Uropathogenic Escherichia coli infection: innate immune disorder, bladder damage, and Tailin Fang II.

Background: Uropathogenic Escherichia coli (UPEC) activates innate immune response upon invading the urinary tract, whereas UPEC can also enter bladder epithelial cells (BECs) through interactions with fusiform vesicles on cell surfaces and subsequently escape from the vesicles into the cytoplasm to establish intracellular bacterial communities, finally evading the host immune system and leading to recurrent urinary tract infection (RUTI). Tailin Fang II (TLF-II) is a Chinese herbal formulation composed of botanicals that has been clinically proven to be effective in treating urinary tract infection (UTI). However, the underlying therapeutic mechanisms remain poorly understood. Methods: Network pharmacology analysis of TLF-II was conducted. Female Balb/C mice were transurethrally inoculated with UPEC CFT073 strain to establish the UTI mouse model. Levofloxacin was used as a positive control. Mice were randomly divided into four groups: negative control, UTI, TLF-II, and levofloxacin. Histopathological changes in bladder tissues were assessed by evaluating the bladder organ index and performing hematoxylin-eosin staining. The bacterial load in the bladder tissue and urine sample of mice was quantified. Activation of the TLR4-NF-κB pathway was investigated through immunohistochemistry and western blotting. The urinary levels of interleukin (IL)-1ß and IL-6 and urine leukocyte counts were monitored. We also determined the protein expressions of markers associated with fusiform vesicles, Rab27b and Galectin-3, and levels of the phosphate transporter protein SLC20A1. Subsequently, the co-localization of Rab27b and SLC20A1 with CFT073 was examined using confocal fluorescence microscopy. Results: Data of network pharmacology analysis suggested that TLF-II could against UTI through multiple targets and pathways associated with innate immunity and inflammation. Additionally, TLF-II significantly attenuated UPEC-induced bladder injury and reduced the bladder bacterial load. Meanwhile, TLF-II inhibited the expression of TLR4 and NF-κB on BECs and decreased the urine levels of IL-1ß and IL-6 and urine leukocyte counts. TLF-II reduced SLC20A1 and Galectin-3 expressions and increased Rab27b expression. The co-localization of SLC20A1 and Rab27b with CFT073 was significantly reduced in the TLF-II group. Conclusion: Collectively, innate immunity and bacterial escape from fusiform vesicles play important roles in UPEC-induced bladder infections. Our findings suggest that TLF-II combats UPEC-induced bladder infections by effectively mitigating bladder inflammation and preventing bacterial escape from fusiform vesicles into the cytoplasm. The findings suggest that TLF-II is a promising option for treating UTI and reducing its recurrence.

Stabilization by Chaperone GroEL in Biogenic Selenium Nanoparticles Produced from Bifidobacterium animalis H15 for the Treatment of DSS-Induced Colitis.

Inflammatory bowel diseases have a high rate of mortality and pose a serious threat to global public health. Selenium is an essential trace element, which has been shown to play important roles in redox control and antioxidant defense. Microorganisms play important roles in the reduction of toxic inorganic selenium (selenite and selenate) to less-toxic biogenic selenium nanoparticles (Bio-SeNPs), which have higher biocompatibility. In the present study, novel Bio-SeNPs with high stability were synthesized using probiotic Bifidobacterium animalis subsp. lactis H15, which was isolated from breastfed infant feces. The Bio-SeNPs with a size of 122 nm showed stability at various ionic strengths, temperatures, and in simulated gastrointestinal fluid, while chemosynthetic SeNPs underwent aggregation. The main surface protein in the Bio-SeNPs was identified as chaperone GroEL by liquid chromatography-tandem mass spectrometry. The overexpression and purification of GroEL demonstrated that GroEL controlled the assembly of Bio-SeNPs both in vitro and in vivo. In vivo, oral administration of Bio-SeNPs could alleviate dextran sulfate sodium-induced colitis by decreasing cell apoptosis, increasing antioxidant capacity and the number of proliferating cells, and improving the function of the intestinal mucosal barrier. In vitro experiments verified that Bio-SeNPs inhibited lipopolysaccharide-induced toll-like receptor 4/NF-κB signaling pathway activation. These results suggest that the Bio-SeNPs with high stability could have potential as a nutritional supplement for the treatment of colitis in nanomedicine applications.

Genome-wide characterization of COMT family and regulatory role of CsCOMT19 in melatonin synthesis in Camellia sinensis.

BACKGROUND: Caffeic acid O-methyltransferase (COMT) is a key enzyme that regulates melatonin synthesis and is involved in regulating the growth, development, and response to abiotic stress in plants. Tea plant is a popular beverage consumed worldwide, has been used for centuries for its medicinal properties, including its ability to reduce inflammation, improve digestion, and boost immune function. By analyzing genetic variation within the COMT family, while helping tea plants resist adversity, it is also possible to gain a deeper understanding of how different tea varieties produce and metabolize catechins, then be used to develop new tea cultivars with desired flavor profiles and health benefits. RESULTS: In this study, a total of 25 CsCOMT genes were identified based on the high-quality tea (Camellia sinensis) plant genome database. Phylogenetic tree analysis of CsCOMTs with COMTs from other species showed that COMTs divided into four subfamilies (Class I, II, III, IV), and CsCOMTs was distributed in Class I, Class II, Class III. CsCOMTs not only undergoes large-scale gene recombination in pairs internally in tea plant, but also shares 2 and 7 collinear genes with Arabidopsis thaliana and poplar (Populus trichocarpa), respectively. The promoter region of CsCOMTs was found to be rich in cis-acting elements associated with plant growth and stress response. By analyzing the previously transcriptome data, it was found that some members of CsCOMT family exhibited significant tissue-specific expression and differential expression under different stress treatments. Subsequently, we selected six CsCOMTs to further validated their expression levels in different tissues organ using qRT-PCR. In addition, we silenced the CsCOMT19 through virus-induced gene silencing (VIGS) method and found that CsCOMT19 positively regulates the synthesis of melatonin in tea plant. CONCLUSION: These results will contribute to the understanding the functions of CsCOMT gene family and provide valuable information for further research on the role of CsCOMT genes in regulating tea plant growth, development, and response to abiotic stress.

Phytochemical profiles, antioxidant activities, and synergistic antiproliferative effects of blueberry and apple peel extracts.

BACKGROUND: Blueberries and apples exhibit favorable bioactivity and health benefits as a result of their rich phytochemicals. Natural phytochemicals exist in complex forms, but there are few reports on whether have additive, synergistic or antagonistic effects between different phytochemicals. The present study aimed to elucidate the synergistic effects of blueberry extract (BE) and apple peel extract (APE) together with respect to inhibiting the proliferation of HepG2 liver cancer cells. Meanwhile, phytochemical characterization of BE and APE was conducted by HPLC, and total antioxidant activity was determined via a cellular antioxidant activity assay, oxygen radical absorption capacity assay and peroxy radical scavenging capacity assay. RESULTS: The results showed that BE and APE were rich in phytochemicals and had potent antioxidant activities, which synergistically inhibited cell proliferation. In the bilateral combination, the dose reduction index value increased by two-fold, and the combination index value at 95% inhibition was less than 1. Additionally, BE + APE supplementation could promote the expression levels of p53 and c-myc genes. In conclusion, the BE and APE had strong antioxidant activity and exhibited synergistic inhibition against proliferation of HepG2 cells. CONCLUSION: The present study can provide a theoretical basis for the synergistic effect of different phytochemicals in health care. © 2023 Society of Chemical Industry.

SuanZaoRen decoction alleviates neuronal loss, synaptic damage and ferroptosis of AD via activating DJ-1/Nrf2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: SuanZaoRen Decoction (SZRD), a famous herbal prescription, and has been widely proven to have positive therapeutic effects on insomnia, depression and Alzheimer's disease (AD). However, the anti-AD molecular mechanism of SZRD remains to be further investigated. AIM OF THE STUDY: To elucidate the molecular mechanism of SZRD's improvement in AD's neuronal loss, synaptic damage and ferroptosis by regulating DJ-1/Nrf2 signaling pathway. MATERIALS AND METHODS: LC-MS/MS was used to detect the active ingredients from SZRD. APP/PS1 mice was treated with SZRD and a ferroptosis inhibitor (Liproxstatin-1), respectively. Upon the completion of behavioral tests, Nissl staining, FJB staining, Golgi staining, immunofluorescence, immunohistochemistry, and transmission electron microscopy were preformed to evaluate the effects of SZRD on neuronal loss, synaptic damage, Aß deposition. Iron staining, transmission electron microscopy, and iron assay kit was performed to estimate the effects of SZRD on ferroptosis. SOD kit, MDA kit, GSH kit, and GSH/GSSG kit were utilized to measure the oxidative stress levels in the hippocampus. The protein expression of TfR1, FTH1, FTL, FPN1, DJ-1, Nrf2, GPX4, SLC7A11, and ACSL4 were detected by Western blot. RESULTS: A total of 16 active ingredients were identified from SZRD extract. SZRD SZRD significantly alleviated learning and memory impairment in APP/PS1 mice. SZRD improved the hippocampal neuronal loss and degenerated neurons in APP/PS1 mice via inhibiting the Aß deposit. SZRD mitigated the hippocampal synaptic damage in APP/PS1 mice. SZRD inhibited iron accumulation, and alleviated the oxidative stress level in the hippocampus of APP/PS1 mice. Meanwhile, SZRD could up-regulate the protein expression level of FPN1, DJ-1, Nrf2, GPX4 and SLC7A11 in the hippocampus, and inhibit TfR1, FTH1, FTL, and ACSL4 protein expression. CONCLUSION: SZRD alleviated neuronal loss, synaptic damage and ferroptosis in AD via activating DJ-1/Nrf2 signaling pathway.

Soft ferroelectret ultrasound receiver for targeted peripheral neuromodulation.

Bioelectronic medicine is a rapidly growing field where targeted electrical signals can act as an adjunct or alternative to drugs to treat neurological disorders and diseases via stimulating the peripheral nervous system on demand. However, current existing strategies are limited by external battery requirements, and the injury and inflammation caused by the mechanical mismatch between rigid electrodes and soft nerves. Here we report a wireless, leadless, and battery-free ferroelectret implant, termed NeuroRing, that wraps around the target peripheral nerve and demonstrates high mechanical conformability to dynamic motion nerve tissue. As-fabricated NeuroRing can act as an ultrasound receiver that converts ultrasound vibrations into electrostimulation pulses, thus stimulating the targeted peripheral nerve on demand. This capability is demonstrated by the precise modulation of the sacral splanchnic nerve to treat colitis, providing a framework for future bioelectronic medicines that offer an alternative to non-specific pharmacological approaches.

Advances in the Study of Selenium-Enriched Probiotics: From the Inorganic Se into Se Nanoparticles.

Selenium (Se) is a momentous metallic element that plays an irreplaceable role in biochemical activities. Se deficiency remains a nutritional challenge across the world. Organic Se supplementation is the most effective treatment means for Se deficiency. Organic Se transformed from Se-enriched probiotics show outstanding excellent properties in antibacteria, anti-oxidation, anti-inflammation, and immunoregulation. Studying the influencing factors for Se enrichment capacity and enrichment mechanisms of Se-enriched probiotics is conducive to the exploit of more potent Se-enriched probiotics. Se-enriched probiotics transform inorganic Se into Se nanoparticles (SeNPs), which have been widely used in animal husbandry and biomedical field. In this paper, the novel development of Se-enriched probiotics is reviewed, and the bioactivities of SeNPs are assessed, so as to display their potential application prospects. The excellent role of SeNPs in anti-oxidation is summarized, and the mechanism by which SeNPs improve Se deficiency and boost animal health is explained.

[Effects of Xihuang Pills on proliferation and apoptosis of prostate cancer LNCaP cells based on AR/m TOR signaling pathway].

Based on the androgen receptor(AR)/mammalian target of rapamycin(mTOR)signaling pathway, the effects of Xihuang Pills-medicated serum on the proliferation and apoptosis of prostate cancer LNCaP cells were investigated. The drug-containing serum of SD rats was prepared by intragastric administration of Xihuang Pills suspension. The effects of low-, medium-, and high-dose Xihuang Pills-containing serum on the in vitro proliferation of LNCaP cells were detected by cell counting kit-8(CCK-8). Flow cytometry was used to detect the apoptosis level of LNCaP cells after intervention with different concentrations of Xihuang Pills. Protein expression of cleaved cysteinyl aspartate-specific proteinase caspase-3(cleaved caspase-3), B-cell lymphoma-2(Bcl-2), and AR as well as the phosphorylation level of mTOR protein were detected by Western blot. The results showed that compared with the blank serum, the drug-medicated serum could blunt the activity of LNCaP cells. Low-, medium-, and high-dose Xihuang Pills-containing serum could significantly increase the cell apoptosis rate, increase the expression of cleaved caspase-3 protein, decrease the expression of Bcl-2 protein, reduce the expression of AR protein, and down-regulate the level of phosphorylated mTOR(p-mTOR). To study the effect of Xihuang Pills on the growth of LNCaP cells in vivo, different doses of Xihuang Pills were used to intervene in the subcutaneous graft model in nude mice inoculated with LNCaP cells. The expression levels of AR, mTOR, p-mTOR, Bcl-2, and cleaved caspase-3 were detected by Western blot. The results showed that the volumes of subcutaneous graft tumor in the low-dose, medium-dose, and high-dose Xihuang Pills groups significantly decreased compared with that in the model group. The weight of subcutaneous transplanted tumor in each group with drug intervention was significantly lower than that in the model group. Compared with the model group, the low-dose, medium-dose, and high-dose Xihuang Pills groups showed increased cleaved caspase-3 protein expression, decreased Bcl-2 and AR protein expression, and reduced p-mTOR protein expression. Further experiments showed that AR agonist R1881 could block the anti-proliferation and pro-apoptotic effects of Xihuang Pills. The mechanism of Xihuang Pills against prostate cancer is related to the inhibition of the AR/mTOR signaling pathway, inhibition of LNCaP cell proliferation, and induction of apoptosis in cancer cells.

Metal-organic framework-encapsulated dihydroartemisinin nanoparticles induces apoptotic cell death in ovarian cancer by blocking ROMO1-mediated ROS production.

Dihydroartemisinin (DHA), a natural product derived from the herbal medicine Artemisia annua, is recently used as a novel anti-cancer agent. However, some intrinsic disadvantages limit its potential for clinical management of cancer patients, such as poor water solubility and low bioavailability. Nowadays, the nanoscale drug delivery system emerges as a hopeful platform for improve the anti-cancer treatment. Accordingly, a metal-organic framework (MOF) based on zeolitic imidazolate framework-8 was designed and synthesized to carry DHA in the core (ZIF-DHA). Contrast with free DHA, these prepared ZIF-DHA nanoparticles (NPs) displayed preferable anti-tumor therapeutic activity in several ovarian cancer cells accompanied with suppressed production of cellular reactive oxygen species (ROS) and induced apoptotic cell death. 4D-FastDIA-based mass spectrometry technology indicated that down-regulated reactive oxygen species modulator 1 (ROMO1) might be regarded as potential therapeutic targets for ZIF-DHA NPs. Overexpression of ROMO1 in ovarian cancer cells significantly reversed the cellular ROS-generation induced by ZIF-DHA, as well as the pro-apoptosis effects. Taken together, our study elucidated and highlighted the potential of zeolitic imidazolate framework-8-based MOF to improve the activity of DHA to treat ovarian cancer. Our findings suggested that these prepared ZIF-DHA NPs could be an attractive therapeutic strategy for ovarian cancer.

A new method to treat onychopapilloma with pulsed dye laser irradiation: a 13-case series report.

Purpose: Onychopapilloma is a rare benign nail tumor affecting the distal matrix and the nail bed. Currently, the only available treatment is surgical resection, which has a recurrence rate of 20% and may lead to various complications. Here we report a new method to treat onychopapilloma with pulsed dye laser (PDL).Materials and methods: We retrospectively analyzed 13 cases and evaluated disease classification, dermoscopic examination, laser treatment parameters, photographs before and after treatment, and treatment outcome.Results: The site distribution of onychopapilloma was consistent with previous reports. PDL treatment was performed with 595 nm laser, with 1.5 ms pulse duration, spot diameter 3-5 mm, and 11.5-13.5 J/cm2 fluence. Irradiation covered the telangiectatic area up to the edge of the nail folds, with the terminal response of purpura occurrence. The overall effective rate was 77%; the effective rates for erythronychia, leukonychia, and melanonychia were 88%, 67%, and 50%, respectively.Conclusions: PDL treatment for onychopapilloma provides an alternative to traditional surgery with comparable effectiveness but much less risk for complications.

Oxytetracycline-induced oxidative liver damage by disturbed mitochondrial dynamics and impaired enzyme antioxidants in largemouth bass (Micropterus salmoides).

Oxytetracycline (OTC), a commonly used tetracycline antibiotic in aquaculture, has been found to cause significant damage to the liver of largemouth bass (Micropterus salmoides). This study revealed that OTC can lead to severe histopathological damage, structural changes at the cellular level, and increased levels of reactive oxygen species (ROS) in M. salmoides. Meanwhile, OTC impairs the activities of antioxidant enzyme (such as T-SOD, CAT, GST, GR) by suppressing the activation of MAPK/Nrf2 pathway. OTC disrupts mitochondrial dynamics and mitophagy through via PINK1/Parkin pathway. The accumulation of damaged mitochondria, combined with the inhibition of the antioxidant enzyme system, contributes to elevated ROS levels and oxidative liver damage in M. salmoides. Further investigations demonstrated that an enzyme-treated soy protein (ETSP) dietary supplement can help maintain mitochondrial dynamic balance by inhibiting the PINK1/Parkin pathway and activate the MAPK/Nrf2 pathway to counteract oxidative damage. In summary, these findings highlight that exposure to OTC disrupts mitochondrial dynamics and inhibits the antioxidant enzyme system, ultimately exacerbating oxidative liver damage in M. salmoides. We propose the use of a dietary supplement as a preventive measure against OTC-related side effects, providing valuable insights into the mechanisms of antibiotic toxicity in aquatic environments.

Integrated Chinese and Western medicine for stable angina pectoris of coronary heart disease: a real-world study including 690 patients.

Objective: We aimed to evaluate the effects of integrated Chinese and Western medical therapeutic modalities on clinical prognosis in a population with stable angina pectoris (SAP) of coronary heart disease (CHD). Methods: In a prospective cohort study, 732 patients with SAP of CHD hospitalized in the Integrated Cardiology Unit of the China-Japan Friendship Hospital From October 2020 to October 2021 were included. The patients were divided into integrated treatment and conventional treatment groups according to whether they had been taking Chinese medicine for more than 6 months per year. The occurrence of composite cardiovascular events (CVEs), including cardiac death, non-fatal myocardial infarction, revascularization, stroke, all-cause death, and readmission due to angina attack, heart failure, or malignant arrhythmia, was recorded during follow-up. The effects of different treatment modalities on prognosis were evaluated using univariate and multifactorial logistic regression. Logistic regression models were evaluated using receiver operating characteristic (ROC) curves. In sensitivity analysis, the correlation between treatment modality and outcome events was corrected by rematching the two groups of patients using the propensity score matching (PSM) method. Results: The data from 690 patients were included in the analysis, with 327 patients in the integrated treatment group and 363 patients in the conventional treatment group. CVEs occurred in 19 patients (5.8%) in the integrated treatment group and 37 patients (10.2%) in the conventional treatment group. The proportion of outcome events was significantly lower in the combination treatment group than in the conventional treatment group (P = 0.037). Covariate correction by multimodal multifactorial logistic regression revealed a lower risk of CVEs in patients receiving integrated therapy compared with conventional therapy (OR = 0.246, 95% CI = 0.097-0.622, P = 0.003). Moreover, a history of renal insufficiency (OR = 3.991, 95% CI = 1.164-13.684, P = 0.028) and a higher Gensini score (OR = 1.039, 95% CI = 1.028-1.050, P < 0.001) were risk factors for the development of CVEs. Model evaluation showed that C-statistic = 0.955 and area under the ROC curve (AUC) = 0.955. After PSM correction, the results still showed that integrated Chinese and Western medical treatment reduced the occurrence of CVEs in patients compared with Western treatment alone (OR = 0.339, 95% CI = 0.131-0.874, P = 0.025). Conclusion: Integrated treatment based on Chinese and Western medicine might improve the prognosis and reduce the risk of CVEs in this disease population. Trial registration: China Clinical Trials Registry, ChiCTR1800017891, Registered 20 August 2018, http://www.chictr.org.cn/showproj.aspx?proj = 30170.

Baicalin inhibits hepatocellular carcinoma cell growth and metastasis by suppressing ROCK1 signaling.

Hepatocellular carcinoma (HCC) is a common malignancy affecting many people worldwide. Baicalin is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi. It can effectively inhibit the occurrence and development of HCC. Nonetheless, the mechanism through which Baicalin inhibits HCC growth and metastasis remain unknown. This work discovered that Baicalin inhibited HCC cell proliferation, invasion, metastasis while inducing cell cycle arrest at the G0/G1 phase and apoptosis. In vivo HCC xenograft results indicated that Baicalin inhibited HCC growth. Western blotting analysis indicated that Baicalin suppressed the expressions of ROCK1, p-GSK-3ß, and ß-catenin, whereas it up-regulated the expressions of GSK-3ß and p-ß-catenin. Baicalin also reduced the expressions of Bcl-2, C-myc, Cyclin D1, MMP-9, and VEGFA, while increasing the expression of Bax. Molecular docking revealed that Baicalin docked in the binding site of the ROCK1 agonist, with a binding energy of -9 kcal/mol between the two. In addition, lentivirus-mediated suppression of ROCK1 expression improved the inhibitory effect of Baicalin on the proliferation, invasion, and metastasis of HCC and the expression of proteins associated with ROCK1/GSK-3ß/ß-catenin signaling pathway. Moreover, restoring ROCK1 expression decreased the anti-HCC efficacy of Baicalin. These findings suggest that Baicalin may decrease HCC proliferation and metastasis by suppressing ROCK1/GSK-3ß/ß-catenin signaling.

Cold shock precooling improves the firmness of chili pepper during postharvest storage and the molecular mechanisms related to pectin.

This research was conducted to explore the influence of cold shock on the firmness, a quality marker in chili pepper during 0-21 d storage and determine mechanism by cold shock impacted pectin. Chili peppers were exposed to cold shock precooling (0 ± 2 °C water/ice mixture) for 0-, 30-, 90- and 150-min, respectively. Results showed that cold shock alleviated loss of firmness throughout storage. Firmness was positively associated with sodium carbonate-soluble pectin content (r = 0.44), methylation degree of CDTA-soluble pectin (r = 0.82) and water-soluble pectin (WSP, r = 0.87), but negatively associated with WSP content (r = -0.76), and the activities of ß-galactosidase (r = -0.72) and pectinlyase (r = -0.74). Cold shock for 90 min was determined to be optimal. This study confirms the applicability of cold shock precooling to maintain firmness and thereby to extend the shelf life of chili pepper.

Molecular markers in tea plant (Camellia sinensis): Applications to evolution, genetic identification, and molecular breeding.

Tea plants have a long cultivation history in the world, and the beverage (tea) made from its leaves is well known in the world. Due to the characteristics of self-incompatibility, long-term natural and artificial hybridization, tea plants have a very complex genetic background, which make the classification of tea plants unclear. Molecular marker, one type of genetic markers, has the advantages of stable inheritance, large amount of information, and high reliability. The development of molecular marker has facilitated the understanding of complex tea germplasm resources. So far, molecular markers had played important roles in the study of the origin and evolution, the preservation and identification of tea germplasms, and the excellent cultivars breeding of tea plants. However, the information is scattered, making it difficult to understand the advance of molecular markers in tea plants. In this paper, we summarized the development process and types of molecular markers in tea plants. In addition, the application advance of these molecular markers in tea plants was reviewed. Perspectives of molecular markers in tea plants were also systematically provided and discussed. The elaboration of molecular markers in this paper should help us to renew understanding of its application in tea plants.

SNS alleviates depression-like behaviors in CUMS mice by regluating dendritic spines via NCOA4-mediated ferritinophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is one of the most common mood disturbances worldwide. The Si-ni-san formula (SNS) is a famous classic Traditional Chinese Medicine (TCM) widely used to treat depression for thousands of years in clinics. However, the mechanism underlying the therapeutic effect of SNS in improving depression-like behaviors following chronic unpredictable mild stress (CUMS) remains unknown. AIM OF THE STUDY: This study aimed to investigate whether SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy in vitro and in vivo. STUDY DESIGN AND METHODS: In vivo, mice were exposed to CUMS for 42 days, and SNS (4.9, 9.8, 19.6 g/kg/d), fluoxetine (10 mg/kg/d), 3-methyladenine (3-MA) (30 mg/kg/d), rapamycin(1 mg/kg/d), and deferoxamine (DFO) (200 mg/kg/d) were conducted once daily during the last 3 weeks of the CUMS procedure. In vitro, a depressive model was established by culture of SH-SY5Y cells with corticosterone, followed by treatment with different concentrations of freeze-dried SNS (0.001, 0.01, 0.1 mg/mL) and rapamycin (10 nM), NCOA4-overexpression, Si-NCOA4. After the behavioral test (open-field test (OFT), sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST), dendritic spines, GluR2 protein expression, iron concentration, and ferritinophagy-related protein levels (P62, FTH, NCOA4, LC3-II/LC3-I) were tested in vitro and in vivo using immunohistochemistry, golgi staining, immunofluorescence, and Western blot assays. Finally, HEK-293T cells were transfected by si-NCOA4 or GluR2-and NCOA4-overexpression plasmid and treated with corticosterone(100 µM), freeze-dried SNS(0.01 mg/mL), rapamycin(25 nM), and 3-MA(5 mM). The binding amount of GluR2, NCOA4, and LC3 was assessed by the co-immunoprecipitation (CO-IP) assay. RESULTS: 3-MA, SNS, and DFO promoted depressive-like behaviors in CUMS mice during OFT, SPT, FST and TST, improved the amount of the total, thin, mushroom spine density and enhanced GluR2 protein expression in the hippocampus. Meanwhile, treatment with SNS decreased iron concentrations and inhibited NCOA4-mediated ferritinophagy activation in vitro and in vivo. Importantly, 3-MA and SNS could prevent the binding of GluR2, NCOA4 and LC3 in corticosterone-treated HEK-293T, and rapamycin reversed this phenomenon after treatment with SNS. CONCLUSION: SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy.

The application of a continuous partnership-based birth plan in China: A randomized controlled trial.

BACKGROUND: The cesarean section rate is as high as 36.7% in China, much higher than the average cesarean section rate of 27% in Asia. With the implementation of the two-children and three-children policy, the primipara with cesarean will also face the choice of repeated or even multiple cesareans, which will increase the risk of maternal perinatal mortality and serious fetal pulmonary morbidity. To reduce the cesarean section rate, a series of midwifery service measures such as the birth plan have been taken in China and it has played a certain role in improving the birth outcome and maternal birth experience. However, the areas carrying out birth plan are often economically developed with advanced medical conditions. the application effect of birth plan in economically underdeveloped areas with limited medical conditions in China is unknown. OBJECTIVE: To evaluate the effects of a continuous partnership-based birth plan on local women's birth outcomes and experience in Haikou which is an economically underdeveloped city in China. DESIGN: A randomized controlled trial study design was used. PARTICIPANTS: 90 primiparous women who received pregnancy service from the obstetrics clinic of one of tertiary hospitals in Haikou city, Hainan Province between July 2020 and December 2020 and planned to give birth in this hospital were recruited. METHODS: After eligibility was determined, consents obtained and baseline surveys completed, 90 participants were randomly allocated to study groups with concealed opaque envelopes by a blinded research assistant and each group were 45 participants. Participants in control group received routine obstetric health service and nursing care, while participants in the experimental group received the continuous partnership service of midwives on the basis of routine care. At the same time, the birth plan was formulated and implemented, and the relevant indicators were recorded and analyzed during and after birth, including cesarean section rate, non-medical indication cesarean section rate, oxytocin use rate, perineal lateral resection rate and anxiety degree. RESULTS: The cesarean rate in the experiment and control groups were 20.45% and 57.14%, of which the non-medical indication cesarean rate in the experiment and control groups were 22.22% and 50.00%, respectively, whereby the difference of cesarean rate and nonmedically indicated cesarean section rate between the groups was statistically significant (χ2 = 12.231, p < 0.001;χ2 = 9.101, p = 0.003). Besides, the differences in anxiety degree, neonatal NICU transfer rate and satisfaction of birth between the two groups were statistically significant (p < 0.05). While there was no significant difference in oxytocin use rate, perineal lateral resection rate, neonatal 1-min and 5-min Alzheimer's score between the two groups (P > 0.05). CONCLUSION: The birth plan based on continuous partnership can reduce medical intervention, improve birth outcomes, reduce anxiety and optimize maternal birth experience of women, which is worthy of promotion in economically underdeveloped areas of China.

Rational Utilization of Black Phosphorus Nanosheets to Enhance Palladium-Mediated Bioorthogonal Catalytic Activity for Activation of Therapeutics.

Pd-catalyzed chemistry has played a significant role in the growing subfield of bioorthogonal catalysis. However, rationally designing Pd nanocatalysts that show outstanding catalytic activity and good biocompatibility poses a great challenge. Herein, we propose an innovative strategy through exploiting black phosphorous nanosheets (BPNSs) to enhance Pd-mediated bioorthogonal catalytic activity. Firstly, the electron-donor properties of BPNSs enable in situ growth of Pd nanoparticles (PdNPs) on it. Meanwhile, due to the superb capability of reducing PdII , BPNSs can act as hard nucleophiles to accelerate the transmetallation in the decaging reaction process. Secondly, the lone pair electrons of BPNSs can firmly anchor PdNPs on their surface via Pd-P bonds. This design endows Pd/BP with the capability to retard tumor growth by activating prodrugs. This work proposes new insights into the design of heterogeneous transition-metal catalysts (TMCs) for bioorthogonal catalysis.

Dihydroartemisinin elicits immunogenic death through ferroptosis-triggered ER stress and DNA damage for lung cancer immunotherapy.

BACKGROUND: The immunosuppressive microenvironment of lung cancer serves as an important endogenous contributor to treatment failure. The present study aimed to demonstrate the promotive effect of DHA on immunogenic cell death (ICD) in lung cancer as well as the mechanism. METHODS: The lewis lung cancer cells (LLC), A549 cells and LLC-bearing mice were applied as the lung cancer model. The apoptosis, ferroptosis assay, western blotting, immunofluorescent staining, qPCR, comet assay, flow cytometry, confocal microscopy, transmission electron microscopy and immunohistochemistry were conducted to analyze the functions and the underlying mechanism. RESULTS: An increased apoptosis rate and immunogenicity were detected in DHA-treated LLC and tumor grafts. Further findings showed DHA caused lipid peroxide (LPO) accumulation, thereby initiating ferroptosis. DHA stimulated cellular endoplasmic reticulum (ER) stress and DNA damage simultaneously. However, the ER stress and DNA damage induced by DHA could be abolished by ferroptosis inhibitors, whose immunogenicity enhancement was synchronously attenuated. In contrast, the addition of exogenous iron ions further improved the immunogenicity induced by DHA accompanied by enhanced ER stress and DNA damage. The enhanced immunogenicity could be abated by ER stress and DNA damage inhibitors as well. Finally, DHA activated immunocytes and exhibited excellent anti-cancer efficacy in LLC-bearing mice. CONCLUSIONS: In summary, the current study demonstrates that DHA triggers ferroptosis, facilitating the ICD of lung cancer thereupon. This work reveals for the first time the effect and underlying mechanism by which DHA induces ICD of cancer cells, providing novel insights into the regulation of the immune microenvironment for cancer immunotherapy by Chinese medicine phytopharmaceuticals.