BDNF mimetics recover palmitic acid-induced injury in cardiomyocytes by ameliorating Akt-dependent mitochondrial impairments.

Cardiac lipotoxicity is a prevalent consequence of lipid metabolism disorders occurring in cardiomyocytes, which in turn precipitates the onset of heart failure. Mimetics of brain-derived neurotrophic factor (BDNF), such as 7,8-dihydroxyflavone (DHF) and 7,8,3'-trihydroxyflavone (THF), have demonstrated significant cardioprotective effects. However, it remains unclear whether these mimetics can protect cardiomyocytes against lipotoxicity. The aim of this study was to examine the impact of DHF and THF on the lipotoxic effects induced by palmitic acid (PA), as well as the concurrent mitochondrial dysfunction. H9c2 cells were subjected to treatment with PA alone or in conjunction with DHF or THF. Various factors such as cell viability, lactate dehydrogenase (LDH) release, death ratio, and mitochondrial function including mitochondrial membrane potential (MMP), mitochondrial-derived reactive oxygen species (mito-SOX) production, and mitochondrial respiration were assessed. PA dose-dependently reduced cell viability, which was restored by DHF or THF. Additionally, both DHF and THF decreased LDH content, death ratio, and mito-SOX production, while increasing MMP and regulating mitochondrial oxidative phosphorylation in cardiomyocytes. Moreover, DHF and THF specifically activated Akt signaling. The protective effects of DHF and THF were abolished when an Akt inhibitor was used. In conclusion, BDNF mimetics attenuate PA-induced injury in cardiomyocytes by alleviating mitochondrial impairments through the activation of Akt signaling.

Catalytic hairpin assembly-based AIEgen/graphene oxide nanocomposite for fluorescence-enhanced and high-precision spatiotemporal imaging of microRNA in living cells.

The low abundance, heterogeneous expression, and temporal changes of miRNA in different cellular locations pose significant challenges for both the detection sensitivity of miRNA liquid biopsy and intracellular imaging. In this work, we report an intelligently assembled biosensor based on catalytic hairpin assembly (CHA) and aggregation-induced emission (AIE), named as catalytic hairpin aggregation-induced emission (CHAIE), for the ultrasensitive detection and intracellular imaging of miRNA-155. To achieve such goal, tetraphenylethylene-N3 (TPE-N3) is used as AIE luminogen (AIEgen), while graphene oxide is introduced to quench the fluorescence. When the target miRNA is present, CHA reaction is triggered, causing the AIEgen to self-assemble with the hairpin DNA. This will restrict the intramolecular rotation of the AIEgen and produce a strong AIE fluorescence. Interestingly, CHAIE does not require any enzyme or expensive thermal cycling equipment, and therefore provides a rapid detection. Under optimal conditions, the proposed biosensor can determine miRNA in the concentration range from 2 pM to 200 nM within 30 min, with the detection limit of 0.42 pM. The proposed CHAIE biosensor in this work offers a low background signal and high sensitivity, making it applicable for highly precise spatiotemporal imaging of target miRNA in living cells.

Effectiveness and safety of Danshen injections in treatment of cardiac failure: a network meta-analysis.

Objective: The purpose of this network meta-analysis (NMA) was to compare the therapeutic effects of various Danshen (Salvia miltiorrhiza Bunge [Lamiaceae; Salviae miltiorrhizae radix et rhizoma]) injections on heart failure to determine the optimal Danshen injection combined with conventional treatment. Methods: 8 databases were searched from the inception of these databases to May 2023 to collect randomized controlled trials (RCTs) on the effectiveness and safety of Danshen injections in the treatment of heart failure. This NMA was performed using Stata 16.0 software and R 4.1.3 software. Results: A total of 24 RCTs involving 2,186 subjects were included. The intervention group received Danshen injections plus conventional treatment, involving the following 7 Danshen injections. The results of the NMA showed that Compound Danshen injection + Common (SUCRA: 79.6%) and Sodium tanshinone ⅡA sulfonate injection + Common (SUCRA: 78.0%) exhibited higher total effective rates. Sodium tanshinone ⅡA sulfonate injection + Common (SUCRA: 94.3%) and Danshen injection + Common (SUCRA: 68.2%) were superior to other traditional Chinese medicines in improving left ventricular ejection fraction (LVEF). Danshen injection + Common (SUCRA: 99.9%) and Shenxiong glucose injection + Common (SUCRA: 77.2%) were the most effective in reducing brain natriuretic peptide (BNP). In addition, compared with conventional treatment, all Danshen injections did not increase the risk of adverse reactions. Conclusion: Current evidence shows that all seven Danshen injections are effective for heart failure. Due to the limited quantity and quality of the included studies, our findings need to be verified by more high-quality studies.

Long-Term Triclocarban Exposure Induced Enterotoxicity by Triggering Intestinal AhR-Mediated Inflammation and Disrupting Microbial Community in Mice.

Exposure to triclocarban (TCC), a commonly used antibacterial agent, has been shown to induce significant intestine injuries and colonic inflammation in mice. However, the detailed mechanisms by which TCC exposure triggered enterotoxicity remain largely unclear. Herein, intestinal toxicity effects of long-term and chronic TCC exposure were investigated using a combination of histopathological assessments, metagenomics, targeted metabolomics, and biological assays. Mechanically, TCC exposure caused induction of intestinal aryl hydrocarbon receptor (AhR) and its transcriptional target cytochrome P4501A1 (Cyp1a1) leading to dysfunction of the gut barrier and disruption of the gut microbial community. A large number of lipopolysaccharides (LPS) are released from the gut lumen into blood circulation owing to the markedly increased permeability and gut leakage. Consequently, toll-like receptor-4 (TLR4) and NF-κB signaling pathways were activated by high levels of LPS. Simultaneously, classic macrophage phenotypes were switched by TCC, shown with marked upregulation of macrophage M1 and downregulation of macrophage M2 that was accompanied by striking upregulation of proinflammatory factors such as Il-1ß, Il-6, Il-17, and Tnf-α in the intestinal lamina propria. These findings provide new evidence for the TCC-induced enterotoxicity.

Omega-3 fatty acids and their influence on hypertension and coronary atherosclerosis: Insights from a Mendelian randomization approach.

It has been suggested that Omega-3 fatty acids may improve endothelial thickness and thereby reduce the onset of cardiovascular diseases such as coronary atherosclerosis and hypertension. However, published observational epidemiological studies on the relationship between cardiovascular disease (CVD) and Omega-3 fatty acids remain inconclusive. Here, we performed a two-sample Mendelian randomisation analysis using publicly available GWAS pooled statistics to study a GWAS dataset of 16 380 466 SNPs in 23 363 cases and 195 429 controls (also of European ancestry) to determine genetic susceptibility to hypertension. We performed random-effects Inverse Variance Weighted (IVW) Mendelian Randomization (MR) analyses supplemented by a series of sensitivity assessments to measure the robustness of the findings and to detect any violations of the MR assumptions. During the course of the study, we used IVW, MR-Egger, and weighted median regression to infer that Omega-3 intake has a potentially adverse effect against atherosclerosis, although the trend was not significant (OR = 1.1198; 95%; CI: 0.9641-1.3006, p = .130). Meanwhile, our analyses showed a statistically significant negative association between Omega-3 fatty acid levels and risk of hypertension (OR = 0.9006; 95% CI: 0.8179-0.9917, p = .033). In addition, we explored the causal relationship between atherosclerosis and hypertension and found a significant correlation (OR = 1.3036; 95% CI: 1.0672-1.5923, p = .009). In conclusion, our extensive data investigated by MR suggest that elevated levels of Omega-3 fatty acids may be associated with an decreased risk of hypertension. Although there is no direct link between hypertension and atherosclerosis, the possibility of a subtle association cannot be categorically excluded.

Fluorescence-Quenching Lateral Flow Immunoassay for "Turn-On" and Sensitive Detection of Anti-SARS-Cov-2 Neutralizing Antibodies in Human Serum.

The titer of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (NAbs) in the human body is an essential reference for evaluating the acquired protective immunity and resistance to SARS-CoV-2 infection. In this study, a fluorescence-quenching lateral flow immunoassay (FQ-LFIA) is established for quantitative detection of anti-SARS-CoV-2 NAbs in the sera of individuals who are vaccinated or infected within 10 min. The ultrabright aggregation-induced emission properties encapsulated in nanoparticles, AIE490 NP, are applied in the established FQ-LFIA with gold nanoparticles to achieve a fluorescence "turn-on" competitive immunoassay. Under optimized conditions, the FQ-LFIA quantitatively detected 103 positive and 50 negative human serum samples with a limit of detection (LoD) of 1.29 IU mL-1 . A strong correlation is present with the conventional pseudovirus-based virus neutralization test (R2  = 0.9796, P < 0.0001). In contrast, the traditional LFIA with a "turn-off" mode can only achieve a LoD of 11.06 IU mL-1 . The FQ-LFIA showed excellent sensitivity to anti-SARS-CoV-2 NAbs. The intra- and inter-assay precisions of the established method are below 15%. The established FQ-LFIA has promising potential as a rapid and quantitative method for detecting anti-SARS-CoV-2 NAbs. FQ-LFIA can also be used to detect various biomarkers.

In Situ Interfacial Polymerized Arginine-Doped Polydopamine Thin-Film Nanocomposite Membranes for High-Separation and Antifouling Reverse Osmosis.

In this work, we synthesized polydopamine nanoparticles (PDNPs-M, M = I, II, III, and IV) with uniform particle sizes but varying l-arginine (Arg) contents (0%, 0.53%, 3.73%, and 6.62%) through a one-pot synthesis approach. Thin-film nanocomposite (TFN) membranes were fabricated via in situ interfacial polymerization (IP). The effects of the PDNPs-M chemical structure on the IP process and the consequent impacts on the structure and properties of the polyamide (PA) selective layer were investigated. The hydrophilicity and dispersibility of PDNPs-M exhibited an upward trend with the Arg content. Furthermore, Arg doping contributes to a denser and smoother PA layer. Among the TFC and TFN membranes, TFN-PDNPs-IV exhibited a water permeability of 3.89 L·m-2·h-1·bar-1 (55.1% higher than that of TFC-0) with a NaCl rejection rate of 98.8%, signifying superior water/salt selectivity. Additionally, TFN-PDNPs-IV exhibited regular pressure stability, commendable acid/alkali stability, and enhanced antifouling properties. These findings highlight the significant impact of nanoparticle hydrophilic functional groups on the structural and functional attributes of TFN membranes, offering a promising approach for developing advanced reverse osmosis membranes.

A novel RF-CEEMD-LSTM model for predicting water pollution.

Accurate water pollution prediction is an important basis for water environment prevention and control. The uncertainty of input variables and the nonstationary and nonlinear characteristics of water pollution series hinder the accuracy and reliability of water pollution prediction. This study proposed a novel water pollution prediction model (RF-CEEMD-LSTM) to improve the performance of water pollution prediction by combining advantages of the random forest (RF) and Long short-term memory (LSTM) models and Complementary ensemble empirical mode decomposition (CEEMD). The experimental results based on measured data show that the proposed RF-CEEMD-LSTM model can accurately predict water pollution trends, with a mean ab-solute percentage error (MAPE) of less than 8%. The RMSE of the RF-CEEMD-LSTM model is reduced by 62.6%, 39.9%, and 15.5% compared to those of the LSTM, RF-LSTM, and CEEMD-LSTM models, respectively, proving that the proposed method has good advantages in predicting non-linear and nonstationary water pollution sequences. The driving force analysis results showed that TN has the most significant impact on water pollution prediction. The research results could provide references for identifying and explaining water pollution variables and improving water pollution prediction method.

Integrated prediction of water pollution and risk assessment of water system connectivity based on dynamic model average and model selection criteria.

In recent years, with the rapid development of economy and society, river water environmental pollution incidents occur frequently, which seriously threaten the ecological health of the river and the safety of water supply. Water pollution prediction is an important basis for understanding development trends of the aquatic environment, preventing water pollution incidents and improving river water quality. However, due to the large uncertainty of hydrological, meteorological and water environment systems, it is challenging to accurately predict water environment quality using single model. In order to improve the accuracy and stability of water pollution prediction, this study proposed an integrated learning criterion that integrated dynamic model average and model selection (DMA-MS) and used this criterion to construct the integrated learning model for water pollution prediction. Finally, based on the prediction results of the integrated learning model, the connectivity risk of the connectivity project was evaluated. The results demonstrate that the integrated model based on the DMA-MS criterion effectively integrated the characteristics of a single model and could provide more accurate and stable predictions. The mean absolute percentage error (MAPE) of the integrated model was only 11.1%, which was 24.5%-45% lower than that of the single model. In addition, this study indicates that the nearest station was the most important factor affecting the performance of the prediction station, and managers should pay increased attention to the water environment of the control section that is close to their area. The results of the connectivity risk assessment indicate that although the water environment risks were not obvious, the connectivity project may still bring some risks to the crossed water system, especially in the non-flood season.

7,8,3'-Trihydroxyflavone prevents doxorubicin-induced cardiotoxicity and mitochondrial dysfunction via activating Akt signaling pathway in H9c2 cells.

Clinical application of the widely used chemotherapeutic agent, doxorubicin (DOX), is limited by its cardiotoxicity. Mitochondrial dysfunction has been revealed as a crucial factor in DOX-induced cardiotoxicity. 7,8,3'-Trihydroxyflavone (THF) is a mimetic brain-derived neurotrophic factor with neuroprotective effects. However, the potential effects of THF on DOX-induced cardiomyocyte damage and mitochondrial disorders remain unclear. H9c2 cardiomyoblasts were exposed to DOX and/or THF at different concentrations. Cardiomyocyte injury was evaluated using lactate dehydrogenase (LDH) assay and Live/Dead cytotoxicity kit. Meanwhile, mitochondrial membrane potential (MMP), morphology, mitochondrial reactive oxygen species (mito-ROS) production, and the oxygen consumption rate of cardiomyocytes were measured. The protein levels of key mitochondria-related factors such as adenosine monophosphate-activated protein kinase (AMPK), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and optic atrophy protein 1 (OPA1) were examined. We found that THF reduced LDH content and death ratio of DOX-treated cardiomyocytes in a concentration-dependent manner, while increasing MMP without significantly affecting the routine and maximum capacity of mitochondrial respiration. Mechanistically, THF increased the activity of Akt and protein levels of Mfn2 and heme oxygenase 1 (HO-1). Moreover, inhibition of Akt reversed the protective role of THF, increased mito-ROS levels, and repressed Mfn2 and HO-1 expression. Therefore, we conclude, THF relieves DOX-induced cardiotoxicity and improves mitochondrial function by activating Akt-mediated Mfn2 and HO-1 pathways. This finding provides promising therapeutic insights for DOX-induced cardiac dysfunction.

Dietary Isoquercetin Ameliorates Bone Loss via Restoration of the Gut Microbiota and Lipopolysaccharide-Triggered Inflammatory Status in Ovariectomy Mice.

Osteoporosis is one of the skeletal degenerative diseases accompanied by bone loss and microstructure disruption. Given that the gut-bone signaling axis highly contributes to bone health, here, dietary isoquercetin (IQ) was shown to effectively improve postmenopausal osteoporosis (PMO) in an ovariectomy (OVX) mouse model through the modulation of the gut-bone cross-talk. An in vivo study showed that OVX induced striking disruption of the microbial community, subsequently causing gut leakage and gut barrier dysfunction. As a result, lipopolysaccharide (LPS)-triggered inflammatory cytokines released from the intestine to bone marrow were determined to be associated with bone loss in OVX mice. Long-term dietary IQ effectively improved microbial community and gut barrier function in the OVX mice and thus markedly improved bone loss and host inflammatory status by repressing the NF-κB signaling pathway. An in vitro study further revealed that IQ treatments dose-dependently inhibited LPS-induced inflammation and partly promoted the proliferation and differentiation of osteoblasts. These results provide new evidence that dietary IQ has the potential for osteoporosis treatment.

An integrated data- and theory-driven crash severity model.

For crash severity modeling, researchers typically view theory-driven models and data-driven models as different or even conflicting approaches. The reason is that the machine-learning models offer good predictability but weak interpretability, while the latter has robust interpretability but moderate predictability. In order to alleviate the tension between them, this study proposes an integrated data- and theory-driven crash-severity model, known as Embedded Fusion model based on Text Vector Representations (TVR-EF), by leveraging the complementary strengths of both. The model specification consists of two parts. (i) the data-driven component not only mitigate the deficiencies of traditional econometric models, where one-hot encoding is frequently used and makes it impossible to observe semantic relatedness between variable categories, but also enhances the interpretability for the relationship between crash severity and potential influencing factors using the learned embedding weight matrix. (ii) In the theory-driven component, the multinomial logit model is implemented as a 2D-Convolutional Neural Network (2D-CNN) to increase flexibility and decrease dependency on prior knowledge for different crash-severity outcomes. A crash dataset from Guangdong Province, China, is utilized to estimate the TVR-EF model, which is then benchmarked against two traditional econometric models and three widely used machine-learning models. Results indicate that TVR-EF model does not only improve the predictive performance but also makes it easier to interpret.

Discovery of a novel small molecule with efficacy in protecting against inflammation in vitro and in vivo by enhancing macrophages activation.

Immune response and inflammation highly contribute to many metabolic syndromes such as inflammatory bowel disease (IBD), ageing and cancer with disruption of host metabolic homeostasis and the gut microbiome. Icariin-1 (GH01), a small-molecule flavonoid derived from Epimedium, has been shown to protect against systemic inflammation. However, the molecular mechanisms by which GH01 ameliorates ulcerative colitis via regulation of microbiota-mediated macrophages polarization remain elusive. In this study, we found that GH01 effectively ameliorated dextran sulfate sodium (DSS)-induced colitis symptoms in mice. Disruption of intestinal barrier function, commensal microbiota and its metabolites were also significantly restored by GH01 in a dose-dependent manner. Of note, we also found that GH01 enhanced phagocytic ability of macrophages and switched macrophage phenotype from M1 to M2 both in vitro and in vivo. Such macrophage polarization was highly associated with intestinal barrier integrity and the gut microbial community. Consequently, GH01 exhibited strong anti-inflammatory capacity by inhibiting TLR4 and NF-κB pathways and proinflammatory factors (IL-6). These findings suggested that GH01 might be a potential nutritional intervention strategy for IBD treatment with the gut microbial community-meditated macrophage as the therapeutic targets.

Triclocarban exposure aggravates dextran sulfate sodium-induced colitis by deteriorating the gut barrier function and microbial community in mice.

Triclocarban (TCC) is an antibacterial component widely used in personal care products with potential toxicity possessing public health issues. Unfortunately, enterotoxicity mechanisms of TCC exposure remain largely unknown. Using a combination of 16S rRNA gene sequencing, metabolomics, histopathological and biological examinations, this study systematically explored the deteriorating effects of TCC exposure on a dextran sulfate sodium (DSS)-induced colitis mouse model. We found that TCC exposure at different doses significantly aggravated colitis phenotypes including shortened colon length and altered colonic histopathology. Mechanically, TCC exposure further disrupted intestinal barrier function, manifested by significant downregulation of the number of goblet cells, mucus layer thickness and expression of junction proteins (MUC-2, ZO-1, E-cadherin and Occludin). The gut microbiota composition and its metabolites such as short-chain fatty acids (SCFAs) and tryptophan metabolites were also markedly altered in DSS-induced colitis mice. Consequently, TCC exposure markedly exacerbated colonic inflammatory status of DSS-treated mice by activating NF-κB pathway. These findings provided new evidence that TCC could be an environmental hazards for development of IBD or even colon cancer.

Dextran-Cholesterol Carrier Encapsulated Efficient Photosensitizer for the Photodynamic Killing of Cancer Cells.

Selective photodynamic therapy (PDT) for cancer cells is more efficient and much safer. Most selective PDTs are realized by antigene-biomarker or peptide-biomarker interactions. Here, we modified dextran with hydrophobic cholesterol as a photosensitizer carrier to selectively target cancer cells, including colon cancer cells, and fulfilled selective PDT. The photosensitizer was designed with regular Aggregation-Induced Emission (AIE) units, including triphenylamine and 2-(3-cyano-4,5,5-trimethylfuran-2-ylidene)propanedinitrile. The AIE units can help to decrease the quenching effect in the aggregate state. The efficiency of the photosensitizer is further improved via the heavy atom effect after bromination modification. We found that the obtained photosensitizer nanoparticles could selectively target and ablate cancer cells after encapsulation into the dextran-cholesterol carrier. This study indicates that the polysaccharide-based carrier may have potential for cancer-targeting therapy beyond expectations.

A novel small molecule effectively ameliorates estrogen deficiency-induced osteoporosis by targeting the gut-bone signaling axis.

Postmenopausal osteoporosis stems mainly from estrogen deficiency leading to a gut microbiome-dependent disruption of host systemic immunity. However, the underlying mechanisms of estrogen deficiency-induced bone loss remain elusive and novel pharmaceutical intervention strategies for osteoporosis are needed. Here we reveal that ovariectomy (ovx)-induced estrogen deficiency in C57BL/6 mice causes significant disruption of gut microbiota composition, consequently leading to marked destruction of intestinal barrier function and gut leakage. As a result, signals transportation between intestinal microbiota and T cells from the gut to bone marrow is identified to contribute to osteoclastogenesis in ovx mice. Notably, we show that icariside I (GH01), a novel small molecule naturally occurring in Herbal Epimedium, has potential to alleviate or prevent ovx-induced bone loss in mice through regulation of gut-bone signaling axis. We find that GH01 treatment can effectively restore the gut microbiota composition, intestinal barrier function and host immune status markedly altered in ovx mice, thus significantly ameliorating bone loss and osteoporosis. These findings not only provide systematic understanding of the gut-immunity-bone axis-associated pathophysiology of osteoporosis, but also demonstrate the high potential of GH01 for osteoporosis treatment by targeting the gut-bone signaling axis.

Dendrobium officinale polysaccharide-based carrier to enhance photodynamic immunotherapy.

Photodynamic therapy (PDT) eradicates tumors via the generation of toxic reactive oxygen species (ROS) by activation of a photosensitizer (PS) with appropriate light. Local PDT toward tumors can trigger the immune response to inhibit distant tumors, but the immune response is usually insufficient. Herein, we used a biocompatible herb polysaccharide with immunomodulatory activity as the carrier of PS to enhance the immune inhibition of tumors after PDT. The Dendrobium officinale polysaccharide (DOP) is modified with hydrophobic cholesterol to serve as an amphiphilic carrier. The DOP itself can promote dendritic cell (DC) maturation. Meanwhile, TPA-3BCP are designed to be cationic aggregation-induced emission PS. The structure of one electron-donor linking to three electron-acceptors endows TPA-3BCP with high efficiency to produce ROS upon light irradiation. And the nanoparticles are designed with positively charged surfaces to capture antigens released after PDT, which can protect the antigens from degradation and improve the antigen-uptake efficiency by DCs. The combination of DOP-induced DC maturation and antigen capture-increased antigen-uptake efficiency by DCs significantly improves the immune response after DOP-based carrier-mediated PDT. Since DOP is extracted from the medicinal and edible Dendrobium officinale, the DOP-based carrier we designed is promising to be developed for enhanced photodynamic immunotherapy in clinic.

Proteogenomics-based functional genome research: approaches, applications, and perspectives in plants.

Proteogenomics (PG) integrates the proteome with the genome and transcriptome to refine gene models and annotation. Coupled with single-cell (SC) assays, PG effectively distinguishes heterogeneity among cell groups. Affiliating spatial information to PG reveals the high-resolution circuitry within SC atlases. Additionally, PG can investigate dynamic changes in protein-coding genes in plants across growth and development as well as stress and external stimulation, significantly contributing to the functional genome. Here we summarize existing PG research in plants and introduce the technical features of various methods. Combining PG with other omics, such as metabolomics and peptidomics, can offer even deeper insights into gene functions. We argue that the application of PG will represent an important font of foundational knowledge for plants.