Astragaloside IV (AS-IV), a bioactive compound renowned for its anti-inflammatory, antioxidant, and anti-apoptotic properties, has not yet been investigated for its potential role in modulating cardiac function under high-altitude conditions. This study elucidates the cardioprotective effects of AS-IV against high-altitude-induced cardiac injury and explores the underlying molecular mechanisms. Under hypobaric hypoxia, we observed significant cardiac dysfunction, hypertrophy, and fibrosis, as confirmed by comprehensive echocardiographic, histopathological, and molecular analyses. Remarkably, AS-IV administration effectively attenuated these pathological changes, restoring cardiac architecture and function while mitigating oxidative stress and apoptosis. Further in vivo and in vitro experiments revealed that AS-IV preserves mitochondrial integrity by enhancing membrane potential, ameliorating mitochondrial impairment, and modulating calcium homeostasis through the calcium-sensing receptor (CaSR)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling axis. Network pharmacology-based screening identified key molecular targets, including epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mouse double minute 2 (MDM2), which were subsequently validated via molecular docking studies demonstrating strong binding affinities between AS-IV and these core proteins. Mechanistic investigations further revealed that siRNA-mediated EGFR knockdown or pharmacological activation of CaSR abolished AS-IV's cardioprotective effects, including its anti-apoptotic, antioxidant, and mitochondrial-stabilizing properties. Taken together, our findings demonstrate that AS-IV exerts its therapeutic effects through a dual-pathway mechanism involving (1) the EGFR-PI3K-AKT-MDM2 axis and (2) CaSR-NF-κB signaling. These insights position AS-IV as a promising candidate for the prevention and treatment of high-altitude-related cardiovascular diseases.

The present study aimed to investigate the therapeutic potential of Osmundacetone (Osu), a natural plant product, for the treatment of rheumatoid arthritis (RA). The study revealed that Osu effectively reduced arthritis-induced swelling and bone destruction, as well as alleviating inflammation-related factors and oxidative stress in animal models. We focused the mechanism exploration on its regulatory mechanism on osteoclastogenesis in the next investigation. In vitro experiments demonstrated a dose-dependent inhibition of osteoclastic differentiation by Osu, as evidenced by tartrate resistant acid phosphatase (TRAP) staining and a reduction in osteoclastic differentiation markers observed through Western blotting analysis. And three different approaches Osu inhibiting osteoclastogenesis were found in our researches: (1) The binding of Receptor Activator of Nuclear Factor Kappa B (RANK) and Osu was revealed by the in-silico analysis. (2) According to 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA) staining, Osu attenuated the level of reactive oxygen species (ROS), and western blotting studies revealed this effect was modulated by the regulation of Kelch-like ECH-associated protein 1 / Nuclear Factor erythroid 2-Related Factor 2 (Keap1/Nrf2) pathway. (3) Interestingly, we found that Osu increased the lipid peroxidation via downregulating the expression of glutathione peroxidase 4 (GPX4) at the same time as reducing the ROS, leading to the reduction of the fluidity of the membrane and the fusion of osteoclasts which could be reversed by using the ferroptosis inhibitor- Ferrostatin-1 (Fer-1). Overall, a natural compound to the existing therapeutics for rheumatoid arthritis was confirmed and a new strategy for inhibiting osteoclastogenesis was added.

As activated hepatic stellate cells (aHSCs) play a central role in fibrogenesis, they have become key target cells for anti-fibrotic treatment. Nevertheless, the therapeutic efficiency is constrained by the exosomes they secrete, which are linked to energy metabolism and continuously stimulate the activation of neighboring quiescent hepatic stellate cells (qHSCs). Herein, an intercellular communication interference strategy is designed utilizing paeoniflorin (PF) loaded and hyaluronic acid (HA) coated copper-doped ZIF-8 (PF@HA-Cu/ZIF-8, PF@HCZ) to reduce energy-related exosome secretion from aHSCs, thus preserving neighboring qHSCs in a quiescent state. Simultaneously, the released copper and zinc ions disrupt key enzymes involved in glycolysis to reduce bioenergy synthesis in aHSCs, thereby promoting the reversion of aHSCs to a quiescent state and further decreasing exosome secretion. Therefore, PF@HCZ can effectively sustain both aHSCs and qHSCs in a metabolically dormant state to ultimately alleviate liver fibrosis. The study provides an enlightening strategy for interrupting exosome-mediated intercellular communication and remodeling the energy metabolic status of HSCs with boosted antifibrogenic activity.

Hypobaric hypoxia-induced hyperuricemia (HUA) is a major health challenge for high-altitude populations, yet its molecular mechanisms remain poorly understood. This study employed metabolomic and proteomic profiling of a high-altitude cohort (10 HUA patients and 10 matched controls) to address this gap. HUA patients exhibited significantly elevated uric acid (UA), creatine kinase, and lactate dehydrogenase levels alongside reduced platelet counts. Metabolomic analysis identified 79 significantly altered metabolites, which were associated with amino acids, lipids, and other pathways, including glycerophospholipid and riboflavin metabolism. Notably, l-cystathionine and serine emerged as potential discriminatory biomarkers for HUA. Parallel proteomics revealed 46 differentially expressed proteins, predominantly linked to complement activation and immune response pathways. Functional enrichment analysis indicated upregulated immune signaling and downregulated hemostasis-related proteins in HUA patients. A machine learning model identified 30 molecular signatures, including both proteins and metabolites, that could distinguish HUA from the control subjects. The resulting signature demonstrated a high discriminatory power. Furthermore, protein-metabolite interaction networks unveiled key regulators and potential therapeutic targets for HUA. These findings provide novel insights into the underlying molecular mechanisms of high-altitude HUA and highlight potential diagnostic and therapeutic strategies for hypobaric hypoxia conditions.

Ethnopharmacological relevance: Beaveria bassiana (Balsamo) Vuillemin (BEA) and cinnamaldehyde (CA), primarily derived from traditional Chinese medicine (TCM) named Bombyx batryticatus and Cinnamomum cassia, play an immunomodulatory role in different disease. Aim of the study: Hepatocellular carcinoma (HCC) is a prevalent malignant tumor characterized by immune dysfunction. In this study, we investigated BEA and CA's regulate ability on T cell mitochondrial metabolism and anti-HCC effect. Materials and methods: We used RT-qPCR, Western blot, Enzyme-linked immune sorbent assay (ELISA), Flow CytoMetry (FCM) methods to examine BEA and CA's regulation of T cell mitochondrial function and anti-HCC ability. Furthermore, the mechanism of PGC-1 alpha/DRP1 pathway on the morphology and function of T cell mitochondria was investigated. Results: Our data demonstrated that the administration of BEA and CA, either alone or in combination, effectively suppressed HCC growth and mitigated T cell apoptosis and mitochondrial dysfunction, assessed by mitochondrial reactive oxygen species (mitoROS), mitochondrial membrane potential (MMP) and ATP level. Moreover, BEA and CA could enhance the release of tumor-killing factors (Perforin (PF) and Granzyme B (Gzm B)) from T cells, inducing H22 cell apoptosis. Additionally, BEA and CA-treated T cell reinfusion into BALB/c nude HCC mice could significantly inhibited HCC growth by promoting T cell infiltration into tumor tissue. T cell mitochondrial biogenesis/fission balance and apoptosis in tumor mice were regulated by PGC-1 alpha/DRP1 pathway. Conclusions: Our findings reveal that BEA and CA enhance anti-HCC effects of T cells by regulating mitochondrial biogenesis and fission through the PGC-1 alpha/DRP1 pathway.

Grape seed proanthocyanidins (GSPs) have been receiving extensive attention due to their outstanding brain protection role in various disease models. This study aimed to explore the therapeutic effects of GSPs against acute high-altitude hypoxia-induced brain injury (AHHBI) and elucidate the underlying mechanism. SD rats and PC12 cells were employed in this study to establish in vivo and in vitro models of acute high-altitude hypoxia, respectively. In compared to mode group rats with hypobaric hypoxia exposure, GSP treatment significantly restored spatial learning and memory abilities of rats, reduced hippocampal inflammatory factor levels and NRLP3 inflammasome, and also enhanced hippocampal autophagy. In hypoxic PC12 cells, GSP treatment increased the survival rate of cells, improved cell morphology, reduced cell cycle arrest and apoptosis, and inhibited the activation of the NLRP3 inflammasome. Furthermore, GSP treatment enhanced autophagy and suppressed the PI3K/Akt/mTOR signaling pathway in hypoxic PC12 cells. However, autophagy inhibitor 3-MA compromised inhibitory effect of GSPs on NLRP3 inflammasome and the protective effects on hypoxic PC12 cells. Our study demonstrated neuroprotective effects of GSPs on rat model with high-altitude hypoxia exposure and PC12 cells experiencing hypoxic damage. The mechanism is related to the increase of autophagic flux promoted by GSPs, and the subsequent attenuation of NLRP3 inflammasome-mediated neuroinflammation. More effects and mechanisms of GSPs on the high-altitude hypoxia-induced brain injury are worthy to be explored in the future.

Hypoxia imposes notable stress on organisms and even causes tissue damage; however, the cellular and molecular mechanisms underlying hypoxic adaptation and maladaptation are elusive. Here, we performed single-cell RNA sequencing to analyze hematopoietic stem and progenitor cells (HSPCs) and erythroid cells in a mouse model of high-altitude polycythemia (HAPC) mimicking long-term high-altitude hypoxia exposure. We identified a distinct erythroid-biased multipotent progenitor subset, FOShi MPP, characterized by a unique responsiveness to interferon (IFN) signaling, which expands under hypoxia conditions. This subset rapidly responds to hypoxia during re-ascent by sustaining low methylation of erythroid-priming genes, suggesting a memory function in HSPCs for faster acclimatization. Additionally, erythroid cells in HAPC mice had active metabolic and autophagic activity, as well as abundant CD47 expression that prevented the phagocytosis of erythrocytes. Finally, CD47 blockade and/or IFNα treatments alleviated erythrocytosis in HAPC mice. These approaches might constitute promising therapeutic strategies for HAPC.

High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.

The composition, quantity, and function of peripheral blood mononuclear cells (PBMCs) are closely correlated with tumorigenesis. However, the mechanisms of PBMCs in lung cancer are not clear. Mitochondria are energy factories of cells, and almost all cellular functions rely on their energy metabolism level. The present study aimed to test whether the mitochondrial function of PBMCs directly determines their tumor immune monitoring function. We recruited 211 subjects, including 105 healthy controls and 106 patients with recently diagnosed with lung cancer. The model of lung carcinogenesis induced by BaP was used in animal experiment, and the Bap carcinogenic metabolite, Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE), was used in cell experiment. We found that mitochondrial function of PBMCs decreased significantly in patients with new lung cancer, regardless of age. In vivo, BaP caused PBMC mitochondrial dysfunction in mice before the appearance of visible malignant tissue. Moreover, mitochondrial function decreased significantly in mice with lung cancers induced by BaP compared to those without lung cancer after BaP intervention. In vitro, BPDE also induced mitochondrial dysfunction and reduced the aggressiveness of PBMCs toward cancer cells. Furthermore, the changes in mitochondrial energy metabolism gene expression caused by BPDE are involved in this process. Thus, the mitochondrial function of PBMCs is a potential prognostic biomarker or therapeutic target to improve clinical outcomes in patients with lung cancer.

Background:Oral squamous cell carcinoma (OSCC) is a common malignant tumor. Recently, Laminin Gamma 2 (LAMC2) has been shown to be abnormally expressed in OSCC; however, how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored. This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC.Methods:To explore the mechanism by which LAMC2 is highly expressed in OSCC, we used small interfering RNA (siRNA) to knock down LAMC2 to further observe the changes in the signaling pathway. Furthermore, we used cell proliferation assays, Transwell invasion assays, and wound-healing assays to observe the changes in OSCC proliferation, invasion, and metastasis. RFP-LC3 was used to detect the level of autophagy intensity. A cell line-derived xenograft (CDX) model was used to detect the effect of LAMC2 on tumor growth in vivo.Results:This study found that the level of autophagy was correlated with the biological behavior of OSCC. The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation, invasion, and metastasis via inhibiting the PI3K/AKT/mTOR pathway. Moreover, autophagy has a dual effect on OSCC, and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis, invasion, and proliferation via the PI3K/AKT/mTOR pathway.Conclusions:LAMC2 interacts with autophagy to regulate OSCC metastasis, invasion, and proliferation via the PI3K/AKT/mTOR pathway. LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration, invasion, and proliferation.

BackgroundThe incidence and mortality rate of gastrointestinal cancers are high worldwide. Increasing studies have illustrated that the occurrence, progression, metastasis and prognosis of cancers are intimately linked to the immune system. Mitochondria, as the main source of cellular energy, play an important role in maintaining the physiological function of immune cells. However, the relationship between mitochondrial function of immune cells and tumorigenesis has not yet been systematically investigated.MethodsA total of 150 cases, including 60 healthy donors and 90 primary gastrointestinal cancer patients without anti-tumor treatments (30 with gastric cancer, 30 with liver cancer and 30 with colorectal cancer) were involved in our study. The oxidant/antioxidant and cytokine levels in plasma, the ROS level, mitochondrial function and apoptosis ratio of peripheral blood mononuclear cells (PBMCs) were evaluated.ResultsThe imbalance between oxidant and antioxidant in plasma was discovered in the primary gastrointestinal cancer patients. The levels of cell reactive oxygen species (ROS) and mitochondrial ROS in PBMCs of primary gastrointestinal cancers were significantly increased compared with that in healthy donors. Meanwhile, the ATP content, the mtDNA copy number and the mitochondrial membrane potential (MMP) in PBMCs of patients with primary gastrointestinal cancers were lower than those in control group. The decreased MMP also occurred in immune cells of gastrointestinal cancers, including T cell, B cell, NK cell and monocyte. Furthermore, the PBMCs apoptosis ratio of primary gastrointestinal cancer patients was significantly higher than that of control group. Importantly, an increase of IL-2 and IL-6 and a decrease of IgG in plasma were found in the patients with primary gastrointestinal cancers. These changes of mitochondrial function in immune cells were consistent among primary gastrointestinal cancers without anti-tumor treatments, such as liver cancer, gastric cancer and colorectal cancer.ConclusionOur study demonstrated that the imbalance of oxidation/antioxidation in primary gastrointestinal cancer patients without anti-tumor treatments results in excessive ROS. The oxidative stress was associated to the mitochondrial dysfunction, the apoptosis of immune cells and eventually the abnormal immune function in primary gastrointestinal cancers. The application of immune cell mitochondrial dysfunction into clinical evaluation is anticipated.

Hypoxia induced by high altitude can lead to severe neurological dysfunction. Mitophagy is known to play a crucial role in hypoxic nerve injury. However, the regulatory mechanism of mitophagy during this injury remains unclear. Recent studies have highlighted the role of Sestrin2 (SESN2), an evolutionarily conserved stress-inducible protein against acute hypoxia. Our study demonstrated that hypoxia treatment increased SESN2 expression and activated mitophagy in PC12 cells. Furthermore, the knock-out of Sesn2 gene led to a significant increase in mitochondrial membrane potential and ATP concentrations, which protected the PC12 cells from hypoxic injury. Although the AMPK/mTOR pathway was significantly altered under hypoxia, it does not seem to participate in mitophagy regulation. Instead, our data suggest that the mitophagy receptor FUNDC1 plays a vital role in hypoxia-induced mitophagy. Moreover, SESN2 may function through synergistic regulation with other pathways, such as SESN2/AMPK, to mediate cellular adaptation to hypoxia, including the regulation of mitophagy in neuron cells. Therefore, SESN2 plays a critical role in regulating neural cell response to hypoxia. These findings offer valuable insights into the underlying molecular mechanisms governing the regulation of mitophagy under hypoxia and further highlight the potential of SESN2 as a promising therapeutic target for hypoxic nerve injury.

Beauvericin is a world-spread mycotoxin isolated from the traditional Chinese medicine, Bombyx batryticatus (BB), which has been widely used to treat various neoplastic diseases. This study investigated the antihepatocellular carcinoma (HCC) activity of beauvericin and its potential mechanism. In this study, H22-bearing mice were intraperitoneally injected with 3, 5, 7 mg/kg of beauvericin once per-week over a threeweek period. TUNEL staining determined the extent of tumor apoptosis induced by beauvericin. ELISA kits detected the level of IL-2, Perforin, and TNF-& alpha;, IFN-& gamma; level in the serum. H22 hepatoma cells were exposed to beauvericin (5, 10, and 20 & mu;mol/L) to investigate the underlying pathway. CCK-8 assay was used to observe the influence of beauvericin on the growth of H22 cells. Flow cytometry was used to detect the cell apoptosis and ROS level. Western blotting was performed to detect apoptotic and PI3K/AKT pathway protein production. The results showed that beauvericin could remarkably inhibit the growth of HCC in mice, combined with elevated TNF-& alpha; and IL-2. In vitro, beauvericin significantly promoted the generation of ROS, up-regulated Bax/Bcl-2 ratio and cleaved caspase-9, cleaved caspase-3 levels, down-regulated p-PI3K/PI3K ratio, p-AKT/AKT ratio, promoted the apoptosis of H22 cells, and inhibited the growth of H22 cells. Remarkably, treatment with PI3K/AKT activator (740Y-P and SC79) could prevent beauvericin-induced H22 cell apoptosis. These findings collectively indicate that beauvericin inhibits HCC growth by inducing apoptosis via the PI3K/AKT pathway.

Benzene is a toxic environmental pollutant that disrupts the immune system in humans. Benzene exposure reduces the abundance of immune cells in multiple immune organs; however, the biological mechanisms underlying benzene-induced immunotoxicity has not been elucidated. In this study, benzene was used to develop mouse model for immune dysfunction. A significant decrease in IgG, IL-2 and IL-6 levels, an increase in oxidative stress and spleen injury were observed after benzene exposure in a dose-dependent manner. Quantitative proteomics revealed that benzene-induced immune dysfunction was associated with deregulation of the B cell receptor (BCR) signaling pathway. Benzene exposure suppressed the expression of CD22, BCL10 and NF-κb p65. Also, a significant decrease in proliferation and an increase in apoptosis of splenic lymphocytes were found after benzene exposure. Moreover, we found that benzene exposure increased mitochondrial reactive oxygen species (mito-ROS) and decreased adenosine triphosphate (ATP). Overall, we revealed the damaging effects of benzene on spleen-related immune function and the underlying biological mechanism, involving the disruption of BCR signaling pathway, NF-κB deactivation, and mitochondrial dysfunction.

An excess of osteoclastogenesis significantly contributes to the development of rheumatoid arthritis (RA). Activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) ligand (RANKL)-induced reactive oxygen species (ROS)-to-NF-κB signaling cascade are important mechanisms regulating osteoclastogenesis; however, whether Nrf2 is involved in RANKL-induced NF-κB activation is controversial. Isoquercitrin, a natural flavonoid compound, has been shown to have Nrf2-dependent antioxidant effects inprevious studies. We sought to verify whether isoquercitrin could modulate RANKL-induced NF-κB activation by activating Nrf2, thereby affecting osteoclastogenesis. Tartrate-resistant acid phosphatase staining, F-actin ring staining and resorption pit assay suggested that isoquercitrin significantly inhibited osteoclastogenesis and osteolytic function. Mitosox staining showed that RANKL-induced ROS generation was significantly inhibited by isoquercitrin from day 3 of the osteoclast differentiation cycle. Quantitative real-time PCR, Western blot, and immunofluorescence indicated that isoquercitrin activated the Nrf2 signaling pathway and inhibited NF-κB expression. And when we used the Nrf2-specific inhibitor ML385, the inhibition of NF-κB by isoquercitrin disappeared. Moreover, we found that Nrf2 is not uninvolved in RANKL-induced NF-κB activation and may be related to the timing of ROS regulation. When we limited isoquercitrin administration to 2 days, Nrf2 remained activated and the inhibition of NF-κB disappeared. In vivo experiments suggested that isoquercitrin attenuated RA modeling-induced bone loss. Overall, isoquercitrin-activated Nrf2 blocked the RANKL-induced ROS-to-NF-κB signaling cascade response, thereby inhibiting osteoclastogenesis and bone loss. These findings provide new ideas for the treatment of RA.

The human gut is a reservoir of antibiotic resistance genes (ARGs). Even in the absence of antibiotics, ARGs are present in large quantities in faeces of adults, children and even newborns. However, where and when ARGs are acquired remains unclear, as does the types of ARGs acquired. Herein, we recruited 82 pairs of women and their caesarean section newborns. Conventional culture methods and quantitative PCR were employed to detect nine species and six ARG types in meconia, faeces from 3-day-old newborns, amniotic fluid, colostrum, and hospital ward air samples. Furthermore, ARG transfer was explored by tracking Staphylococcus epidermidis isolated from faeces of 3-day-old newborns, colostrum and ward air samples using multi-locus sequence typing (MLST). No ARGs or microorganisms were detected in meconia or amniotic fluid. One or more ARGs were detected in 90.2% of faeces from 3-day-old newborns, and the mecA gene exhibited the highest detection rate (45.1%). ARGs were detected in 85.4% of colostra consistent with ARGs in faeces from 3-day-old newborns. Some ARGs were detected in ward air, and might also be a source of ARGs in neonatal faeces. Isolation of S. epidermidis from neonatal faeces was consistent with antibiotic resistance and gene profiles for colostrum samples. Traceability analysis of S. epidermidis showed that ARGs in neonatal faeces mainly originated from colostrum, and partly from ward air. After birth, neonates born by caesarean section obtain a variety of ARGs mainly from colostrum, and partly from ward air.

Hypoxia at high-altitude leads to osteoporosis. Resveratrol (RES), as an antioxidant, has been reported to promote osteoblastogenesis and suppress osteoclastogenesis. However, the therapeutic effect of RES against osteoporosis induced by high-altitude hypoxia remains unclear. Thus, this study was intended to investigate the potential effects of RES on high-altitude hypoxia-induced osteoporosis both in vivo and in vitro. Male Wistar rats were given RES (400 mg/kg) once daily for nine weeks under hypoxia, while the control was allowed to grow under normoxia. Bone mineral density (BMD), the levels of bone metabolism-related markers, and the changes on a histological level were measured. Bone marrow-derived mesenchymal stem cells (BMSCs) and RAW264.7 were incubated with RES under hypoxia, with a control growing under normoxia, followed by the evaluation of proliferation and differentiation. The results showed that RES inhibited high-altitude hypoxia-induced reduction in BMD, enhanced alkaline phosphatase (ALP), osteocalcin (OCN), calcitonin (CT) and runt-related transcription factor 2 (RUNX2) levels, whereas it reduced cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I) levels and tartrate-resistant acid phosphatase (TRAP) activity in vivo. In addition, RES attenuated histological deteriorations in the femurs. In vitro, RES promoted osteoblastogenesis and mineralization in hypoxia-exposed BMSCs, along with promotion in RUNX2, ALP, OCN and osteopontin (OPN) levels, and inhibited the proliferation and osteoclastogenesis of RAW264.7. The promotion effects of RES on osteoblastogenesis were accompanied by the down-regulation of reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) induced by hypoxia. These results demonstrate that RES can alleviate high-altitude hypoxia-induced osteoporosis via promoting osteoblastogenesis by suppressing the ROS/HIF-1α signaling pathway. Thus, we suggest that RES might be a potential treatment with minimal side effects to protect against high-altitude hypoxia-induced osteoporosis.

Benzene can impair peripheral immunity and immune organs; however, the recovery of benzene impairment has rarely been reported. In this study, we developed an immune dysfunction mouse model using a benzene gavage (500 mg/kg). Female Balb/c mice were treated with Bombyx batryticatus (BB, 5 g/kg), raw pinellia (RP, 5 g/kg), or a combination of Valproic acid and Coenzyme Q10 (CM, 150 mg/kg VPA & 100 mg/kg CoQ10) medication for four weeks. The immune function of the peripheral blood mononuclear cells (PBMCs), spleen, and thymus was determined to evaluate whether the observed impairment could be altered by medications in the mouse model. Results showed that medications could alleviate benzene-induced structural and functional damage of spleen and thymus. Benzene exposure decreased the ATP level of PBMC, which can be improved by BB, RP or CM. Importantly, BB, RP or CM could relieve benzene induced-oxidative stress by increasing the activities of glutathione peroxidase (GSH) and superoxide dismutase (SOD) and decreasing the contents of malondialdehyde (MDA). In conclusion, BB, RP, and CM were able to alleviate the benzene-induced immune dysfunction and redox imbalance. Improvement of the oxidative and antioxidant imbalance may represent a mechanism by which medicine prevents benzene-induced immune dysfunction.

The prevalence of various antibiotic resistance genes (ARGs) and resistant bacteria has caused global public health risks. The carrier transport mediated by phages or membrane vesicles is an important way for horizontal transfer of ARGs. Nano metal oxide particles (NMOPs), which can enter cell through the cell membrane, may be used as the carriers of genes. However, whether they can be used as transmembrane delivery vectors for the horizontal ARG transfer remains unknown. Here, we set up a model of MONPs-mediated transfer of ARGs, and demonstrate that NMOPs, especially for nano-Al2O3, can act as carriers mediating the transduction-like ARG transformation in water. The highest transfer rate mediated by nano-Al2O3 is 4.53 × 104 cfu/mmol, and it is 104 times higher than that of control. Nano-Al2O3 can combine with plasmid coding for ARGs to form high-density package and prevent ARGs from degradation by endonuclease. The results of superresolution fluorescence microscopy and transmission electron microscopy show that nano-Al2O3 can carry ARGs for transmembrane transport. Genome-wide transcription microarray and qPCR indicate that SOS response was closely related to transduction-like ARG transformation mediated by nano-Al2O3. This study is the first to demonstrate that as a new transmembrane carrier, nano-Al2O3 can also cause ARGs diffusion in water.