white appearance. Type X collagen α1 chain (COL10A1) is a specific cleaved fragment of type X collagen. However, the expression, prognostic significance, clinicopathological attributes and immune-related associations of COL10A1 in prostate cancer as well as in pan-cancer contexts remain poorly understood. METHODS: Using bioinformatic analysis of data from the most recent databases (TCGA, GTEx and GEO databases), we have extensively elucidated the role played by COL10A1 in terms of its expression patterns, prognostic implications, and immune efficacy across a pan-cancer spectrum. Subsequently, the biological functions of COL10A1 in prostate cancer were elucidated by experimental validation. RESULTS: Our findings have confirmed that COL10A1 was highly expressed in most cancers and was associated with poorer prognosis in cancer patients. Immune correlation analysis of COL10A1 in various cancers showed its significant correlation with Tumor mutational burden (TMB), microsatellite instability (MSI) and immune cell infiltration. In addition, knockdown of COL10A1 in prostate cancer resulted in a substantial reduction in the proliferation, migration, and invasive potential of prostate cancer cells. CONCLUSION: Our pan-cancer analysis of COL10A1 gene provided novel insights into its pivotal role in cancer initiation, progression, and therapeutic implications, underscoring its potential significance in prognosis and immunotherapeutic interventions for cancer, particularly prostate cancer.

Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure.

BACKGROUND: Therapies are urgently required to ameliorate pathological cardiac hypertrophy and enhance cardiac function in heart failure. Our preliminary experiments have demonstrated that exogenous NADPH exhibits a positive inotropic effect on isolated heart. This study aims to investigate the positive inotropic effects of NADPH in pathological cardiac hypertrophy and heart failure, as well as the underlying mechanisms involved. METHODS: Endogenous plasma NADPH contents were determined in patients with chronic heart failure and control adults. The positive inotropic effects of NADPH were investigated in isolated toad heart or rat heart. The effects of NADPH were investigated in isoproterenol (ISO)-induced cardiac hypertrophy or transverse aortic constriction (TAC)-induced heart failure. The underlying mechanisms of NADPH were studied using SIRT3 knockout mice, echocardiography, Western blotting, transmission electron microscopy, and immunoprecipitation. FINDINGS: The endogenous NADPH content in the blood of patients and animals with pathological cardiac hypertrophy or heart failure was significantly reduced compared with age-sex matched control subjects. Exogenous NADPH showed positive inotropic effects on the isolated normal and failing hearts, while antagonism of ATP receptor partially abolished the positive inotropic effect of NADPH. Exogenous NADPH administration significantly reduced heart weight indices, and improved cardiac function in the mice with pathological cardiac hypertrophy or heart failure. NADPH increased SIRT3 expression and activity, deacetylated target proteins, improved mitochondrial function and facilitated ATP production in the hypertrophic myocardium. Importantly, inhibition of SIRT3 abolished the positive inotropic effect of NADPH, and the anti-heart failure effect of NADPH was significantly reduced in the SIRT3 Knockout mice. INTERPRETATION: Exogenous NADPH shows positive inotropic effect and improves energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. NADPH thus may be one of the potential candidates for the treatment of pathological cardiac hypertrophy or heart failure. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (No. 81973315, 82173811, 81730092), Natural Science Foundation of Jiangsu Higher Education (20KJA310008), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

Cucurbitacin B Exerts Significant Antidepressant-Like Effects in a Chronic Unpredictable Mild Stress Model of Depression: Involvement of the Hippocampal BDNF-TrkB System.

BACKGROUND: Although depression has been a serious neuropsychiatric disorder worldwide, current antidepressants used in clinical practice have various weaknesses, including delayed onset and low rates of efficacy. Recently, the development of new antidepressants from natural herbal medicine has become one of the important research hotspots. Cucurbitacin B is a natural compound widely distributed in the Cucurbitaceae and Cruciferae families and has many pharmacological activities. The present study aimed to investigate whether cucurbitacin B possess antidepressant-like effects in mice. METHODS: The antidepressant-like effects of cucurbitacin B on mice behaviors were explored using the forced swim test, tail suspension test, open field test, sucrose preference test, and a chronic unpredictable mild stress model of depression together. Then, western blotting and immunofluorescence were used to examine the effects of cucurbitacin B on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling cascade and neurogenesis in the hippocampus of mice. Furthermore, BDNF-short hairpin RNA, K252a, and p-chlorophenylalanine methyl ester were adopted together to determine the antidepressant mechanism of cucurbitacin B. RESULTS: It was found that administration of cucurbitacin B indeed produced notable antidepressant-like effects in mice, which were accompanied with significant promotion in both the hippocampal BDNF-TrkB pathway and neurogenesis. The antidepressant mechanism of cucurbitacin B involves the hippocampal BDNF-TrkB system but not the serotonin system. CONCLUSIONS: Cucurbitacin B has the potential to be a novel antidepressant candidate.