Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma.

Ferroptosis has been demonstrated a promising way to counteract chemoresistance of multiple myeloma (MM), however, roles and mechanism of bone marrow stromal cells (BMSCs) in regulating ferroptosis of MM cells remain elusive. Here, we uncovered that MM cells were more susceptible to ferroptotic induction under the interaction of BMSCs using in vitro and in vivo models. Mechanistically, BMSCs elevated the iron level in MM cells, thereby activating the steroid biosynthesis pathway, especially the production of lanosterol, a major source of reactive oxygen species (ROS) in MM cells. We discovered that direct coupling of CD40 ligand and CD40 receptor constituted the key signaling pathway governing lanosterol biosynthesis, and disruption of CD40/CD40L interaction using an anti-CD40 neutralizing antibody or conditional depletion of Cd40l in BMSCs successfully eliminated the iron level and lanosterol production of MM cells localized in the Vk*MYC Vk12653 or NSG mouse models. Our study deciphers the mechanism of BMSCs dictating ferroptosis of MM cells and highlights the therapeutic potential of non-apoptosis strategies for managing refractory or relapsed MM patients.

Knowledge of urinary incontinence among women 6 weeks to 1 year after delivery.

BACKGROUND: Urinary incontinence (UI) is common among postpartum women, but many do not seek medical help due to limited knowledge. Understanding the level of knowledge about UI in this population is essential for improving care-seeking behaviors and implementing targeted interventions. OBJECTIVE: The objective was to examine knowledge regarding UI among postpartum women with UI within 6 weeks to 1 year after delivery. METHODS: A cross-sectional study was conducted at obstetric clinic in two level-three grade A hospitals in Shenzhen, China, from January 2023 to June 2023. Women in their 6 weeks to 1 year after delivery with UI were asked to complete a questionnaire comprising three sections: (1) demographic variable; (2) International Consultation on Incontinence Questionnaire Short Form (ICIQ-UI SF); and (3) The Urinary Incontinence Quiz (UIQ). RESULTS: A total of 1228 women completed the questionnaire. Their mean UIQ score was 6.63 ± 3.51 (minimum = 2, maximum = 15), indicating the deficiency of UI knowledge among Chinese postpartum women. A total of 86.4% of participants experienced slight or moderate postpartum UI. The results of multivariate linear regression models for UIQ reveal significant independent associations between questionnaire scores and two variables: experience in pelvic floor muscle training (PFMT) (p < 0.001) and UI treatment in the past (p < 0.001). The overall model fit was R2 = 0.559 (p < 0.001). The regression coefficients for the experience in PFMT and UI treatment in the past were 2.301 and 4.916, respectively. However, no other discernible factors were identified to distinguish between those with and without adequate knowledge. CONCLUSIONS: Postpartum women with UI within 6 weeks to 1 year after delivery had poor knowledge of UI. Targeted educational interventions focusing on PFMT and early treatment for UI are essential.

The Lipophilic Extract from Ginkgo biloba L. Leaves Promotes Glucose Uptake and Alleviates Palmitate-Induced Insulin Resistance in C2C12 Myotubes.

Ginkgo biloba L. (ginkgo) is a widely used medicinal plant around the world. Its leaves, which have been used as a traditional Chinese medicine, are rich in various bioactive components. However, most of the research and applications of ginkgo leaves have focused on terpene trilactones and flavonol glycosides, thereby overlooking the other active components. In this study, a lipophilic extract (GL) was isolated from ginkgo leaves. This extract is abundant in lipids and lipid-like molecules. Then, its effect and potential mechanism on glucose uptake and insulin resistance in C2C12 myotubes were investigated. The results showed that GL significantly enhanced the translocation of GLUT4 to the plasma membrane, which subsequently promoted glucose uptake. Meanwhile, it increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream targets. Both knockdown of AMPK with siRNA and inhibition with AMPK inhibitor compound C reversed these effects. Additionally, GL ameliorated palmitate-induced insulin resistance by enhancing insulin-stimulated glucose uptake, increasing the phosphorylation of protein kinase B (PKB/AKT), and restoring the translocation of GLUT4 from the cytoplasm to the membrane. However, pretreatment with compound C abolished these beneficial effects of GL. In conclusion, GL enhances basal glucose uptake in C2C12 myotubes and improves insulin sensitivity in palmitate-induced insulin resistant myotubes through the AMPK pathway.

Unveiling the hub genes in the SIGLECs family in colon adenocarcinoma with machine learning.

Background: Despite the recognized roles of Sialic acid-binding Ig-like lectins (SIGLECs) in endocytosis and immune regulation across cancers, their molecular intricacies in colon adenocarcinoma (COAD) are underexplored. Meanwhile, the complicated interactions between different SIGLECs are also crucial but open questions. Methods: We investigate the correlation between SIGLECs and various properties, including cancer status, prognosis, clinical features, functional enrichment, immune cell abundances, immune checkpoints, pathways, etc. To fully understand the behavior of multiple SIGLECs' co-evolution and subtract its leading effect, we additionally apply three unsupervised machine learning algorithms, namely, Principal Component Analysis (PCA), Self-Organizing Maps (SOM), K-means, and two supervised learning algorithms, Least Absolute Shrinkage and Selection Operator (LASSO) and neural network (NN). Results: We find significantly lower expression levels in COAD samples, together with a systematic enhancement in the correlations between distinct SIGLECs. We demonstrate SIGLEC14 significantly affects the Overall Survival (OS) according to the Hazzard ratio, while using PCA further enhances the sensitivity to both OS and Disease Free Interval (DFI). We find any single SIGLEC is uncorrelated to the cancer stages, which can be significantly improved by using PCA. We further identify SIGLEC-1,15 and CD22 as hub genes in COAD through Differentially Expressed Genes (DEGs), which is consistent with our PCA-identified key components PC-1,2,5 considering both the correlation with cancer status and immune cell abundance. As an extension, we use SOM for the visualization of the SIGLECs and show the similarities and differences between COAD patients. SOM can also help us define subsamples according to the SIGLECs status, with corresponding changes in both immune cells and cancer T-stage, for instance. Conclusion: We conclude SIGLEC-1,15 and CD22 as the most promising hub genes in the SIGLECs family in treating COAD. PCA offers significant enhancement in the prognosis and clinical analyses, while using SOM further unveils the transition phases or potential subtypes of COAD.

Switchable Single- to Multiwavelength Conventional Soliton and Bound-State Soliton Generated from a NbTe2 Saturable Absorber-Based Passive Mode-Locked Erbium-Doped Fiber Laser.

As a member of transition metal dichalcogenides (TMDs), NbTe2 has a work function of 5.32 eV and a band gap of 0 eV at the Fermi level, which enables it to possess broadband absorption characteristics and has huge potential in optoelectronic devices. In this work, a combination of liquid phase exfoliation (LPE) and optical deposition methods (ODMs) were used to fabricate a NbTe2 saturable absorber (SA). Based on the NbTe2 SA, a ring passive mode-locked erbium-doped fiber laser (PML-EDFL) was constructed by adding NbTe2 SA into the laser cavity. A switchable single- to multiwavelength (dual/triple/quadruple) conventional soliton (CS) and a bound-state soliton (BS) were observed for the first time. The results reveal that NbTe2 SA has excellent saturable absorption characteristics (modulation depth of 2.6%, saturation intensity of 177.4 MW/cm2, and unsaturated loss of 63.8%) and can suppress mode competition and stabilize multiwavelength oscillation. This study expands the applications of NbTe2 nanosheets in ultrafast optoelectronics. The proposed switchable PML-EDFL has extensive applications in high-capacity all-optical communication, high-sensitivity optical fiber sensing, high-precision spectral measurements, and high-energy-efficiency photon neural networks.

Regulation of interstitial fluid flow in adventitia along vasculature by heartbeat and respiration.

Converging studies showed interstitial fluid (ISF) adjacent to blood vessels flows in adventitia along vasculature into heart and lungs. We aim to reveal circulatory pathways and regulatory mechanism of such adventitial ISF flow in rat model. By MRI, real-time fluorescent imaging, micro-CT, and histological analysis, ISF was found to flow in adventitial matrix surrounded by fascia and along systemic vessels into heart, then flow into lungs via pulmonary arteries and back to heart via pulmonary veins, which was neither perivascular tissues nor blood or lymphatic vessels. Under physiological conditions, speckle-like adventitial ISF flow rate was positively correlated with heart rate, increased when holding breath, became pulsative during heavy breathing. During cardiac or respiratory cycle, each dilation or contraction of heart or lungs can generate to-and-fro adventitial ISF flow along femoral veins. Discovered regulatory mechanisms of adventitial ISF flow along vasculature by heart and lungs will revolutionize understanding of cardiovascular system.

China's carbon-neutral policies will reduce short-term PM2.5-associated excess incidence of cardiovascular diseases.

China's carbon-neutral target could have benefits for ambient fine particulate matter (PM2.5)-associated mortality. Although previous studies have researched such benefits, the potential impact on cardiovascular disease incidence burden is yet to be investigated thoroughly. Here, we first estimate the association between short-term PM2.5 exposure and the incidence of stroke and coronary heart disease (CHD) via a case-crossover study before projecting future changes in short-term PM2.5-associated excess incidence across China from 2025 to 2060 under three different emission scenarios. We find that, compared to the 2015-2020 baseline, average PM2.5 concentrations nationwide in 2060 under SSP119 (an approximation of a carbon-neutral scenario) are projected to decrease by 81.07%. The short-term PM2.5-related excess incidence of stroke and CHD is projected to be reduced to 3,352 cases (95% confidence interval: 939, 5,738)-compared with 34,485 cases under a medium-emissions scenario (SSP245)-and is expected to be accompanied by a 95% reduction in the related economic burden. China's carbon-neutral policies are likely to bring health benefits for cardiovascular disease by reducing short-term PM2.5-related incidence burden.

The joint effects of prenatal exposure to PM2.5 constituents and reduced fetal growth on children's accelerated growth in the first 3 years: a birth cohort study.

BACKGROUND: Prenatal fine particulate matter (PM2.5) constituents exposure and reduced fetal growth may be risk factors for accelerated growth in early childhood, an important indicator for lifelong health. OBJECTIVE: The study investigated whether the joint effects are present between PM2.5 constituents and reduced fetal growth. METHODS: The study was embedded in a birth cohort in China, including 5424 mother-child pairs. Prenatal PM2.5 and its constituents' [organic carbon (OC), elementary carbon (EC), ammonium (NH4+), nitrate (NO3-), and sulfate (SO42-)] concentrations were estimated based on maternal residential addresses. Fetal growth was evaluated by fetal growth trajectory in utero and preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA). Children's accelerated growth was defined as body mass index (BMI) Z-score change of >0.67 between birth and 3 years. Generalized logistic regression was used to analyze the effects of prenatal PM2.5 constituents exposure and fetal growth on children's accelerated growth. Joint effect was tested on multiplicative scale and additive scale with the relative excess risk due to interaction (RERI). RESULTS: Children with lower fetal growth trajectory, PTB, LBW, and SGA had increased odds of children's accelerated growth, with odds ratios (ORs) ranging from 1.704 to 11.605. Compared with lower exposure (≤median), higher exposure (>median) of PM2.5, OC, and SO42- were significantly associated with increased odds of children's accelerated growth, varying in ORs from 1.163 to 1.478. Prenatal exposure to OC had joint effects with lower fetal growth on children's accelerated growth. We observed that the interaction was statistically significant on an additive scale in OC and lower fetal growth trajectory (RERI: 0.497, 95% CI: 0.033,0.962). IMPACT: Fine particulate matter (PM2.5) is a huge threat to human health worldwide, causing 6.7 million death globally in 2019. According to the theory of DOHaD, prenatal PM2.5 exposure could influence early childhood growth, which is important for lifelong health. We found that prenatal exposure to PM2.5, OC, and SO42- was associated with higher risk of accelerated childhood growth in the first 3 years. More importantly, reduced fetal growth moderated these associations. Our findings highlight the need for policies and interventions on PM2.5 constituents to improve lifelong health, especially for those vulnerable populations with reduced fetal growth.

Enhanced predictive validity of integrative models for refractory hyperthyroidism considering baseline and early therapy characteristics: a prospective cohort study.

BACKGROUND: A subset of Graves' disease (GD) patients develops refractory hyperthyroidism, posing challenges in treatment decisions. The predictive value of baseline characteristics and early therapy indicators in identifying high risk individuals is an area worth exploration. METHODS: A prospective cohort study (2018-2022) involved 597 newly diagnosed adult GD patients undergoing methimazole (MMI) treatment. Baseline characteristics and 3-month therapy parameters were utilized to develop predictive models for refractory GD, considering antithyroid drug (ATD) dosage regimens. RESULTS: Among 346 patients analyzed, 49.7% developed ATD-refractory GD, marked by recurrence and sustained Thyrotropin Receptor Antibody (TRAb) positivity. Key baseline factors, including younger age, Graves' ophthalmopathy (GO), larger goiter size, and higher initial free triiodothyronine (fT3), free thyroxine (fT4), and TRAb levels, were all significantly associated with an increased risk of refractory GD, forming the baseline predictive model (Model A). Subsequent analysis based on MMI cumulative dosage at 3 months resulted in two subgroups: a high cumulative dosage group (average ≥ 20 mg/day) and a medium-low cumulative dosage group (average < 20 mg/day). Absolute values, percentage changes, and cumulative values of thyroid function and autoantibodies at 3 months were analyzed. Two combined predictive models, Model B (high cumulative dosage) and Model C (medium-low cumulative dosage), were developed based on stepwise regression and multivariate analysis, incorporating additional 3-month parameters beyond the baseline. In both groups, these combined models outperformed the baseline model in terms of discriminative ability (measured by AUC), concordance with actual outcomes (66.2% comprehensive improvement), and risk classification accuracy (especially for Class I and II patients with baseline predictive risk < 71%). The reliability of the above models was confirmed through additional analysis using random forests. This study also explored ATD dosage regimens, revealing differences in refractory outcomes between predicted risk groups. However, adjusting MMI dosage after early risk assessment did not conclusively improve the prognosis of refractory GD. CONCLUSION: Integrating baseline and early therapy characteristics enhances the predictive capability for refractory GD outcomes. The study provides valuable insights into refining risk assessment and guiding personalized treatment decisions for GD patients.

Agaro-oligosaccharides mitigate deoxynivalenol-induced intestinal inflammation by regulating gut microbiota and enhancing intestinal barrier function in mice.

Agarose-derived agaro-oligosaccharides (AgaroS) have been extensively studied in terms of structures and bioactivities; they reportedly possess antioxidant and anti-inflammatory activities that maintain intestinal homeostasis and host health. However, the protective effects of AgaroS on deoxynivalenol (DON)-induced intestinal dysfunction remain unclear. We investigated the effects of AgaroS on DON-induced intestinal dysfunction in mice and explored the underlying protective mechanisms. In total, 32 mice were randomly allocated to four treatments (n = 8 each) for 28 days. From day 1 to day 21, the control (CON) and DON groups received oral phosphate-buffered saline (200 µL per day); the AgaroS and AgaroS + DON groups received 200 mg AgaroS per kg body weight once daily by orogastric gavage. Experimental intestinal injury was induced by adding DON (4.8 mg per kg body weight) via gavage from day 21 to day 28. Phosphate-buffered saline was administered once daily by gavage in the CON and AgaroS groups. Herein, AgaroS supplementation led to a higher final body weight and smaller body weight loss and a lower concentration of plasma inflammatory cytokines, compared with the DON group. The DON group showed a significantly reduced ileal villus height and villus height/crypt depth, compared with the CON and AgaroS + DON groups. However, AgaroS supplementation improved DON-induced intestinal injury in mice. Compared with the DON group, ileal and colonic protein expression levels of claudin, occludin, Ki67, and mucin2 were significantly higher in the AgaroS supplementation group. Colonic levels of the anti-inflammatory cytokine IL-1ß tended to be higher in the DON group than in the AgaroS + DON group. AgaroS altered the gut microbiota composition, accompanied by increased production of short-chain fatty acids in mice. In conclusion, our findings highlight a promising anti-mycotoxin approach whereby AgaroS alleviate DON-induced intestinal inflammation by modulating intestinal barrier functional integrity and gut microbiota in mice.

Association between Ambient Volatile Organic Compounds Exposome and Emergency Hospital Admissions for Cardiovascular Disease.

The limited research on volatile organic compounds (VOCs) has not taken into account the interactions between constituents. We used the weighted quantile sum (WQS) model and generalized linear model (GLM) to quantify the joint effects of ambient VOCs exposome and identify the substances that play key roles. For a 0 day lag, a quartile increase of WQS index for n-alkanes, iso/anti-alkanes, aromatic, halogenated aromatic hydrocarbons, halogenated saturated chain hydrocarbons, and halogenated unsaturated chain hydrocarbons were associated with 1.09% (95% CI: 0.13, 2.06%), 0.98% (95% CI: 0.22, 1.74%), 0.92% (95% CI: 0.14, 1.69%), 1.03% (95% CI: 0.14, 1.93%), 1.69% (95% CI: 0.48, 2.91%), and 1.85% (95% CI: 0.93, 2.79%) increase in cardiovascular disease (CVD) emergency hospital admissions, respectively. Independent effects of key substances on CVD-related emergency hospital admissions were also reported. In particular, an interquartile range increase in 1,1,1-trichloroethane, methylene chloride, styrene, and methylcyclohexane is associated with a greater risk of CVD-associated emergency hospital admissions [3.30% (95% CI: 1.93, 4.69%), 3.84% (95% CI: 1.21, 6.53%), 5.62% (95% CI: 1.35, 10.06%), 8.68% (95% CI: 3.74, 13.86%), respectively]. We found that even if ambient VOCs are present at a considerably low concentration, they can cause cardiovascular damage. This should prompt governments to establish and improve concentration standards for VOCs and their sources. At the same time, policies should be introduced to limit VOCs emission to protect public health.

A Polymer-Based Antigen Carrier Activates Two Innate Immune Pathways for Adjuvant-Free Subunit Vaccines.

The activation of multiple Pattern Recognition Receptors (PRRs) has been demonstrated to trigger inflammatory responses and coordinate the host's adaptive immunity during pathogen infections. The use of PRR agonists as vaccine adjuvants has been reported to synergistically induce specific humoral and cellular immune responses. However, incorporating multiple PRR agonists as adjuvants increases the complexity of vaccine design and manufacturing. In this study, we discovered a polymer that can activate both the Toll-like receptor (TLR) pathway and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. The polymer was then conjugated to protein antigens, creating an antigen delivery system for subunit vaccines. Without additional adjuvants, the antigen-polymer conjugates elicited strong antigen-specific humoral and cellular immune responses. Furthermore, the antigen-polymer conjugates, containing the Receptor Binding Domain (RBD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein or the Monkeypox Antigen M1R as the antigens, were found to induce potent antigen-specific antibodies, neutralizing antibodies, and cytotoxic T cells. Immunization with M1R-polymer also resulted in effective protection in a lethal challenge model. In conclusion, this vaccine delivery platform offers an effective, safe, and simple strategy for inducing antigen-specific immunity against infectious diseases.

Dust particulate matter increases pulmonary embolism onset: A nationwide time-stratified case-crossover study in China.

BACKGROUND: Particulate matter (PM) has been found to elevate the risk of pulmonary embolism (PE) onset. Among the contributors to PM, dust PM stands as the second natural source, and its emissions are escalating due to climate change. Despite this, information on the effect of dust PM on PE onset is scarce. Hence, this study aims to investigate the impacts of dust PM10, dust PM2.5-10, and dust PM2.5 on PE onset. METHODS: A nationwide time-stratified case-crossover study was conducted between 2015 and 2020, using data from 18,616 PE onset cases across 1,921 hospitals in China. The analysis employed a conditional logistic regression model to quantify the associations between dust PM10, dust PM2.5-10, and dust PM2.5 and PE onset. Furthermore, the study explored the time-distributed lag pattern of the effect of dust PM on PE development. Stratified analyses were performed based on sex, age, region, and season. RESULTS: Dust PM10, dust PM2.5-10, and dust PM2.5 exhibited significant health effects on PE onset, particularly concerning exposure on the same day. The peak estimates were observed at lag 01 day, with the odds ratio being 1.011 [95 % confidence interval (CI): 1.003, 1.019], 1.014 (95 % CI: 1.003, 1.026), and 1.039 (95 % CI: 1.011, 1.068), for a 10 µg/m3 increase in the concentration of dust PM10, dust PM2.5-10, and dust PM2.5, respectively. In addition, the study identified a higher risk of PE onset associated with dust PM exposure during the warm season than that in cool season, particularly for dust PM2.5. CONCLUSIONS: The findings from this study suggest that short-term exposure to dust PM, particularly dust PM2.5, may trigger PE onset, posing a significant health threat. Implementing measures to mitigate dust PM emissions and protect patients with PE from dust PM exposure is imperative.

Acute Effects of Low Temperatures and Cold Waves on Elderly Infectious Pneumonia Mortality - Jinan City, Shandong Province, China, 2014-2022.

What is already known about this topic?: The mortality rate due to pneumonia varies depending on the infectious agents present in a low- temperature environment. What is added by this report?: This study aimed to examine the relationship between low temperatures and cold waves and the risk of mortality from infectious pneumonia in the elderly. The findings indicate a significant increase in the risk of infectious pneumonia, specifically bacterial pneumonia, during periods of low temperatures and cold waves. What are the implications for public health practice?: This study presents compelling evidence that highlights the importance of proactive public responses to infectious pneumonia among the elderly population during periods of cold waves.

The spatial correlation network structure and its formation mechanism of urban high-quality economic development: a comparative analysis from the Yangtze River Economic Belt and the Yellow River Basin in China.

In the context of regional integration, it is more than crucial to compare and analyze the spatial correlation network structure and formation mechanism of high-quality economic development in the Yangtze River Economic Belt and the Yellow River Basin urban cities as an attempt to strengthen collaborative work on high-quality economic development in both river basins. The paper measured high-quality economic development of the Yangtze River Economic Belt and the Yellow River Basin from 2010 to 2021. Then, it employed social network analysis and the QAP method to study the network structure's characteristics and formation mechanism. The conclusion of the research illustrates a few points clearly that first, the high-quality economic development of the two rivers presents a complex and multithreaded network structure. Although the network structure is hold at a comparatively stable state, the correlation degree needs improvement. Second, cities such as Chongqing, Wuhan, Hefei, Nanjing, Hangzhou, Shanghai, and Changsha and cities like Zhengzhou, Xi'an, Luoyang, Yulin, Hulunbuir, Ordos, and Nanyang are at the very central as well as central position of the network. The spatial correlation networks of the Yangtze River Economic Belt and the Yellow River Basin can be divided into four plates: "agent plate," "main outflow plate," "bidirectional spillover plate," and "main inflow plate." Third, reverse geographical distance and differences in the digital economy attach great significance to the spatial correlation networks of the two basins. The difference in urbanization level makes significant impacts only on the spatial correlation network of the Yangtze River Economic Belt, while the difference in environmental regulation and material capital accumulation only significantly influences the spatial correlation network of the Yellow River Basin.

A Review of the Interactive Effects of Climate and Air Pollution on Human Health in China.

PURPOSE OF REVIEW: Through a systematic search of peer-reviewed epidemiologic studies, we reviewed the literature on the human health impacts of climate and ambient air pollution, focusing on recently published studies in China. Selected previous literature is discussed where relevant in tracing the origins. RECENT FINDINGS: Climate variables and air pollution have a complex interplay in affecting human health. The bulk of the literature we reviewed focuses on the air pollutants ozone and fine particulate matter and temperatures (including hot and cold extremes). The interaction between temperature and ozone presented substantial interaction, but evidence about the interactive effects of temperature with other air pollutants is inconsistent. Most included studies used a time-series design, usually with daily mean temperature and air pollutant concentration as independent variables. Still, more needs to be studied about the co-occurrence of climate and air pollution. The co-occurrence of extreme climate and air pollution events is likely to become an increasing health risk in China and many parts of the world as climate changes. Climate change can interact with air pollution exposure to amplify risks to human health. Challenges and opportunities to assess the combined effect of climate variables and air pollution on human health are discussed in this review. Implications from epidemiological studies for implementing coordinated measures and policies for addressing climate change and air pollution will be critical areas of future work.

Exploring the mechanism of action of Sparganii Rhizoma-Curcumae Rhizoma for in treating castration-resistant prostate cancer: a network-based pharmacology and experimental validation study.

Sparganii Rhizoma-Curcumae Rhizoma (SR-CR) is a classic drug pair for the treatment of castration-resistant prostate cancer (CRPC), but its mechanism has not been clarified. The study aims to elucidate the potential mechanism of SR-CR in the management of CRPC. The present study employed the TCMSP as well as the SwissTargetPrediction platform to retrieve the chemical composition and targets of SR-CR. The therapeutic targets of CRPC were identified through screening the GeneCards, Disgenet, and OMIM databases. Subsequently, the Venny online platform was utilized to identify the shared targets between the SR-CR and CRPC. The shared targets were enrichment analysis using the Bioconductor and Kyoto encyclopedia of genes and genomes (KEGG) databases. The active ingredients and core targets were verified through molecular docking and were validated using PC3 cells in the experimental validation phase. A total of 7 active ingredients and 1126 disease targets were screened from SR-CR, leading to a total of 59 shared targets. Gene Ontology (GO) analysis resulted in 1309 GO entries. KEGG pathways analysis yielded 121 pathways, primarily involving cancer-related signaling pathways. The results from molecular docking revealed stable binding interactions between the core ingredients and the core targets. In vitro cellular assays further demonstrated that SR-CR effectively suppressed the activation of the Prostate cancer signaling pathway in PC3 cells, leading to the inhibition of cell proliferation and promotion of apoptosis. The SR-CR exert therapeutic effects on CRPC by inhibiting cell proliferation and promoting apoptosis through the Prostate cancer signaling pathway.

Reticulon 3 deficiency ameliorates post-myocardial infarction heart failure by alleviating mitochondrial dysfunction and inflammation.

Multiple molecular mechanisms are involved in the development of heart failure (HF) after myocardial infarction (MI). However, interventions targeting these pathological processes alone remain clinically ineffective. Therefore, it is essential to identify new therapeutic targets for alleviating cardiac dysfunction after MI. Here, gain- and loss-of-function approaches were used to investigate the role of reticulon 3 (RTN3) in HF after MI. We found that RTN3 was elevated in the myocardium of patients with HF and mice with MI. Cardiomyocyte-specific RTN3 overexpression decreased systolic function in mice under physiological conditions and exacerbated the development of HF induced by MI. Conversely, RTN3 knockout alleviated cardiac dysfunction after MI. Mechanistically, RTN3 bound and mediated heat shock protein beta-1 (HSPB1) translocation from the cytosol to the endoplasmic reticulum. The reduction of cytosolic HSPB1 was responsible for the elevation of TLR4, which impaired mitochondrial function and promoted inflammation through toll-like receptor 4 (TLR4)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha(PGC-1α) and TLR4/Nuclear factor-kappa B(NFκB) pathways, respectively. Furthermore, the HSPB1 inhibitor reversed the protective effect of RTN3 knockout on MI. Additionally, elevated plasma RTN3 level is associated with decreased cardiac function in patients with acute MI. This study identified RTN3 as a critical driver of HF after MI and suggests targeting RTN3 as a promising therapeutic strategy for MI and related cardiovascular diseases.