Structural Engineering of Co-Metal-Organic Frameworks via Ce Incorporation for Improved Oxygen Evolution.

The rational design of metal-organic framework (MOF)-based electrocatalysts plays a key role in achieving high-efficiency oxygen evolution reaction (OER). Herein, a synergetic morphology and electronic structure engineering strategy are proposed to design a Co-MOF nanoflower grown on carbon paper via rare-earth cerium doping (CoCe-MOF/CP). Compared with Co-MOF/CP, the developed CoCe-MOF/CP exhibited superior OER performance with a low overpotential of 267 mV at 10 mA cm-2 and outstanding long-term stability over 100 h. Theoretical calculations show that the unique 4f valence electron structure of Ce induced charge redistribution of the Co-MOF surface through the strong Co 3d-O 2p-Ce 4f orbital electronic coupling below the Fermi level. Ce-doped plays a key role in the engineering of the electronic states of the Co sites to endow them with the optimal free energy landscape for enhanced OER catalytic activity. This work provides new insights into comprehending the RE-enhanced mechanism of electrocatalysis and provides an effective strategy for the design of MOF-based electrocatalysts.

Improvement of TaC9-ABE mediated correction of human SMN2 gene.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Gene editing technology repairs the conversion of the 6th base T to C in exon 7 of the paralogous SMN2 gene, compensating for the SMN protein expression and promoting the survival and function of motor neurons. However, low editing efficiency and unintended off-target effects limit the application of this technology. Here, we optimized a TaC9-adenine base editor (ABE) system by combining Cas9 nickase with the transcription activator-like effector (TALE)-adenosine deaminase fusion protein to effectively and precisely edit SMN2 without detectable Cas9 dependent off-target effects in human cell lines. We also generated human SMA-induced pluripotent stem cells (SMA-iPSCs) through the mutation of the splice acceptor or deletion of the exon 7 of SMN1. TaC9-R10 induced 45% SMN2 T6 > C conversion in the SMA-iPSCs. The SMN2 T6 > C splice-corrected SMA-iPSCs were directionally differentiated into motor neurons, exhibiting SMN protein recovery and antiapoptosis ability. Therefore, the TaC9-ABE system with dual guides from the combination of Cas9 with TALE could be a potential therapeutic strategy for SMA with high efficacy and safety.

Clinical significance of miR-200a in systemic lupus erythematosus and renal damage in children.

The purpose was to analyze the clinical significance of miR-200a in children with initially diagnosed SLE and renal damage. Children with initially diagnosed SLE (n=100) and healthy children (n=50) undergoing physical examinations during the same period were recruited. Disease activity of SLE children was determined based on SLEDAI (systemic lupus erythematosus disease activity index), and they were divided to SLEDAI≤9 group and SLEDAI>9 group, respectively. Moreover, SLE children were divided to LN group and non-LN group based on the occurrence of lupus nephritis. Differential level of miR-200a between groups was detected by qRT-PCR. Spearman correlation test was conducted to analyze the influence of miR-200a on SLEDAI and other laboratory indexes of SLE children. Its diagnostic potential in SLE and LN was assessed through depicting ROC curves. MiR-200a level was remarkably lower in SLE children than that of healthy children. Lower level of miR-200a was detected in SLE children with high SLEDAI or accompanied LN. MiR-200a level was negatively correlated to SLEDAI (r=-0.425), ESR (r=-0.284), CRP (r=-0.338), BUN (r=-0.263) and Scr (r=-0.345), while it was positively correlated to C3 (r=0.631), C4 (r=0.524) and ALB (r=0.394) in SLE children. The AUC of miR-200a in diagnosing SLE was 0.8379 (cut-off value=2.225, sensitivity=70%, specificity=70%). Besides, the AUC of miR-200a in diagnosing LN was 0.7619 (cut-off value=2.005, sensitivity=80%, specificity=76%). MiR-200a level has a certain correlation to the disease activity of children with initially diagnosed SLE, which can be utilized as an adjuvant indicator in evaluating SLE severity. Meanwhile, miR-200a has predictive value for SLE-induced renal damage.

Transcranial Magneto-Acoustic Stimulation Protects Synaptic Rehabilitation from Amyloid-Beta Plaques via Regulation of Microglial Functions.

Transcranial magneto-acoustic stimulation (TMAS), which is characterized by high spatiotemporal resolution and high penetrability, is a non-invasive neuromodulation technology based on the magnetic-acoustic coupling effect. To reveal the effects of TMAS treatment on amyloid-beta (Aß) plaque and synaptic plasticity in Alzheimer's disease, we conducted a comparative analysis of TMAS and transcranial ultrasound stimulation (TUS) based on acoustic effects in 5xFAD mice and BV2 microglia cells. We found that the TMAS-TUS treatment effectively reduced amyloid plaque loads and plaque-associated neurotoxicity. Additionally, TMAS-TUS treatment ameliorated impairments in long-term memory formation and long-term potentiation. Moreover, TMAS-TUS treatment stimulated microglial proliferation and migration while enhancing the phagocytosis and clearance of Aß. In 5xFAD mice with induced microglial exhaustion, TMAS-TUS treatment-mediated Aß plaque reduction, synaptic rehabilitation improvement, and the increase in phospho-AKT levels were diminished. Overall, our study highlights that stimulation of hippocampal microglia by TMAS treatment can induce anti-cognitive impairment effects via PI3K-AKT signaling, providing hope for the development of new strategies for an adjuvant therapy for Alzheimer's disease.

Establishment and characterization of Lesch-Nyhan syndrome rabbit model.

Lesch-Nyhan syndrome (LNS) is a congenital defect disease that results in defective purine metabolism. It is caused by pathogenic variants of the HPRT gene. Its clinical symptoms mainly include high uric acid levels, gout, and kidney stones and damage. The mechanism of LNS has not been fully elucidated, and no cure exists. Animal models have always played an important role in exploring causative mechanisms and new therapies. This study combined CRISPR/Cas9 and microinjection to knock out the HPRT gene to create an LNS rabbit model. A sgRNA targeting exon 3 of HPRT gene was designed. Subsequently, Cas9 mRNA and sgRNA were injected into rabbit zygotes, and injected embryos were transferred to the uterus. The genotype and phenotype of rabbits were analyzed after birth. Four infant rabbits (named R1, R2, R3 and R4), which showed varying levels of gene modification, were born. The gene-editing efficiency was 100%. No wild-type sequences at the target HPRT gene were detected in R4 rabbit. Next, 6-thioguanine drug testing confirmed that HPRT enzymatic activity was deficient in R4 infant rabbit. HE staining revealed kidney abnormalities in all infant rabbits. Overall, an sgRNA capable of knocking out the HPRT gene in rabbits was successfully designed, and HPRT gene-modified rabbits were successfully constructed by using CRISPR/Cas9 technology and microinjection. This study provides a new nonrodent animal model for studying LNS syndrome.

Thermochromic Ni(II) Organometallics With High Optical Transparency and Low Phase-Transition Temperature for Energy-Saving Smart Windows.

Thermochromic smart windows with rational modulation in indoor temperature and brightness draw considerable interest in reducing building energy consumption, which remains a huge challenge to meet the comfortable responsive temperature and the wide transmittance modulation range from visible to near-infrared (NIR) light for their practical application. Herein, a novel thermochromic Ni(II) organometallic of [(C2 H5 )2 NH2 ]2 NiCl4 for smart windows is rationally designed and synthesized via an inexpensive mechanochemistry method, which processes a low phase-transition temperature of 46.3 °C for the reversible color evolution from transparent to blue with a tunable visible transmittance from 90.5% to 72.1%. Furthermore, cesium tungsten bronze (CWO) and antimony tin oxide (ATO) with excellent NIR absorption in 750-1500 and 1500-2600 nm are introduced in the [(C2 H5 )2 NH2 ]2 NiCl4 -based smart windows, realizing a broadband sunlight modulation of a 27% visible light modulation and more than 90% of NIR shielding ability. Impressively, these smart windows demonstrate stable and reversible thermochromic cycles at room temperature. Compared with the conventional windows in the field tests, these smart windows can significantly reduce the indoor temperature by 16.1 °C, which is promising for next-generation energy-saving buildings.

Prospects and challenges of CRISPR/Cas9 gene-editing technology in cancer research.

Cancer, one of the leading causes of death, usually commences and progresses as a result of a series of gene mutations and dysregulation of expression. With the development of clustered regularly interspaced palindromic repeat (CRISPR)/Cas9 gene-editing technology, it is possible to edit and then decode the functions of cancer-related gene mutations, markedly advance the research of biological mechanisms and treatment of cancer. This review summarizes the mechanism and development of CRISPR/Cas9 gene-editing technology in recent years and describes its potential application in cancer-related research, such as the establishment of human tumor disease models, gene therapy and immunotherapy. The challenges and future development directions are highlighted to provide a reference for exploring pathological mechanisms and potential treatment protocols of cancer.

Rogue wave generation using a chaotic semiconductor laser with energy redistribution.

We demonstrate for the first time that optical rogue waves (RWs) can be generated using a chaotic semiconductor laser with energy redistribution. Chaotic dynamics are numerically generated using the rate equation model of an optically injected laser. The chaotic emission is then sent to an energy redistribution module (ERM) that consists of a temporal phase modulation and a dispersive propagation. The process enables a temporal energy redistribution of the chaotic emission waveforms, where coherent summation of consecutive laser pulses leads to random generation of giant intensity pulses. Efficient generation of optical RWs are numerically demonstrated by varying the ERM operating parameters in the entire injection parameter space. The effects of the laser spontaneous emission noise on the generation of RWs are further investigated. The RW generation approach offers a relatively high flexibility and tolerance in the choice of ERM parameters according to the simulation results.

Effects of Holliday Junction-Recognition Protein-Mediated C-Jun N-Terminal Kinase/ Signal Transducer and Activator of Transcription 3 Signaling Pathway on Cell Proliferation, Cell Cycle and Cell Apoptosis in Bladder Urothelial Carcinoma.

The Holliday Junction-Recognition Protein (HJURP) was upregulated in several tumors, which was associated with poor outcome. This study investigated the effects of the HJURP-mediated c-Jun N-terminal kinase (JNK)/ signal transducer and activator of transcription 3 (STAT3) pathway on bladder urothelial carcinoma (BLUC). Online databases were used to analyze HJURP expression in BLUC and the correlation of HJURP to JNK1 [mitogen-activated protein kinase 8 (MAPK8)], JNK2 (MAPK9), STAT3, marker of proliferation Ki-67 (MKI67), proliferating cell nuclear antigen (PCNA), cyclin dependent kinase 2 (CDK2), CDK4 and CDK6. HJURP expression was detected in BLUC cells and human normal primary bladder epithelial cells (BdECs). BLUC cells were treated with HJURP lentivirus activation /shRNA lentivirus particles or JNK inhibitor SP600125. HJURP was upregulated in BLUC tissues and correlated with poor prognosis of patients (all P < 0.05). HJURP in tumor positively correlated with MAPK8 (R = 0.30), MAPK9 (R = 0.30), STAT3 (R = 0.15), MKI67 (R = 0.60), PCNA (R = 0.46), CDK2 (R = 0.39), CDK4 (R = 0.24) and CDK6 (R = 0.21). The JNK inhibitor SP600125 decreased p-JNK/JNK and p-STAT3/STAT3 in BLUC cells, which was reversed by HJURP overexpression (P < 0.05). The HJURP-mediated JNK/STAT3 pathway promoted BLUC cell proliferation and inhibited cell apoptosis (P < 0.05). HJURP reversed the arrested G0/G1 phase of BLUC cells by SP600125. HJURP acted as an oncogene to regulate BLUC cell proliferation, apoptosis and the cell cycle by mediating the JNK/STAT3 pathway. Therefore, HJURP targeting might be an attractive novel therapeutic target for early diagnosis and treatment in BLUC.

Indirubin regulates T cell differentiation by promoting αVß8 expression in bone marrow-derived dendritic cells to alleviate inflammatory bowel disease.

Inflammatory bowel disease is a disease that can invade the whole digestive tract and is accompanied by immune abnormalities. Immune dysfunction involving dendritic cells (DCs) and T cells is recognized as a key factor in diseases. Indirubin (IDRB) exerts antiinflammatory effects and can help in treating immune diseases. This study aimed to isolate bone marrow-derived dendritic cells (BMDCs) using lipopolysaccharide (LPS) to obtain mature DCs (mDCs). The expression of CD80, CD86, CD40, and MHC-II was detected using flow cytometry after treatment with IDRB. αVß8 siRNA was used to knock down αVß8 in mDCs, and the expression of CD80, CD86, CD40, and MHC-II was detected. Meanwhile, DCs were co-cultured with T cells. Then, T cell differentiation was detected using flow cytometry, and the cytokine levels were detected using enzyme-linked immunosorbent assay. The animal model of dextran sulfate sodium (DSS)-induced inflammatory bowel disease was established in mice. After intervention with IDRB and αVß8 shRNA, the intestinal tissues were evaluated using H&E staining, disease activity index (DAI) score, and histological damage index, and the corresponding factors and cytokines to regulatory T cells (Treg) and Th17 were measured. The results showed that αVß8 was expressed in immature DCs and mDCs. CD80, CD86, CD40, and MHC-II expression decreased after IDRB treatment in mDCs. Meanwhile, the expression of TNF-α and TGF-ß also decreased after IDRB treatment. The effect of IDRB on the expression of CD80, CD86, CD40, MHC-II, TNF-α, and TGF-ß in mDCs was reversed by αVß8 siRNA. The Treg differentiation increased after IDRB treatment, while the differentiation of Th17 cells was inhibited. This effect of IDRB was reversed by mDCs after treatment with αVß8 siRNA. In vivo experiments showed that IDRB alleviated the symptoms of inflammatory bowel disease in animals. Enteritis significantly reduced, and the effect of IDRB was reversed by αVß8 shRNA. The results suggested that IDRB regulated the differentiation of T cells by mediating the maturation of BMDCs through αVß8. This study confirmed the therapeutic effect of IDRB in inflammatory bowel disease and suggested that IDRB might serve as a potential drug.

NEDD4L inhibits migration, invasion, cisplatin resistance and promotes apoptosis of bladder cancer cells by inactivating the p62/Keap1/Nrf2 pathway.

PURPOSE: This study identified the function of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) on bladder cancer (BLCA). METHODS: NEDD4L expression in BLCA patients was scrutinized. The function of NEDD4L on the viability, apoptosis, migration and invasion of BLCA cells was evaluated by cell counting kit-8, flow cytometry and Transwell assays. The effect of NEDD4L on the cisplatin (DDP) resistance of the DDP-resistant BLCA cells was explored. The influence of NEDD4L on the p62/Keap1/Nrf2 pathway activity in BLCA cells was tested by Western blot. Rescue experiments were implemented to verify whether NEDD4L regulated BLCA cell malignant behavior by mediating the Keap1/Nrf2 pathway activity via p62. The effect of NEDD4L on the growth and the p62/Keap1/Nrf2 pathway activity in vivo was researched in xenograft tumor nude mice models. RESULTS: The down-regulated NEDD4L in BLCA patients was associated with unfavorable survival. NEDD4L suppressed the viability (inhibition rate 57.1%/49.0%), migration (inhibition rate 49.7%/77.1%), invasion (inhibition rate 50.6%/75.7%), promoted the apoptosis of T24/5637 cells (promotion rate 243.8%/201.9%), reduced IC 50 of DDP-resistant T24/5637 cells from 132.2/101.8 to 57.81/59.71 µM, respectively, and inactivated the p62/Keap1/Nrf2 pathway in T24/5637 cells. p62 up-regulation partially abrogated the inhibition of NEDD4L on the Keap1/Nrf2 pathway activity, the malignant behavior of BLCA cells, and the DDP resistance of DDP-resistant BLCA cells. NEDD4L overexpression inhibited the tumor growth and the p62/Keap1/Nrf2 pathway activity in vivo in BLCA. CONCLUSION: NEDD4L inhibits the progression of BLCA by inactivating the p62/Keap1/Nrf2 pathway. It may be an effective target for BLCA treatment.

Beneficial Effects of Pleurotus citrinopileatus Polysaccharide on the Quality of Cherry Tomatoes During Storage.

Cherry tomatoes are highly well-liked and have a lot of nutritional value. However, the edible value of cherry tomatoes rapidly declines as their storage duration is extended. Pleurotus citrinopileatus polysaccharide (PCP) is a kind of polysaccharide obtained from P. citrinopileatus by water extraction. The effects of PCP were investigated to identify a way to maximally postpone cherry tomato degradation. The results showed that PCP had inhibitory effects on all 10 tested strains, and the inhibitory effect on Pseudomonas aeruginosa was the strongest. PCP could effectively reduce the weight loss rate and malondialdehyde accumulation of cherry tomatoes during storage, weaken the activity of polyphenol oxidase, and delay the decline of hardness, titratable acid content, and VC content compared with untreated cherry tomatoes. PCP solution at a concentration of 2 g/L exerted the best preservation effects. Therefore, PCP can potentially contribute to the preservation of vegetables and fruits.

Development of a rabbit model of Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is a severe recessive X-linked immunodeficiency resulting from loss-of-function mutations in the WAS gene. Mouse is the only mammalian model used for investigation of WAS pathogenesis. However, the mouse model does not accurately recapitulate WAS clinical phenotypes, thus, limiting its application in WAS clinical research. Herein, we report the generation of WAS knockout (KO) rabbits via embryo co-injection of Cas9 mRNA and a pair of sgRNAs targeting exons 2 and 7. WAS KO rabbits exhibited many symptoms similar to those of WAS patients, including thrombocytopenia, bleeding tendency, infections, and reduced numbers of T cell in the spleen and peripheral blood. The WAS KO rabbit model provides a new valuable tool for preclinical trials of WAS treatment.

New Trajectory of Clinical and Biomarker Changes in Sporadic Alzheimer's Disease.

Identifying dynamic changes in biomarkers and clinical profiles is essential for understanding the progression of Alzheimer's disease (AD). The relevant studies have primarily relied on patients with autosomal dominant AD; however, relevant studies in sporadic AD are poorly understood. Here, we analyzed longitudinal data from 665 participants (mean follow-up 4.90 ± 2.83 years). By aligning normal cognition (CN) baseline with a clinical diagnosis of mild cognitive impairment (MCI) or AD, we studied the progression of AD using a linear mixed model to estimate the clinical and biomarker changes from stable CN to MCI to AD. The results showed that the trajectory of hippocampal volume and fluorodeoxyglucose (FDG) was consistent with the clinical measures in that they did not follow a hypothetical sigmoid curve but rather showed a slow change in the initial stage and accelerated changes in the later stage from MCI conversion to AD. Dramatic hippocampal atrophy and the ADAS13 increase were, respectively, 2.5 and 1 years earlier than the MCI onset. Besides, cognitively normal people with elevated and normal amyloid showed no significant differences in clinical measures, hippocampal volume, or FDG. These results reveal that pre-MCI to pre-AD may be a better time window for future clinical trial design.

Investigation of the effects of face masks on thermal comfort in Guangzhou, China.

Wearing masks to study and work places has become a daily protective measure during the COVID-19 pandemic. In the summer of 2021, environmental parameters were monitored, and students in a university library in Guangzhou, China, were surveyed to analyze the possible symptoms of wearing masks for a long time, and to assess the sensitivity of various body parts to the environmental parameters. Concurrently, the preference of subjects wearing masks for various environmental parameters was also analyzed. Additionally, the relationship between thermal sensation and thermal index was analyzed to identify acceptable and comfortable temperature ranges. The expected duration of wearing masks was counted. Subjects wearing masks had greater requirements for environmental comfort, and reported increased thermal discomfort of the face and head, compared to those without masks. More than 70% of the subjects wearing masks reported that they experienced discomfort on their faces. Among the subjects who experienced discomfort, 62.7% reported that facial fever was the main symptom; while some reported symptoms of dyspnea (25.4%) and rapid heartbeat (9.1%). More than 75% of the subjects were expected to wear masks for 2.0 h or less. Evaluation of environmental thermal sensation, including overall, facial, and head thermal sensation, differed among subjects who wore and did not wear masks. The indexes of neutral Operative temperature/Standard Effective Temperature (T op /SET*) and preferred T op /SET* were lower among subjects with masks than among those without masks. The neutral T op /SET* deviation was 0.3 °C, and the preferred T op /SET* deviation was 0.5 °C. Additionally, the acceptable and comfortable temperature zones differed between the two cases. The subjects who wore masks preferred colder temperatures. These findings indicated that the environmental parameters should be adjusted to improve the thermal comfort of the human body while wearing masks in work or study places.

[Research progress on effective components and mechanisms of anti-depressive Chinese medicine].

Since the pathogenesis of depression is complicated, the therapeutic effects of western medicine are poor accompanied by severe side effects. Chinese medicine has unique advantages in the treatment based on syndrome differentiation and contains many effective components against depression, including flavonoids, terpenes, phenylpropanoids, quinones, and alkaloids. These chemical components can delay the course of the disease, improve the curative effect, and reduce side effects of western medicine by regulating the biochemical abnormalities of monoamine neurotransmitters, brain tissue protein content, and internal environment as well as energy metabolism to make the treatment of Chinese medicine highlighted and recognized. This study systematically reviewed the effective components and mechanisms of anti-depressive Chinese medicine to inspire the rational development and utilization of new Chinese medicines against depression.

Optimizing diffusion MRI acquisition efficiency of rodent brain using simultaneous multislice EPI.

Diffusion tensor imaging (DTI) of the brain provides essential information on the white matter integrity and structural connectivity. However, it suffers from a low signal-to-noise ratio (SNR) and requires a long scan time to achieve high spatial and/or diffusion resolution and wide brain coverage. With recent advances in parallel and simultaneous multislice (multiband) imaging, the SNR efficiency has been improved by reducing the repetition time (TR ). However, due to the limited number of RF coil channels available on preclinical MRI scanners, simultaneous multislice acquisition has not been practical. In this study, we demonstrate the ability of multiband DTI to acquire high-resolution data of the mouse brain with 84 slices covering the whole brain in 0.2 mm isotropic resolution without a coil array at 9.4 T. Hadamard-encoding four-band pulses were used to acquire four slices simultaneously, with the reduction in the TR maximizing the SNR efficiency. To overcome shot-to-shot phase variations, Hadamard decoding with a self-calibrated phase was developed. Compared with single-band DTI acquired with the same scan time, the multiband DTI leads to significantly increased SNR by 40% in the white matter. This SNR gain resulted in reduced variations in fractional anisotropy, mean diffusivity, and eigenvector orientation. Furthermore, the cerebrospinal fluid signal was attenuated, leading to reduced free-water contamination. Without the need for a high-density coil array or parallel imaging, this technique enables highly efficient preclinical DTI that will facilitate connectome studies.

MMP9 rs17576 Is Simultaneously Correlated with Symptomatic Intracranial Atherosclerotic Stenosis and White Matter Hyperintensities in Chinese Population.

PURPOSE: The aim of this study was screening for single nucleotide polymorphisms (SNPs) associated with white matter hyperintensities (WMHs) in symptomatic intracranial atherosclerotic stenosis (sICAS) patients and exploring a possible connection in the genetic background between macrovascular disease and small vessel disease. METHODS: There were 400 sICAS patients enrolled in the study. Fazekas scores were applied to WMH classification. Healthy controls were referred to 1,000 Genome Project and GeneSky company who provided 1,007 Chinese healthy controls. Fast target sequencing technology was used to select the SNPs of 102 genes related to the pathogenesis of sICAS in the sICAS patients. RESULTS: The allele frequencies of 88 SNPs were significantly different between the sICAS group and the healthy controls (p < 0.05). The allele frequencies of 53 SNPs were significantly different between the sICAS patients with and without WMHs (p < 0.05). Further analysis found that matrix metalloproteinase 9 (MMP9) rs17576 was simultaneously related to sICAS and WMHs. The frequency of the rs17576 A allele was significantly lower in sICAS patients when compared to the normal controls (p = 0.03, OR [95% CI] = 0.75 [0.625-0.91]). Also, the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.009), dominant (p = 0.014), and recessive (p= 0.023) models. The frequency of the rs17576 A allele was significantly higher in sICAS with WMH patients, compared to those without WMHs (p = 0.022, OR [95% CI] = 1.54 [1.06-2.22]); the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.019) and recessive (p = 0.032) models. Logistic regression analysis showed that age, hypertension, and MMP9 rs17576 AA genotype were independent risk factors for sICAS with WMHs. CONCLUSION: MMP9 rs17576 may be simultaneously associated with the risk of sICAS and WMHs.

Flutamide induces uterus and ovary damage in the mouse via apoptosis and excessive autophagy of cells following triggering of the unfolded protein response.

Intrauterine exposure to flutamide not only causes abnormal development of the reproductive organs in male offspring, but also damages ovaries and uteri. The unfolded protein response (UPR) is believed to play an important role in embryo development and teratogenic processes. In the present study, pregnant mice were administered either flutamide (300mg kg-1 day-1, p.o.) on an equivalent volume of soybean oil (control) on Days 12-18 of gestation. Eight weeks after birth, female offspring in the flutamide-treated group had a lower bodyweight and lower ovarian and uterine weights, but there was no significant difference in uterine and ovarian weights normalised by bodyweight between the flutamide-treated and control groups. Furthermore, histopathological changes were observed in all uteri and ovaries in the flutamide-treated group, with fewer and less-developed follicles in the ovaries. In both the uteri and ovaries, flutamide increased the expression of UPR members, although the expression of cell cycle-related genes remained unchanged compared with the control group. Flutamide increased the expression of all autophagy- and apoptosis-related genes evaluated in the uterus, as well as some in the ovary. The results suggest that the in utero exposure of mice to flutamide may contribute to uterine and ovarian damage in the offspring, with endoplasmic reticulum stress possibly triggered by the UPR leading to the induction of excessive autophagy and apoptosis.

Xi Lei San Attenuates Dextran Sulfate Sodium-Induced Colitis in Rats and TNF-α-Stimulated Colitis in CACO2 Cells: Involvement of the NLRP3 Inflammasome and Autophagy.

OBJECTIVE: Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory bowel disease with an unclear etiology. The active ingredients of traditional Chinese medicines (TCMs) exert anti-inflammatory, antitumor, and immunomodulatory effects, and their multitarget characteristics provide them with a unique advantage for treating IBD. However, the therapeutic effects and underlying mechanisms of Xi Lei San in treatment of IBD remain unknown. This study was designed to investigate whether Xi Lei San exerted an anti-inflammatory effect in IBD via a mechanism involving NLRP3 inflammasomes and autophagy. METHODS: We successfully established a rat model of dextran sulfate sodium- (DSS-) induced colitis as well as a cellular model of TNF-α-induced colitis. Xi Lei San and indirubin were identified by HPLC analysis. Rats were treated with Xi Lei San or alum crystals, and their body weights and morphology of intestinal tissues were examined. A western blot analysis was performed to determine the expression levels of inflammasome-related proteins and autophagy-related proteins, ELISA was performed to analyze IL-1ß, IL-18, and IL-33 concentrations, and flow cytometry was used to monitor cell apoptosis and ROS levels. RESULTS: Xi Lei San and indirubin were identified by HPLC analysis. We found that Xi Lei San could significantly increase the weights of rats and improve the structure of the intestinal tissues in DSS-induced colitis model rats. We also found that Xi Lei San significantly inhibited NLRP3 inflammasome activity, reduced the levels of inflammatory cytokines, and suppressed autophagy in DSS-induced colitis model rats. In vitro experiments revealed that Xi Lei San could repress apoptosis as well as ROS and inflammatory cytokine production in TNF-α-induced CACO2 cells by reducing the activity of NLRP3 inflammasomes and autophagy. CONCLUSIONS: Our findings showed that Xi Lei San significantly ameliorated IBD by inhibiting NLRP3 inflammasome, autophagy, and oxidative stress.