Astragaloside IV Alleviates Doxorubicin-Induced Cardiotoxicity by Inhibiting Cardiomyocyte Pyroptosis through the SIRT1/NLRP3 Pathway.

Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug used to treat a wide spectrum of tumors. However, its clinical application is limited due to cardiotoxic side effects. Astragaloside IV (AS IV), one of the major compounds present in aqueous extracts of Astragalus membranaceus, possesses potent cardiovascular protective properties, but the underlying molecular mechanisms are unclear. Thus, the aim of this study was to investigate the effect of AS IV on DOX-induced cardiotoxicity (DIC). Our findings revealed that DOX induced pyroptosis through the caspase-1/gasdermin D (GSDMD) and caspase-3/gasdermin E (GSDME) pathways. AS IV treatment significantly improved the cardiac function and alleviated myocardial injury in DOX-exposed mice by regulating intestinal flora and inhibiting pyroptosis; markedly suppressed the levels of cleaved caspase-1, N-GSDMD, cleaved caspase-3, and N-GSDME; and reversed DOX-induced downregulation of silent information regulator 1 (SIRT1) and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mice. The SIRT1 inhibitor EX527 significantly blocked the protective effects of AS IV. Collectively, our results suggest that AS IV protects against DIC by inhibiting pyroptosis through the SIRT1/NLRP3 pathway.

Seizing the fate of lymph nodes in immunotherapy: To preserve or not?

Lymph node dissection has been a long-standing diagnostic and therapeutic strategy for metastatic cancers. However, questions over myriad related complications and survival outcomes are continuously debated. Immunotherapy, particularly neoadjuvant immunotherapy, has revolutionized the conventional paradigm of cancer treatment, yet has benefited only a fraction of patients. Emerging evidence has unveiled the role of lymph nodes as pivotal responders to immunotherapy, whose absence may contribute to drastic impairment in treatment efficacy, again posing challenges over excessive lymph node dissection. Hence, centering around this theme, we concentrate on the mechanisms of immune activation in lymph nodes and provide an overview of minimally invasive lymph node metastasis diagnosis, current best practices for activating lymph nodes, and the prognostic outcomes of omitting lymph node dissection. In particular, we discuss the potential for future comprehensive cancer treatment with effective activation of immunotherapy driven by lymph node preservation and highlight the challenges ahead to achieve this goal.

WITHDRAWN: The Natural Products as Novel Anti-Obesity Agents: Mechanisms Based on Adipose Tissue

The article has been withdrawn at the request of the authors of the journal Current Diabetes Reviews.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

ASTRAGALOSIDE â £ MODULATES GUT MACROPHAGES M1/M2 POLARIZATION BY RESHAPING GUT MICROBIOTA AND SHORT CHAIN FATTY ACIDS IN SEPSIS.

ABSTRACT: M1 macrophage-mediated inflammation is critical in sepsis. We previously found the protective role of astragaloside intravenous (AS-IV) in sepsis-associated gut impairment, whose specific mechanism remains unknown. Gut microbiota modulates gut homeostatic balance to avoid excessive inflammation. Here, we aimed to investigate effects of AS-IV on gut macrophages polarization and potential roles of gut microbiota and short chain fatty acids (SCFAs) in septic gut damage. Mice were pretreated by AS-IV gavage for 7 days before cecal ligation and puncture. M1 polarization of gut lamina propria macrophages (LpMs) was promoted by cecal ligation and puncture, accompanied by abnormal cytokines release and intestinal barrier dysfunction. NLRP3 inflammasome was activated in M1 LpMs. 16S rRNA sequencing demonstrated gut microbiota imbalance. The levels of acetate, propionate, and butyrate in fecal samples decreased. Notably, AS-IV reversed LpMs M1/M2 polarization, lightened gut inflammation and barrier injury, reduced NLRP3 inflammasome expression in LpMs, restored the diversity of gut microbiome, and increased butyrate levels. Similarly, these benefits were mimicked by fecal microbiota transplantation or exogenous butyrate supplementation. In Caco-2 and THP-1 cocultured model, LPS and interferon γ caused THP-1 M1 polarization, Caco-2 barrier impairment, abnormal cytokines release, and high NLRP3 inflammasome expression in THP-1 cells, all of which were mitigated by butyrate administration. However, these protective effects of butyrate were abrogated by NLRP3 gene overexpression in THP-1. In conclusion, AS-IV can ameliorate sepsis-induced gut inflammation and barrier dysfunction by modulating M1/M2 polarization of gut macrophages, whose underlying mechanism may be restoring gut microbiome and SCFA to restrain NLRP3 inflammasome activation.

Type-I Photosensitizer-Triggered Controllable Carbon Monoxide Release for Effective Treatment of Staph Skin Infection.

Staphylococcus aureus (S. aureus) infection is a major infectious skin disease that is highly resistant to conventional antibiotic treatment and host immune defense, leading to recurrence and exacerbation of bacterial infection. Herein, we developed a photoresponsive carbon monoxide (CO)-releasing nanocomposite by integrating anion-π+ type-I photosensitizer (OMeTBP) and organometallic complex (FeCO) for the treatment of planktonic S. aureus and biofilm-associated infections. After optimizing the molar ratio of FeCO and OMeTBP, the prepared nanoparticles, OMeTBP@FeCONPs, not only ensured sufficient loading of CO donors and efficient CO generation but also showed negligible free ROS leakage under light irradiation, which helped to avoid tissue damage caused by excessive ROS. Both in vitro and in vivo results demonstrated that OMeTBP@FeCONPs could effectively inhibit S. aureus methicillin-resistant S. aureus (MRSA), and bacterial biofilm. Our design has the potential to overcome the resistance of conventional antibiotic treatment and provide a more effective option for bacterial infections.

A Novel Algorithmic Structure of EEG Channel Attention Combined With Swin Transformer for Motor Patterns Classification.

With the development of brain-computer interfaces (BCI) technologies, EEG-based BCI applications have been deployed for medical purposes. Motor imagery (MI), applied to promote neural rehabilitation for stroke patients, is among the most common BCI paradigms that. The Electroencephalogram (EEG) signals, encompassing an extensive range of channels, render the training dataset a high-dimensional construct. This high dimensionality, inherent in such a dataset, tends to challenge traditional deep learning approaches, causing them to potentially disregard the intrinsic correlations amongst these channels. Such an oversight often culminates in erroneous data classification, presenting a significant drawback of these conventional methodologies. In our study, we propose a novel algorithmic structure of EEG channel-attention combined with Swin Transformer for motor pattern recognition in BCI rehabilitation. Effectively, the self-attention module from transformer architecture could captures temporal-spectral-spatial features hidden in EEG data. The experimental results verify that our proposed methods outperformed other state-of-art approaches with the average accuracy of 87.67%. It is implied that our method can extract high-level and latent connections among temporal-spectral features in contrast to traditional deep learning methods. This paper demonstrates that channel-attention combined with Swin Transformer methods has great potential for implementing high-performance motor pattern-based BCI systems.

Hypothalamic TrkB.FL overexpression improves metabolic outcomes in the BTBR mouse model of autism.

BTBR T+ Itpr3tf/J (BTBR) mice are used as a model of autism spectrum disorder (ASD), displaying similar behavioral and physiological deficits observed in patients with ASD. Our recent study found that implementation of an enriched environment (EE) in BTBR mice improved metabolic and behavioral outcomes. Brain-derived neurotrophic factor (Bdnf) and its receptor tropomyosin kinase receptor B (Ntrk2) were upregulated in the hypothalamus, hippocampus, and amygdala by implementing EE in BTBR mice, suggesting that BDNF-TrkB signaling plays a role in the EE-BTBR phenotype. Here, we used an adeno-associated virus (AAV) vector to overexpress the TrkB full-length (TrkB.FL) BDNF receptor in the BTBR mouse hypothalamus in order to assess whether hypothalamic BDNF-TrkB signaling is responsible for the improved metabolic and behavioral phenotypes associated with EE. Normal chow diet (NCD)-fed and high fat diet (HFD)-fed BTBR mice were randomized to receive either bilateral injections of AAV-TrkB.FL or AAV-YFP as control, and were subjected to metabolic and behavioral assessments up to 24 weeks post-injection. Both NCD and HFD TrkB.FL overexpressing mice displayed improved metabolic outcomes, characterized as reduced percent weight gain and increased energy expenditure. NCD TrkB.FL mice showed improved glycemic control, reduced adiposity, and increased lean mass. In NCD mice, TrkB.FL overexpression altered the ratio of TrkB.FL/TrkB.T1 protein expression and increased phosphorylation of PLCγ in the hypothalamus. TrkB.FL overexpression also upregulated expression of hypothalamic genes involved in energy regulation and altered expression of genes involved in thermogenesis, lipolysis, and energy expenditure in white adipose tissue and brown adipose tissue. In HFD mice, TrkB.FL overexpression increased phosphorylation of PLCγ. TrkB.FL overexpression in the hypothalamus did not improve behavioral deficits in either NCD or HFD mice. Together, these results suggest that enhancing hypothalamic TrkB.FL signaling improves metabolic health in BTBR mice.

The Relationship between Meaning in Life and Depression among Chinese Junior High School Students: The Mediating and Moderating Effects of Cognitive Failures and Mindfulness.

In recent years, the incidence of depression among adolescents has been increasing yearly, and the severe damage of depression on adolescents' physical and mental health development has caused extensive concern worldwide. Previous research on adults has confirmed that meaning in life is a crucial buffer factor for depression, and developing meaning in life is an essential task in adolescence. Moreover, prior researchers also pointed out that frequent cognitive failures can induce negative emotions in individuals, whereas mindfulness can regulate individuals' depression levels. However, few studies have investigated the impact of meaning in life on depression in adolescents and the underlying psychological mechanisms. Accordingly, based on the theoretical framework of the Cognitive Vulnerability-Stress Theory of Depression, this study aimed to explore the relationship between meaning in life and depression in junior high school students, as well as the mediating effect of cognitive failures and the moderating effect of mindfulness. We collected data from 948 adolescents aged 11 to 17 in two junior high schools in Henan Province, China, and tested the theoretical model through the PROCESS macro for SPSS. The results showed that: (1) meaning in life had a significant negative predictive effect on depression (ß = -0.24, p < 0.001); (2) cognitive failures partially mediated the relationship between meaning in life and depression (ß = 0.31, p < 0.001); (3) the relationship between cognitive failures and depression was moderated by mindfulness (ß = -0.05, p < 0.05). This study implied that we could start by cultivating adolescents' meaning in life and improving their level of mindfulness to prevent and intervene in adolescent depression.

Rumination and "hot" executive function of middle school students during the COVID-19 pandemic: A moderated mediation model of depression and mindfulness.

Background: The outbreak of COVID-19 had a widely negative effect on adolescents' academics, stress, and mental health. At a critical period of cortical development, adolescents' cognition levels are highly developed, while the ability of emotion control is not developed at the same pace. Faced with negative emotions such as stress and social loneliness caused by COVID-19, adolescents' "hot" executive function encounters severer emotional regulation challenges than ever before. Objective: The present study established a moderated mediation model to investigate the impact of rumination on "hot" execution function among Chinese middle school students during the COVID-19 pandemic, and the specific role of depression and mindfulness in the association. Materials and methods: This cross-sectional study was conducted on 650 students recruited from a province in central China. The participants completed questionnaires and experiment between July 2021 and August 2021. Rumination Responses Scales, Self-rating Depression Scale, and Mindful Attention Awareness Scale were used to measure the level of rumination, depression, and mindfulness. The reaction time and accuracy of the emotional conflict experiment were recorded to reflect the "hot" executive function. Results: The results of the moderated mediation model indicated that rumination of middle school students significantly and positively predicted depression in adolescents (ß = 0.26, p < 0.001). Meanwhile, the indirect effect of depression on the relationship between rumination and "hot" executive function was significant; depression partially mediated this relationship (word-face congruent condition: ß = -0.09, p < 0.01; word-face incongruent condition: ß = -0.07, p < 0.05). Furthermore, mindfulness buffered the association between rumination and depression, according to moderated mediation analysis (ß = -0.11, p < 0.001). For adolescents with low levels of mindfulness, the relationship was substantially stronger. Conclusion: In the context of the COVID-19 pandemic, middle school students' rumination would lead to depression, which can negatively impact their "hot" executive function. Besides, mindfulness could resist the adverse effect of rumination on depression. The educators should pay more attention to students' mental health, provide targeted strategies that boost mindfulness to promote their cognitive flexibility, and thus protect the normal development of their executive function during crisis events.

Maternal organic selenium supplementation during gestation enhances muscle fiber area and muscle fiber maturation of offspring in porcine model.

BACKGROUND: Organic selenium supplementation during gestation improves the antioxidant status and reproductive performance of sows and increases the antioxidative capacity of the intestines of their offspring. This study was conducted to investigate the effect of maternal basel diet (control) supplemented with an organic Se, 2-hydroxy-4-methylselenobutanoic acid (HMSeBA), or inorganic sodium selenite (Na2SeO3) during gestation on the antioxidant status and development of muscle in newborn and weaned piglets. Newborn piglets before colostrum intake and weaned piglets were selected for longissimus dorsi (LD) muscle collection and analysis. RESULTS: The results showed that maternal HMSeBA supplementation increased the muscle area and content of Se in the LD muscle of newborn piglets, improved gene expression of selenoproteins, and decreased oxidative status in the LD muscle of both newborn and weaned piglets compared with the control. The expression of muscle development-related genes of newborn piglets in the HMSeBA group was lower than in the control group, whereas the expression of MRF4 in weaned piglets was higher in the HMSeBA group than in the control and Na2SeO3 groups. In addition, HMSeBA supplementation decreased the mRNA expressions of myosin heavy chains (MyHC) IIx and MyHC IIb and the percentage of MyHC IIb; increased the expression of PGC-1α in the LD muscle of newborn piglets; increased the gene expression of MyHC IIa; and decreased the protein expression of slow MyHC and the activity of malate dehydrogenase in the LD muscle of weaned piglets compared with the control group. CONCLUSIONS: Maternal HMSeBA supplementation during gestation can improve the antioxidative capacity of the muscle of their offspring and promote the maturity of muscle fibres in weaned offspring.

Computed tomography enterography predicts surgical-free survival in symptomatic stricturing Crohn's disease.

OBJECTIVES: The study aimed to predict surgical risks for patients with symptomatic stricturing Crohn's disease (CD) using computed tomography enterography (CTE) and to assess the association between CTE findings and pathological changes. METHODS: Crohn's disease patients with symptomatic stricture(s) were included. Exclusion criteria were concomitant penetrating disease, intra-abdominal abscess, previous bowel resection, or asymptomatic. Patients from January 2016 to December 2019 were identified as the primary cohort and those from January 2020 to June 2020 were identified as the validation cohort. Two independent experienced radiologists evaluated CTE variables including mucosal enhancement, mural stratification, wall enhancement, comb sign, lymphadenopathy, thick non-enhancing wall, bowel wall thickness, luminal diameter, and upstream lumen. Receiver operating characteristic, logistic regression, and nomogram were performed to identify the independent predictors of surgical-free survival. Histopathological scores of surgical specimens were also evaluated. RESULTS: 198 patients (primary cohort, 123 with surgery and 75 under non-surgical intervention, and 41 patients (validation cohort) were analyzed. Bowel wall thickness < 5.9 mm, luminal stenosis > 3.35 mm, and upstream lumen < 27.5 mm were predictors of surgical-free survival for symptomatic stricturing CD patients. Logistic analysis showed the three CTE variables were the independent predictors of surgical-free survival (p < 0.001). A nomogram was developed with the concordance indexes of 0.905 and 0.892 in the primary and validation cohorts. Histopathological analysis showed bowel wall muscular hyperplasia/hypertrophy significantly correlated with luminal stenosis (r = - 0.655, p = 0.008) and combined CTE variable (r = - 0.683, p = 0.005). CONCLUSIONS: CTE is highly predictive of disease course and surgical-free survival for patients with symptomatic stricturing CD, suggesting the important role of CTE in decision-making of treatment.

Construction of polysaccharide scaffold-based perfusion bioreactor supporting liver cell aggregates for drug screening.

Rebuilding a suitable microenvironment of liver cells is the key challenge to enhancing the expression of hepatic functions for drug screening in vitro. To improve the microenvironment by providing the specific adhesive ligands for hepatocytes in the three-dimensional dynamic culture, a perfusion bioreactor with a pectin/alginate blend porous scaffold was constructed in this study. The galactosyl component in the main chain of pectin was able to be specifically recognized by the asialoglycoprotein receptor on the surface of hepatocytes, and subsequently promoted the adhesion and aggregation of hepatocytes co-cultured with hepatic non-parenchymal cells. The bioreactor was optimized for 4 h of dynamic inoculation followed by perfusion at a flow rate of 2 mL/min, which provided adequate oxygen supply and good mass transfer to the liver cells. During dynamic cultured in the bioreactor for 14 days, more multicellular aggregates were formed and were evenly distributed in the pectin/alginate blend scaffolds. The expressions of intercellular interaction and hepatic functions of the hepatocytes in aggregates were significantly enhanced in the three-dimensional dynamic group. Furthermore, the bioreactor not only markedly upregulated the cell polarity markers expression of hepatocytes but also enhanced their metabolic capacity to acetaminophen, isoniazid, and tolbutamide, which exhibited a significant concentration-dependent manner. Therefore, the pectin/alginate blend scaffold-based perfusion bioreactor appeared to be a promising candidate in the field of drug development and liver regeneration research.

Performance enhancement and population structure of denitrifying phosphorus removal system over redox mediator at low temperature.

The development of denitrifying polyphosphate accumulating organisms (DPAOs) presents a strategy to carbon competition between denitrifying bacteria and phosphorus removing bacteria. However, low temperature inhibits the rate of enzyme-catalyzed and substrate diffusion during denitrifying phosphorus removal (DPR). Therefore, the present study assessed the addition of NQS (100 µmol/L) for enhancing the removal of TP and TN in DPR reactors operated at alternating anaerobic and anoxic phases and different influent phosphate concentrations. The results showed that the removal efficiency of TP and TN in NQS-DPR system at 10 °C were 99.9% and 42.0%, respectively, which were 2.1 and 2.0 times higher than that of DPR system. Adding NQS significantly alleviated the increase of pH under anoxic condition and decreased the ORP value of the reactor, which in turn enhanced the PHAs accumulation process. The determination of functional genes (nirK, narG and phoD) showed that Dechloromonas, Lentimicrobium, and Terrimonas were the dominant functional bacteria in NQS-DPR system at 10 °C with the relative abundance of 3.09%, 2.99% and 2.28%, respectively. This study can provide valuable information for the effects of the addition of the redox mediator on denitrifying phosphorus removal technology.

Study on Lung Injury Caused by Fine Particulate Matter and Intervention Effect of Rhodiola wallichiana.

Objective: The objective of this study was to observe the protective effect of Rhodiola wallichiana drops in a rat model of fine particulate matter (PM2.5) lung injury. Methods: Forty male Wistar rats were randomly divided into blank control (NC), normal saline (NS), PM2.5-infected (PM), and Rhodiola wallichiana (RW) groups. Rats in the NC group were not provided any interventions, whereas those in the NS and PM groups were administered normal saline and PM2.5 suspension by trachea drip once a week for four weeks. Rats in the RW group were intraperitoneally administered Rhodiola wallichiana for 14 days and then administered PM2.5 suspension by trachea drip 7 days after drug delivery. The levels of inflammatory factors such as interleukin-6, interleukin-1ß, and tumor necrosis factor-alpha and oxidative stress biomarkers such as 8-hydroxy-2'-deoxyguanosine, 4-hydroxynonenal, and protein carbonyl content were determined in the serum and bronchoalveolar lavage fluid by ELISA. The level of 4-hydroxynonenal in the lung was also determined using Western blotting and immunohistochemical staining. Results: Levels of inflammatory factors and oxidative stress biomarkers were all increased in the PM group but decreased in the RW group. Western blotting revealed increased 4-hydroxynonenal levels in the PM group but decreased levels in the RW group. Immunohistochemical staining also provided similar results. Conclusion: Rhodiola wallichiana could protect rats from inflammation and oxidative stress injury caused by PM2.5.

Risk Factors for Worsening of Bone Loss in Patients Newly Diagnosed with Inflammatory Bowel Disease.

Background: Bone loss is common in patients with inflammatory bowel disease (IBD). The aim of the present study was to determine the prevalence of metabolic bone disease in patients newly diagnosed with IBD and to identify the risk factors for bone loss over time. Methods: We performed a retrospective, both cross-sectional and longitudinal, study to extract the risk factors of bone loss (including osteopenia and osteoporosis) in patients newly diagnosed with IBD, using dual-energy X-ray absorptiometry (DXA). Results: A total of 639 patients newly diagnosed with IBD that had at least one DXA were included in the cross-sectional study. Osteopenia and osteoporosis were diagnosed in 24.6% and 5.4% of patients, respectively. Age at diagnosis, body mass index, and serum phosphorus were identified as independent factors associated with bone loss at baseline. A total of 380 of the 639 IBD patients (including 212 CD patients and 168 UC patients) with at least a second DXA scan were included in the longitudinal study. 42.6% of the patients presented a worsening of bone loss in the follow-up study. Menopause, albumin, and use of corticosteroids were identified as independent factors associated with worsening of bone loss. Conclusions: Metabolic bone disease is common in IBD patients, and there is a significant increase in prevalence of bone loss over time. Postmenopausal female, malnourished patients, and those requiring corticosteroid treatment are at risk for persistent bone loss. Therefore, BMD measurements and early intervention with supplementation of calcium and vitamin D are recommended in IBD patients with high-risk factors.

Efficacy of Bushen Yiqi Huayu Decoction on Ovarian Reserve and Inflammatory Factors in Patients after Hysterectomy plus Salpingectomy.

Objective: To assess the efficacy of Bushen Yiqi Huayu Decoction on ovarian reserve and inflammatory factors in patients after hysterectomy plus salpingectomy. Methods: Between January 2020 and December 2020, sixty patients with benign uterine lesions scheduled for a hysterectomy plus salpingectomy in the obstetrics and gynecology department of our hospital were recruited and assigned at a ratio of 1 : 1 via the random number table method to receive conventional therapy (control group) or conventional therapy plus Bushen Yiqi Huayu Decoction (study group) for 2 months. The traditional Chinese medicine (TCM) symptom scores, TCM efficacy, various postoperative recovery time indexes, inflammatory factor levels, and hormone levels were compared between the two groups of patients. Results: The study group had lower TCM symptom scores and milder inflammatory responses compared to the control group after treatment (P < 0.05). The Bushen Yiqi Huayu Decoction plus conventional therapy achieved an efficacy of 96.67% versus the efficacy of 76.67% by conventional therapy alone (P < 0.05). In contrast to the control group, a shorter postoperative recovery duration of patients was recorded in the study group (P < 0.05). The study group showed significantly better improvement in hormone levels than the control group after treatment (P < 0.05). Conclusion: Bushen Yiqi Huayu Decoction can significantly mitigate the inflammatory response of patients after hysterectomy plus salpingectomy, improve the hormone level and the ovarian reserve of patients, and promote rapid recovery, so it is worthy of clinical promotion.

Zuogui pills maintain the stemness of oogonial stem cells and alleviate cyclophosphamide-induced ovarian aging through Notch signaling pathway.

BACKGROUND: Zuogui pills (ZGP), a classical prescription of traditional Chinese medicine, have been widely used in the treatment of ovarian aging. Previous studies have demonstrated its efficacy on protecting ovarian aging, and the mechanisms were mostly relevant to inhibiting the apoptosis of follicles and activating the primordial follicles. However, whether ZGP could stimulate the oogonial stem cells (OSCs) to refresh the follicle pool remains poorly understood. PURPOSE: To investigate the effects of ZGP on the stemness of OSCs in cyclophosphamide (Cy)-induced ovarian aging. STUDY DESIGN AND METHODS: Female Sprague-Dawley (SD) rats were randomly divided into 8 groups: control group, model group, ZGP groups (low / high dose groups), estradiol valerate (EV) groups (low / high dose groups), DAPT group and DAPT+ZGP-L group. After modeling with Cy, the ZGP groups and EV groups were treated with ZGP and EV for 8 weeks respectively. Meanwhile, the DAPT groups were treated with DAPT twice a week. Additionally, OSCs were also isolated after modeling, and then treated with drug serum containing ZGP or EV. Ovarian volume and the ratio of weight of total ovaries to the body weight were measured. The serum hormones were measured by ELISA. Quantities and location of OSCs in ovaries were detected by flow cytometry and immunofluorescence. Cell viability was measured by CCK8. And OSCs were identified by immunofluorescence. Biomarkers of germ cells, stem cells and associated to differentiation and meiosis were detected by qPCR and western blot. Proteins in Notch signaling pathway were detected by western blot and immunofluorescence. RESULTS: After treating with ZGP, ovarian volume and the ratio of weight of total ovaries to the body weight increased. ZGP could increase serum AMH and E2 level and decrease serum FSH level. Quantities and cell viability of OSCs increased after ZGP treatment in vivo and in vitro. In addition, treatment with ZGP could increase not only the expression of MVH, Oct4 and DAZL, but also the expression of ZP1 and ZP2. Furthermore, ZGP could up-regulate the expression of Notch intracellular domain (NICD), HES1 and HES5. After blocking the Notch signaling pathway, ZGP could increase not only the expression of NICD, HES1 and HES5, but also the expression of MVH, Oct4, DAZL, ZP1 and ZP3. CONCLUSION: In conclusion, the mechanism of ZGP on treating ovarian aging may be relevant to maintain the stemness of OSCs by up-regulating Notch signaling pathway, which added the mechanism of ZGP on the perspective of OSCs at first time.

A light-driven dual-nanotransformer with deep tumor penetration for efficient chemo-immunotherapy.

Designing a transformable nanosystem with improved tumor accumulation and penetration by tuning multiple physicochemical properties remains a challenge. Here, a near-infrared (NIR) light-driven nanosystem with size and charge dual-transformation for deep tumor penetration is developed. Methods: The core-shell nanotransformer is realized by integrating diselenide-bridged mesoporous organosilica nanoparticles as a reactive oxygen species (ROS)-responsive core with an indocyanine green (ICG)-hybrid N-isopropyl acrylamide layer as a thermosensitive shell. After loading doxorubicin (DOX), negatively charged nanomedicine prevents DOX leakage, rendering prolonged blood circulation time and high tumor accumulation. Results: Upon NIR light irradiation, mild photothermal effects facilitate the dissociation of the thermosensitive shell to achieve negative-to-positive charge reversal. Meanwhile, ICG-generated ROS cleave the diselenide bond of the organosilica core, resulting in rapid matrix degradation that produces DOX-containing smaller fragments. Such a light-driven dual-transformable nanomedicine simultaneously promotes deep tumor penetration and implements sufficient chemotherapy, along with evoking robust immunogenic cell death effects in vitro and in vivo. With the combination of a programmed cell death protein-1 (PD-1) checkpoint blockade, the nanotransformer remarkably blocks primary tumor growth and pulmonary metastasis of breast cancer with low systemic toxicity. Conclusions: This study develops a promising strategy to realize high tumor accumulation and deep penetration of light-transformable nanomedicine for efficient and safe chemo-immunotherapy.

ACT001 inhibits pituitary tumor growth by inducing autophagic cell death via MEK4/MAPK pathway.

ACT001, derived from traditional herbal medicine, is a novel compound with effective anticancer activity in clinical trials. However, little is known regarding its role in pituitary adenomas. Here, we demonstrated that ACT001 suppressed cell proliferation and induced cell death of pituitary tumor cells in vitro and in vivo. ACT001 was also effective in suppressing the growth of different subtypes of human pituitary adenomas. The cytotoxic mechanism ACT001 employed was mainly related to autophagic cell death (ACD), indicated by autophagosome formation and LC3-II accumulation. In addition, ACT001-mediated inhibitory effect decreased when either ATG7 was downregulated or cells were cotreated with autophagy inhibitor 3-methyladenine (3-MA). RNA-seq analysis showed that mitogen-activated protein kinase (MAPK) pathway was a putative target of ACT001. Specifically, ACT001 treatment promoted the phosphorylation of JNK and P38 by binding to mitogen-activated protein kinase kinase 4 (MEK4). Our study indicated that ACT001-induced ACD of pituitary tumor cells via activating JNK and P38 phosphorylation by binding with MEK4, and it might be a novel and effective anticancer drug for pituitary adenomas.

Exploring the mechanisms underlying the therapeutic effect of the drug pair Rhubarb-Coptis in diabetic nephropathy using network pharmacology and molecular docking analysis.

Background: To use network pharmacology to explore the mechanism of the drug pair Rhubarb-Coptis in the treatment of diabetic nephropathy (DN). Methods: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of drug pair Rhubarb-Coptis. Targets were obtained using the TCMSP and SwissTargetPrediction databases. DN disease targets were extracted from the Online Mendelian Inheritance in Man (OMIM), GeneCards, and Therapeutic Target database (TTD) databases. A "drug-compound-target" network and protein-protein interaction (PPI) network were constructed and analyzed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and Cytoscape software. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed in the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Molecular docking was performed using AutoDock Vina and PyMOL software. Results: A total of 30 active components and 609 targets of Rhubarb-Coptis were screened out, and 98 common targets of DN and Rhubarb-Coptis were obtained. Quercetin, berberine, epiruberine, epautin, and moupinamide were the main active components in the treatment of DN. The STAT3, CTNNB1, PIK3R1, PIK3CA, and TP53 genes were identified as the potential 5 key targets. The GO enrichment analysis showed that these 5 key targets mainly involved in inflammation, oxidative stress, and apoptosis. KEGG enrichment analysis showed that the pathways were mainly enriched in the AGE-RAGE and HIF-1 signaling pathways. Molecular docking revealed that the 5 key targets could combine well with their corresponding active compounds. Conclusions: This study expounds the therapeutic effect of Rhubarb-Coptis on DN from a holistic perspective, and provides a valuable basis for clinical application and academic research.