Heat stress induces a three-phase thermoregulatory response in different hot and humid environments in rats.

As global warming intensifies, heat waves occur more frequently around the world. Heat stress from hot and humid environments poses a significant threat to human health. It can cause a significant increase in core body temperature (CBT), and even lead to life-threatening heat stroke. Extremely high CBT is considered the most important clinical symptom and prognostic indicator of heat stroke. To study it, we implanted temperature-monitoring capsules into the abdominal cavities of rats to measure their CBT values. The rats were then exposed to different hot and humid environments to monitor the resultant changes in their CBTs. The results showed that heat stress could induce a three-phase thermoregulatory response in rats under different conditions. A temperature plateau was observed as part of the three-phase thermoregulatory response, at a similar CBT across different conditions. The duration of this plateau can reflect the thermotolerance of rats in hot and humid environments. The third stage of the three-phase thermoregulatory response reflects the pathogenesis of heat stroke, which may present the key stage of heat injury. Moreover, a certain range of humidity did not affect the thermoregulatory responses of rats, but exerted a significant impact once a certain threshold was reached. In this study, the CBTs of the rats in different environments were monitored to characterize their thermoregulatory responses under heat stress. In particular, the discovery of the plateau phase and humidity threshold may help to better understand the effects of high temperature and humidity conditions on living organisms.

DNAJA1 regulates protein ubiquitination and is essential for spermatogenesis in the testes of mice and rats.

DNAJA1 is a member of type I DnaJ proteins, which is essential for spermatogenesis and male fertility. However, its expression pattern in the testes and its impact on spermatogenesis remains unclear. Our study aimed to elucidate the mechanism of action of DNAJA1. We employed DNAJA1 knockout mice in this study. Western blotting and immunofluorescence analysis were conducted to determine the protein abundance of DNAJA1 in testes at various developmental stages. Our results revealed that DNAJA1 is predominantly expressed in the testes, and its knockout leads to complete infertility in male mice. We observed that DNAJA1 protein levels increased on postnatal days 14, 21, and 28, peaking on postnatal day 35 in mice. Immunofluorescence staining indicated that DNAJA1 expression varies across different stages of the spermatogenesis cycle. Additionally, DNAJA1 was absent in epididymal sperm. In early- and mid-stage tubules, DNAJA1 protein distribution was co-localized with residual bodies in elongating spermatids. Furthermore, we found that DNAJA1 knockout significantly reduced protein polyubiquitination in the testis. Analysis of the GEO database showed that DNAJA1 levels were significantly decreased in semen samples from subjects with teratozoospermia, asthenozoospermia, and impaired spermatogenesis. Our findings suggest that DNAJA1 is an essential protein for spermatogenesis, and its deletion reduces protein polyubiquitination in the testis, ultimately resulting in infertility and spermatogenesis defects.

Heat acclimation with probiotics-based ORS supplementation alleviates heat stroke-induced multiple organ dysfunction via improving intestinal thermotolerance and modulating gut microbiota in rats.

Heat stroke (HS) is a critical condition with extremely high mortality. Heat acclimation (HA) is widely recognized as the best measure to prevent and protect against HS. Preventive administration of oral rehydration salts III (ORSIII) and probiotics have been reported to sustain intestinal function in cases of HS. This study established a rat model of HA that was treated with probiotics-based ORS (ORSP) during consecutive 21-day HA training. The results showed that HA with ORSP could attenuate HS-induced hyperthermia by regulating thermoregulatory response. We also found that HA with ORSP could significantly alleviate HS-induced multiple organ injuries. The expression levels of a series of heat-shock proteins (HSPs), including HSP90, HSP70, HSP60, and HSP40, were significantly up-regulated from the HA training. The increases in intestinal fatty acid binding protein (I-FABP) and D-Lactate typically seen during HS were decreased through HA. The representative TJ proteins including ZO-1, E-cadherin, and JAM-1 were found to be significantly down-regulated by HS, but sustained following HA. The ultrastructure of TJ was examined by TEM, which confirmed its protective effect on the intestinal barrier protection following HA. We also demonstrated that HA raised the intestinal levels of beneficial bacteria Lactobacillus and lowered those of the harmful bacteria Streptococcus through 16S rRNA gene sequencing. These findings suggest that HA with ORSP was proven to improve intestinal thermotolerance and the levels of protective gut microbiota against HS.

Celastrol reduces lung inflammation induced by multiwalled carbon nanotubes in mice via NF-κb-signaling pathway.

Multiwalled carbon nanotubes (MWCNTs) have numerous applications in the field of carbon nanomaterials. However, the associated toxicity concerns have increased significantly because of their widespread use. The inhalation of MWCNTs can lead to nanoparticle deposition in the lung tissue, causing inflammation and health risks. In this study, celastrol, a natural plant medicine with potent anti-inflammatory properties, effectively reduced the number of inflammatory cells, including white blood cells, neutrophils, and lymphocytes, and levels of inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, in mice lungs exposed to MWCNTs. Moreover, celastrol inhibited the activation of the NF-κB-signaling pathway. This study confirmed these findings by demonstrating comparable reductions in inflammation upon exposure to MWCNTs in mice with the deletion of NF-κB (P50-/-). These results indicate the utility of celastrol as a promising pharmacological agent for preventing MWCNT-induced lung tissue inflammation.

Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy.

Photothermal therapy (PTT) of nanomaterials is an emerging novel therapeutic strategy for breast cancer. However, there exists an urgent need for appropriate strategies to enhance the antitumor efficacy of PTT and minimize damage to surrounding normal tissues. Piezo1 might be a promising novel photothermal therapeutic target for breast cancer. This study aims to explore the potential role of Piezo1 activation in the hyperthermia therapy of breast cancer cells and investigate the underlying mechanisms. Results showed that the specific agonist of Piezo1 ion channel (Yoda1) aggravated the cell death of breast cancer cells triggered by heat stress in vitro. Reactive oxygen species (ROS) production was significantly increased following heat stress, and Yoda1 exacerbated the rise in ROS release. GSK2795039, an inhibitor of NADPH oxidase 2 (NOX2), reversed the Yoda1-mediated aggravation of cellular injury and ROS generation after heat stress. The in vivo experiments demonstrate the well photothermal conversion efficiency of TiCN under the 1,064 nm laser irradiation, and Yoda1 increases the sensitivity of breast tumors to PTT in the presence of TiCN. Our study reveals that Piezo1 activation might serve as a photothermal sensitizer for PTT, which may develop as a promising therapeutic strategy for breast cancer.

DNAJA1­knockout alleviates heat stroke­induced endothelial barrier disruption via improving thermal tolerance and suppressing the MLCK­MLC signaling pathway.

Endothelial barrier disruption plays a key role in the pathophysiology of heat stroke (HS). Knockout of DNAJA1 (DNAJA1­KO) is thought to be protective against HS based on a genome­wide CRISPR­Cas9 screen experiment. The present study aimed to illustrate the function of DNAJA1­KO against HS in human umbilical vein endothelial cells. DNAJA1­KO cells were infected using a lentivirus to investigate the role of DNAJA1­KO in HS­induced endothelial barrier disruption. It was shown that DNAJA1­KO could ameliorate decreased cell viability and increased cell injury, according to the results of Cell Counting Kit­8 and lactate dehydrogenase assays. Moreover, HS­induced endothelial cell apoptosis was inhibited by DNAJA1­KO, as indicated by Annexin V­FITC/PI staining and cleaved­caspase­3 expression using flow cytometry and western blotting, respectively. Furthermore, the endothelial barrier function, as measured by transepithelial electrical resistance and FITC­Dextran, was sustained during HS. DNAJA1­KO was not found to have a significant effect on the expression and distribution of cell junction proteins under normal conditions without HS. However, DNAJA1­KO could effectively protect the HS­induced decrease in the expression and distribution of cell junction proteins, including zonula occludens­1, claudin­5, junctional adhesion molecule A and occludin. A total of 4,394 proteins were identified using proteomic analysis, of which 102 differentially expressed proteins (DEPs) were activated in HS­induced wild­type cells and inhibited by DNAJA1­KO. DEPs were investigated by enrichment analysis, which demonstrated significant enrichment in the 'calcium signaling pathway' and associations with vascular­barrier regulation. Furthermore, the 'myosin light­chain kinase (MLCK)­MLC signaling pathway' was proven to be activated by HS and inhibited by DNAJA1­KO, as expected. Moreover, DNAJA1­KO mice and a HS mouse model were established to demonstrate the protective effects on endothelial barrier in vivo. In conclusion, the results of the present study suggested that DNAJA1­KO alleviates HS­induced endothelial barrier disruption by improving thermal tolerance and suppressing the MLCK­MLC signaling pathway.

The role of HSP40 in cancer: Recent advances.

Heat shock proteins (HSPs) are a family of proteins involved in protein folding and maturation that are expressed by cells in response to stressors including heat shock. Recent studies have demonstrated that HSPs play major roles in carcinogenesis by regulating angiogenesis, cell proliferation, migration, invasion, metastasis, apoptosis, as well as therapy resistance to certain anticancer drugs. Despite being the largest and most diverse subgroup of the HSP family, HSP40 (DNAJ) is an understudied family of co-chaperones. HSP40 family members are also known to be involved in various types of cancers. In this article, we review the involvement of human HSP40 family members in various aspects of cancer biology. In addition, we highlight the possible potential of HSP40 as a tumor biomarker or drug target for improving the prognosis and treatment of cancer patients in the future.

An NIR-II-photoresponsive CoSnO3 nanozyme for mild photothermally augmented nanocatalytic cancer therapy.

The main challenges of nanozyme-based tumor catalytic therapy (NCT) lie in the unsatisfactory catalytic activity accompanied by a complex tumor microenvironment (TME). A few nanozymes have been designed to possess both enzyme-like catalytic activities and photothermal properties; however, the previously reported nanozymes mainly utilize the inefficient and unsafe NIR-I laser, which has a low maximum permissible exposure limit and a limited penetration depth. Herein, we report for the first time an all-in-one strategy to realize mild NIR-II photothermally amplified NCT by synthesizing amorphous CoSnO3 nanocubes with efficient triple enzyme-like catalytic activities and photothermal conversion properties. The presence of Co2+ and Sn4+ endows CoSnO3 nanocubes with the triple enzyme-like catalytic activities, not only achieving enhanced reactive oxygen species (ROS) generation through the Co2+-mediated peroxidase-like catalytic reaction to generate ˙OH and Sn4+-mediated depletion of overexpressed GSH, but also realizing the catalytic decomposition of endogenous H2O2 for relieving tumor hypoxia. More importantly, the obtained CoSnO3 nanocubes with a high photothermal conversion efficiency of 82.1% at 1064 nm could achieve mild hyperthermia (43 °C), which further improves the triple enzyme-like catalytic activities of the CoSnO3 nanozyme. The synergetic therapeutic efficacy of the NIR-II-responsive CoSnO3 nanozyme through mild NIR-II PTT-enhanced NCT could realize all-in-one multimodal tumor therapy to completely eliminate tumors without recurrence. This study will open a new avenue to explore NIR-II-photoresponsive nanozymes for efficient tumor therapy.

A Two-Generation Reproductive Toxicity Study of Cerium Nitrate in Sprague-Dawley Rats.

A two-generation reproductive toxicity study was performed to evaluate the effects of cerium nitrate on the development of the parent, offspring, and third generation of Sprague-Dawley (SD) rats. A total of 240 SD rats (30 rats/sex/group) were randomly divided into four dosage groups according to body weight: 0 mg/kg, 30 mg/kg, 90 mg/kg, and 270 mg/kg. The rats were administered different dosages of cerium nitrate by oral gavage. There were no observed changes related to cerium nitrate in body weight, food consumption, sperm survival rate, motility, mating rate, conception rate, abortion rate, uterine plus fetal weight, uterine weight, corpus luteum number, implantation rate, live fetus number (rate), stillbirth number (rate), absorbed fetus number (rate), appearance, visceral, and skeletal in rats of each generation dosage group. In addition, the pathological findings showed no significant lesions associated with cerium nitrate toxicity in all tissues and organs, including reproductive organs. In conclusion, the present study showed that long-term oral gavage of cerium nitrate at 30 mg/kg, 90 mg/kg, and 270 mg/kg had no significant effect on reproduction and the developmental ability of their offspring in rats. The no-observed-adverse-effect level (NOAEL) of cerium nitrate in SD rats was higher than 270 mg/kg.

A Sonoresponsive and NIR-II-Photoresponsive Nanozyme for Heterojunction-Enhanced "Three-in-One" Multimodal Oncotherapy.

Although low-cost nanozymes with excellent stability have demonstrated the potential to be highly beneficial for nanocatalytic therapy (NCT), their unsatisfactory catalytic activity accompanied by intricate tumor microenvironment (TME) significantly hinders the therapeutic effect of NCT. Herein, for the first time, a heterojunction (HJ)-fabricated sonoresponsive and NIR-II-photoresponsive nanozyme is reported by assembling carbon dots (CDs) onto TiCN nanosheets. The narrow bandgap and mixed valences of Ti3+ and Ti4+ endow TiCN with the capability to generate reactive oxygen species (ROS) when exposed to ultrasound (US), as well as the dual enzyme-like activities of peroxidase and glutathione peroxidase. Moreover, the catalytic activities and sonodynamic properties of the TiCN nanosheets are boosted by the formation of HJs owing to the increased speed of carrier transfer and the enhanced electron-hole separation. More importantly, the introduction of CDs with excellent NIR-II photothermal properties could achieve mild hyperthermia (43 °C) and thereby further improve the NCT and sonodynamic therapy (SDT) performances of CD/TiCN. The synergetic therapeutic efficacy of CD/TiCN through mild hyperthermia-amplified NCT and SDT could realize "three-in-one" multimodal oncotherapy to completely eliminate tumors without recurrence. This study opens a new avenue for exploring sonoresponsive and NIR-II-photoresponsive nanozymes for efficient tumor therapy based on semiconductor HJs.

Therapeutic potential of traditional Chinese medicine on heat stroke.

As global warming progresses, heat waves are becoming increasingly frequent and intense, meanwhile the incidence of heat stroke (HS) has increased sharply during the past decades. HS is typically associated with significant morbidity and mortality, and there is an urgent need for further research to solve this difficult issue. There currently exists difficulties regarding on-site emergency treatment methods and limited in-hospital treatment approaches, and better treatments are required as soon as possible. Theories and therapies from various traditional Chinese medicine (TCM) academic groups have been widely reported. Therefore, an exploration of prevention and protection methods should consider TCM experiences as an alternative. This article primarily reviews TCM herbal therapies and external therapies that have been described in various clinical reports and demonstrated in relevant studies. Herbal therapies, including herbal formulas, Chinese patent medicines (CPMs), single Chinese herbs, and associated extracts or monomers, are summarized based on the shared perspectives of the underlying mechanisms from TCM. In addition, external therapies including acupuncture, bloodletting, cupping, Gua sha and Tui na that have rarely been rarely mentioned and considered in most cases, are introduced and discussed to offer a unique perspective in the search for novel interventions for HS. In summary, TCM may provide abundant potential clinical benefits and research directions in the fight against HS.

Subchronic toxicity study of ferric oxide nanoparticles through intragastric administration: A 94-d, repeated dose study in Sprague Dawley rats.

In this study, the toxicity of ferric oxide nanoparticles (Fe2O3 NPs) administered through gavage to Sprague Dawley (SD) rats for 94 d, consecutively and the recovery after Fe2O3 NPs withdrawal for 30 d were evaluated. The vehicle control group, low-, medium-, and high-dose groups were administered with the vehicle (0.5% sodium carboxymethyl cellulose [CMC-Na]), 125, 250, and 500 mg/kg of Fe2O3 NPs, respectively, administered every morning for 94 d. There was no significant difference in the body weight, food intake, hematological, blood biochemical, and urine indices of SD rats in each administration group and the control group (P > 0.05). There was no significant difference in organ weight, organ indices, and the coefficient of the visceral brain between the SD rats in the different dosage groups and the SD rats in the vehicle control group (P > 0.05). Histopathological observations showed that there was no correlation between the pathological lesions of the organs observed in this study and the dose of Fe2O3 NPs (P > 0.05). The no-observed-adverse-effect level (NOAEL) dose of Fe2O3 NPs was initially determined to be 500 mg/kg administered to SD rats through oral gavage for 94 d, consecutively, followed by recovery after Fe2O3 NPs withdrawal for 30 d.

Celastrol alleviates oxidative stress induced by multi-walled carbon nanotubes through the Keap1/Nrf2/HO-1 signaling pathway.

Multi-walled carbon nanotubes (MWCNTs) mainly induce oxidative stress through the overproduction of reactive oxygen species (ROS), which can lead to cytotoxicity. Celastrol, a plant-derived compound, can exert antioxidant effects by reducing ROS production. Our results indicated that exposure to MWCNTs decreased cell viability and increased ROS production. Nrf2 knockdown (kd) led to increased ROS production and enhanced MWCNT-induced cytotoxicity. Keap1-kd led to decreased ROS production and attenuated cytotoxicity. Treatment with celastrol significantly decreased ROS production and promoted Keap1 protein degradation through the lysosomal pathway, thereby enhancing the translocation of Nrf2 from the cytoplasm to the nucleus and increasing HO-1 expression. The in vivo results showed that celastrol could alleviate the inflammatory damage of lung tissues, increase the levels of the antioxidants, GSH and SOD, as well as promote the expression of the antioxidant protein, HO-1 in MWCNT-treated mice. Celastrol can alleviate MWCNT-induced oxidative stress through the Keap1/Nrf2/HO-1 signaling pathway.

The reproductive toxicity of yttrium nitrate in a two-generation study in Sprague-Dawley rats.

OBJECTIVE: To evaluate the effects of yttrium nitrate on the development of the parent, offspring and third generation of Sprague-Dawley (SD) rats by using a two-generation reproductive toxicity test. METHODS: The SD rats were randomly divided into 0 mg/kg group, 10.0 mg/kg group, 30.0 mg/kg group and 90.0 mg/kg group according to the different doses of yttrium nitrate administration. The reproductive toxicity of parent, offspring and third generation SD rats were compared. RESULTS: The weight gains of F1a female rats and F2a female rats in the low-dose groups were significantly lower than those of the control groups (p < 0.05), the weight gains of F1a male rats in the medium-dose and high-dose groups were significantly lower than those of the control groups (p < 0.05), and the weight gains of F2a male rats in the low-dose, medium-dose and high-dose groups were significantly lower than those of the control groups (p < 0.05). In F0 male rats, the absolute weight and relative weight of the liver in the low-dose, middle-dose, and high-dose groups were significantly lower than those of the control group (p < 0.05). In F1b male rats, the absolute and relative weights of the liver in the medium-dose and high-dose groups were significantly lower than those of the control group (p < 0.05). In F2b male rats, the absolute and relative weights of the liver and spleen of the medium-dose and high-dose groups were significantly lower than those of the control group (p < 0.05). In F2a female rats, the absolute weight and relative weight of oviduct in the high-dose group were significantly lower than those in the control group (p < 0.05). The absolute and relative weights of lung, spleen, brain and uterus of F2b female rats in the high-dose group were higher than those of the control group (p < 0.05). But the pathological test results showed no hepatotoxicity. There was no statistically significant difference in sperm count and sperm motility between male rats in the yttrium nitrate administration groups and the control group (p > 0.05). There was no significant correlation between F0, F1a, F1b, F2a, F2b SD rats' reproductive organ lesions and the dose of yttrium nitrate. CONCLUSION: Yttrium nitrate at a dose of 90 mg/kg has no reproductive toxicity to two generations of SD rats, but 30.0 mg/kg dose of yttrium nitrate is toxic to the liver weight of male two generations of SD rats, but no hepatotoxicity.

Evaluation of subchronic toxicity of the compound of diphenhydramine hydrochloride and caffeine after 28 days of repeated oral administration in Sprague-Dawley rats and beagle dogs.

This study was designed to evaluate the subchronic toxicity of the compound of diphenhydramine hydrochloride (DH) and caffeine in Sprague-Dawley (SD) rats and beagle dogs. A total of 180 SD rats (15/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (51, 102, 204 mg/kg), DH group (60 mg/kg), caffeine group (144 mg/kg) and the vehicle control group. Sixty beagle dogs (5/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (male: 14.20, 28.30, 56.60 mg/kg, female: 5.66, 14.20, 28.30 mg/kg), DH group (male: 16.60 mg/kg, female: 8.30 mg/kg), caffeine group (male: 40.00 mg/kg, female: 20.00 mg/kg) and the vehicle control group. Rats and dogs were given continuous oral administration for 28 days following a 28-day recovery period. The adverse effects of the compound on rats and beagle dogs mainly included anorexia and liver function impairment. Most adverse effects induced by administration were reversible. Under the experimental conditions, the no-observed-adverse-effect level (NOAEL) of the compound of DH and caffeine was 51 mg/kg/day for SD rats and 28.30 mg/kg/day (male) and 5.66 mg/kg/day (female) for beagle dogs.

Carbon Dot@MXene Nanozymes with Triple Enzyme-Mimic Activities for Mild NIR-II Photothermal-Amplified Nanocatalytic Therapy.

Nanozymes have shown promising potential in disease treatment owing to the advantages of low-cost, facile fabrication, and high stability. However, the highly complex tumor microenvironment (TME) and inherent low catalytic activity severely restrict the clinical applications of nanozymes. Herein, a novel mild hyperthermia-enhanced nanocatalytic therapy platform based on Z-scheme heterojunction nanozymes by depositing N-doped carbon dots (CDs) onto Nb2 C nanosheets is constructed. CD@Nb2 C nanozymes not only display outstanding photothermal effects in the safe and efficient NIR-II window but also possess triple enzyme-mimic activities to obtain amplified ROS levels. The triple enzyme-mimic activities and NIR-II photothermal properties of CD nanozymes are enhanced by the construction of Z-scheme heterojunctions owing to the accelerated carrier transfer process. More importantly, the introduction of mild hyperthermia can further improve the peroxidase-mimic and catalase-mimic activities as well as the glGSH depletion abilities of CD@Nb2 C nanozymes, thereby producing more ROS to efficiently inhibit tumor growth. The combined therapy effect of CD@Nb2 C nanozymes through mild NIR-II photothermal-enhanced nanocatalytic therapy can achieve complete tumor eradication. This work highlights the efficient tumor therapy potential of heterojunction nanozymes.

Vascular toxicity of multi-walled carbon nanotubes targeting vascular endothelial growth factor.

Multiwalled carbon nanotubes (MWCNTs) are currently widely used and are expected to be used as drug carriers and contrast agents in clinical practice. Previous studies mainly focused on their lung toxicity; therefore, their effects on the vascular endothelium are unclear. In this study, a human angiogenesis array was used to determine the effect of MWCNTs on the expression profile of angiogenic factors in endothelial cells and to clarify the role of vascular endothelial growth factor (VEGF) in MWCNT-induced endothelial cell injury at the cellular and animal levels. The results indicated that MWCNTs (20-30 nm and 30-50 nm) could enter endothelial cells and disrupt human umbilical vein endothelial cell (HUVECs) activity in a concentration-dependent manner. MWCNTs disrupted the tube formation ability and cell migration function of HUVECs. The results from a Matrigel Plug experiment in mice showed that angiogenesis in the MWCNT experimental group was significantly reduced. The results of a protein chip analysis indicated that VEGF expression in the MWCNT treatment group was decreased, a finding that was validated by ELISA results. The protein expression levels of AKT and eNOS in the MWCNT treatment group were significantly decreased; the administration of recombinant VEGF significantly alleviated the migration ability and tube formation ability of endothelial cells injured by MWCNTs, upregulated the protein expression of AKT and eNOS, and increased the number of neovascularization in mice in the MWCNT treatment group. This study demonstrated that MWCNTs affect angiogenesis via the VEGF-Akt-eNOS axis which can be rescued by VEGF endothelial treatment.

Activating α7nAChR ameliorates abdominal aortic aneurysm through inhibiting pyroptosis mediated by NLRP3 inflammasome.

Abdominal aortic aneurysm (AAA) is defined as a dilated aorta in diameter at least 1.5 times of a normal aorta. Our previous studies found that activating α7 nicotinic acetylcholine receptor (α7nAChR) had a protective effect on vascular injury. This work was to investigate whether activating α7nAChR could influence AAA formation and explore its mechanisms. AAA models were established by angiotensin II (Ang II) infusion in ApoE-/- mice or in wild type and α7nAChR-/- mice. In vitro mouse aortic smooth muscle (MOVAS) cells were treated with tumor necrosis factor-α (TNF-α). PNU-282987 was chosen to activate α7nAChR. We found that cell pyroptosis effector GSDMD and NLRP3 inflammasome were activated in abdominal aorta, and inflammatory cytokines in serum were elevated in AAA models of ApoE-/- mice. Activating α7nAChR reduced maximal aortic diameters, preserved elastin integrity and decreased inflammatory responses in ApoE-/- mice with Ang II infusion. While α7nAChR-/- mice led to aggravated aortic injury and increased inflammatory cytokines with Ang II infusion when compared with wild type. Moreover, activating α7nAChR inhibited NLRP3/caspase-1/GSDMD pathway in AAA model of ApoE-/- mice, while α7nAChR deficiency promoted this pathway. In vitro, N-acetylcysteine (NAC) inhibited NLRP3 inflammasome activation and NLRP3 knockdown reduced GSDMD expression, in MOVAS cells treated with TNF-α. Furthermore, activating α7nAChR inhibited oxidative stress, reduced NLRP3/GSDMD expression, and decreased cell pyroptosis in MOVAS cells with TNF-α. In conclusion, our study found that activating α7nAChR retarded AAA through inhibiting pyroptosis mediated by NLRP3 inflammasome. These suggested that α7nAChR would be a potential pharmacological target for AAA.

A Two-Generation Reproductive Toxicity Study of Lanthanum Nitrate in SD Rats.

In order to evaluate the effects of lanthanum nitrate on the development of the parent, offspring, and the third generation of Sprague-Dawley (SD) rats, a two-generation reproductive toxicity experiment, was conducted. Two hundred and forty specific pathogen-free (SPF) healthy SD rats were randomly divided into the control group, low-, medium-, and high-dose group, with 30 male and 30 female rats in each group. The rats in each group were given 0 mg/kg, 10.0 mg/kg, 30.0 mg/kg, and 90.0 mg/kg lanthanum nitrate by gavage, respectively. There was no statistically significant difference between the weight gain and food intake of rats in each group. High-dose lanthanum nitrate had no effect on rat implantation and no embryo toxicity. The absolute and relative liver weights of F1a and F1b male rats in the high-dose group were significantly decreased. The absolute liver and spleen weight of F1b female rats in the high-dose group decreased significantly, but the relative weight did not change significantly. Histopathological examination results showed that there were no significant differences in the effects of different doses of lanthanum nitrate on the uterus, ovaries, oviduct, testes and epididymis, and liver of SD rats. Under the experimental conditions, 90.0 mg/kg lanthanum nitrate had an effect on the liver weight of the SD rats, but there was no liver toxicity. The no visible harmful effect level (NOAEL) of lanthanum nitrate on SD rats' reproduction toxicity is 90 mg/kg.

Pyruvate Kinase M2 Mediates Glycolysis Contributes to Psoriasis by Promoting Keratinocyte Proliferation.

Psoriasis is characterized by keratinocyte proliferation and immune cell infiltration. M2 isoform of pyruvate kinase (PKM2) was reported to have an important role in cell proliferation, which is a rate-limiting enzyme that regulates the final step of glycolysis. However, how PKM2 regulates cell metabolism and proliferation in psoriatic keratinocytes is still poorly understood. Interestingly, we found that PKM2 was highly expressed in psoriatic epidermis from patients and mouse models. PKM2 overexpression promoted keratinocyte glycolytic metabolism while knockdown inhibited keratinocyte proliferation and glycolysis. Mice lacking PKM2 specifically in keratinocytes, pharmacological inhibition of PKM2 or glycolysis inhibited keratinocyte proliferation and showed obvious remission in an imiquimod-induced psoriatic mouse model. Moreover, the inhibitor of the EGF-receptor blocked EGF-stimulated PKM2 expression and glycolysis in keratinocytes. We identify PKM2 as an upregulated gene in psoriasis. PKM2 is essential in keratinocyte over-proliferation and may represent a therapeutic target for psoriasis.