Objective To explore the effects of dodecanoylcarnitine(DA)and myristoleic acid(MA)on the function of mouse alveolar epithelial cell line MLE-12 and their underlying mechanisms.Methods An inflammatory model was established by stimulating MLE-12 cells with IL-4.The expression levels of DA,MA,and sphingosine-1-phosphate(S1P)in the cell supernatant were detected by ELISA.MLE-12 cells were separately intervened with DA and MA.RT-PCR and flow cytometry were used to detect the expression changes of inflammatory factors IL-6 and tumor necrosis factor-α(TNF-α)and the level of intracellular reactive oxygen species(ROS).Additionally,Western blot was performed to detect the expression of key proteins such as p38 mitogen-activated protein kinase(p-38 MAPK)and src homology 2 domain-containing phosphatase 1(SHP-1).To explore the role of S1PR2 in the effects of DA and MA,MLE-12 cells were pretreated with the S1PR2 inhibitor JTE-013,and the above experiments were repeated.Results IL-4 stimulation significantly upregulated the levels of DA,MA,and S1P in MLE-12 cells(P<0.05).DA/MA treatment groups exhibited significantly increased expression of IL-6 and TNF-α compared with the control group(P<0.05),along with elevated ROS levels(P<0.05).Western blot analysis revealed that DA/MA promoted SHP-1 dephosphorylation and phosphorylated p38 MAPK activation in MLE-12 cells.Notably,JTE-013 pre-treatment completely reversed these effects(P<0.05).Conclusion Asthma-related metabolites DA and MA exacerbate the inflammatory and oxidative stress responses of MLE-12 cells by activating the S1PR2 receptor,promoting the dephosphorylation of SHP-1 and the activation of the p-p38 MAPK pathway.This study reveals the core regulatory role of S1PR2 in this pathway as well.

Objective:To compare the safety and efficacy of 3D-printed porous bioceramic artificial bone and artificial bone substitutes in the treatment of limb bone defects.Methods:A total of 220 patients with post-traumatic limb bone defects admitted to Xijing Hospital Affiliated to Air Force Medical University of the Chinese People's Liberation Army (34 cases), the Third Hospital of Hebei Medical University (60 cases), Xi'an Honghui Hospital (28 cases), the Third Hospital of Southern Medical University (18 cases), Changsha Third Hospital (28 cases), Foshan Traditional Chinese Medicine Hospital (16 cases), Foshan Fuxing Chancheng Hospital (12 cases), and Henan Provincial Orthopaedic Hospital (24 cases) from May 2022 to October 2023 were included as research subjects. According to the manufacturing method of the bone graft material, the subjects were randomly divided into the 3D printed porous bioceramic artificial bone group (3D printing group) and the artificial bone substitute group (non-3D printing group) at a ratio of 1:1 by the envelope method. Adverse events that might be related to the surgery were selected through correlation evaluation and classified as abnormal laboratory indicators, systemic or other site symptoms and abnormalities, and local symptoms and abnormalities of the affected limb. The safety of the two groups was compared. The bone graft fusion rate, bone defect repair and healing rate, and short form 12 (SF-12) score of the two groups were calculated to evaluate the postoperative recovery.Results:Thirty-two cases were excluded (4 cases refused to use their data after reconsideration, 7 cases were not used after preoperative assessment, and 21 cases exceeded the standard for body mass index and laboratory indicators upon re-examination). A total of 188 cases were randomly divided into the 3D printing group and the non-3D printing group according to the random method, with 94 cases in each group. Among them, 11 cases in the 3D printing group and 9 cases in the non-3D printing group dropped out due to loss to follow-up. Finally, 168 cases completed the follow-up, including 83 cases in the 3D printing group and 85 cases in the non-3D printing group. In the 3D printing group, there were 53 males and 30 females, with an average age of 47.9±12.7 years; in the non-3D printing group, there were 53 males and 32 females, with an average age of 48.6±12.9 years. A total of 51 cases in the two groups experienced adverse events related to the surgery, including 13 cases of abnormal laboratory indicators (5 cases in the 3D printing group and 8 cases in the non-3D printing group), 15 cases of systemic or other site symptoms and abnormalities (9 cases in the 3D printing group and 6 cases in the non-3D printing group), and 23 cases of local symptoms and abnormalities of the affected limb (13 cases in the 3D printing group and 10 cases in the non-3D printing group). There was no statistically significant difference in the incidence of adverse events between the two groups ( P>0.05). The bone graft fusion rates of the 3D printing group and the non-3D printing group at 6 months after surgery were 99%(82/83) and 99%(84/85), respectively, and the bone defect repair and healing rates were 89%(74/83) and 89%(76/85), respectively. At the time of 12 months after surgery, the bone graft fusion rates were 99%(82/83) and 99%(84/85), respectively, and the bone defect repair and healing rates were 94%(78/83) and 92%(78/85), respectively. There was no statistically significant difference in the bone graft fusion rate and bone defect repair and healing rate between the two groups ( P>0.05). The SF-12 scores during the screening period were 27.82±2.96 points and 27.22±4.23 points in the 3D printing group and the non-3D printing group, respectively, and at 3 months after surgery were 28.08±3.13 points and 27.64±3.16 points, at 6 months after surgery were 29.42±3.10 points and 28.55±3.45 points, and at 12 months after surgery were 29.78±2.80 points and 29.58±2.94 points, respectively. There was no statistically significant difference between the groups ( P>0.05). Both groups of surgeries were successfully completed without any serious surgical or bone graft-related complications. Conclusion:The safety and efficacy of 3D-printed porous bioceramic artificial bone in the treatment of limb bone defects are not significantly different from those of currently clinically applied artificial bone substitutes.

Diabetic nephropathy(DN)is a serious complication of diabetes mellitus and a leading cause of end-stage renal diseases.In DN patients,key pathological mechanisms include proteinuria,glomerulo-sclerosis,and fibrosis,largely driven by poor glycemic control and oxidative stress caused by prolonged hyperglycemia.This stress damages renal podocytes and triggers inflammatory mesenchymal infiltration of renal tubular cells,exacerbating the progression of proteinuria and fibrosis.Human umbilical cord-de-rived mesenchymal stem cells(hUC-MSCs)offer promising potential for treating DN due to their strong anti-oxidative properties.In this study,we developed a DN mouse model and treated the mouse via tail vein injections of hUC-MSCs(1×106 cells/mouse).The results indicated that hUC-MSCs significantly lowered fasting blood glucose levels(22.5±3.0 vs 14.7±1.1,P＜0.01)and improved glucose toler-ance,as shown by intraperitoneal glucose tolerance test(IPGTT)results(P＜0.05).Additionally,the renal function improved in hUC-MSCs-treated mice,with marked reductions in oxidative stress markers,including blood urea nitrogen(BUN),urinary creatinine(Ucr),urinary protein(PRO),superoxide dismutase(SOD),and malondialdehyde(MDA)(P＜0.05).Histological analyses through hematoxy-lin-eosin(H&E),Periodic Acid-Schiff(PAS),and Sirius red staining demonstrated alleviation of glo-merular mesangial hyperplasia,glomerular hypertrophy,and tubular inflammation.Furthermore,hUC-MSCs treatment downregulated the expression of oxidative stress-related proteins,such as NADPH oxi-dase 4(NOX4)and thioredoxin-interacting protein(TXNIP),and reduced reactive oxygen species(ROS)production(P＜0.05).Meanwhile,human renal cortical proximal tubule epithelial cells(HK-2 cells)were selected for validation in vitro experiments using high glucose treatment followed by super-natants of hUC-MSCs(MSC-CM),and Western blotting showed that the expression of both NOX4 and TXNIP was inhibited(P＜0.05)and ROS expression was reduced.In conclusion,hUC-MSC treatment effectively lowered blood glucose levels and improved renal function in DN mice,likely through the sup-pression of NOX4 expression and TXNIP-mediated oxidative stress.

This study aims to explore the scientific connotation of sinking Rehmanniae Radix has the best quality and compare the quality between floating and sinking fresh Rehmanniae Radix samples. Ultra-performance liquid chromatography tandem quadrupole electrostatic field Orbitrap high-resolution mass spectrometry(UHPLC-Q-Orbitrap HRMS) was employed to detect the chemical components in floating and sinking fresh Rehmanniae Radix samples. The fingerprint of fresh Rehmanniae Radix was established by high performance liquid chromatography(HPLC), and four index components were determined simultaneously. The cluster analysis, principal component analysis(PCA), and orthogonal partial least squares-discriminant analysis(OPLS-DA) were conducted to compare the quality of floating and sinking fresh Rehmanniae Radix samples. An evaporative light-scattering detector was used to compare the content of five sugars. The extract yield and drying rate were determined, and the quality connotation of sinking Rehmanniae Radix has the best quality was explained by multiple indicators. A total of 41 components were preliminarily identified from fresh Rehmanniae Radix by UHPLC-Q-Orbitrap HRMS, including 7 iridoid glycosides, 9 phenylethanol glycosides, 6 amino acids, 4 sugars, 3 phenolic acids, 5 nucleosides, 3 organic acids, 1 ionone, 1 furan, 1 coumarin, and 1 phenylpropanoid. The results showed that the main chemical components were consistent between floating and sinking fresh Rehmanniae Radix. Nine common peaks were identified in the fingerprints of 15 batches of floating and sinking fresh Rehmanniae Radix samples, and the similarity of fingerprints was greater than 0.9. The cluster analysis, PCA, and OPLS-DA classified floating and sinking fresh Rehmanniae Radix sasmples into two categories, indicating differences in the quality between them. The total content of catalpol, rehmannioside D, ajugol, and verbascoside in sinking fresh Rehmanniae Radix samples was higher than that in floating samples of the same batch and specification, and the main differential component was catalpol. The total content of fructose, glucose, sucrose, raffinose, and stachyose in sinking fresh Rehmanniae Radix samples was higher than that in floating samples of the same batch and specification, and the main differential component was stachyose. The extract yield and drying rate of the sinking samples were higher than those of floating samples. This study preliminarily showed that floating and sinking fresh Rehmanniae Radix samples had the same components but great differences in the content of medicinal substance basis. The total content of four glycosides and five sugars, extract yield, and drying rate of sinking fresh Rehmanniae Radix samples is higher than that of floating samples of the same batch and specification. These findings, to a certain extent, explains the scientificity of sinking Rehmanniae Radix has the best quality recorded in ancient books and provide a reference for the quality control and clinical application of fresh Rehmanniae Radix.
Chromatography, High Pressure Liquid/methods* ; Drugs, Chinese Herbal/chemistry* ; Rehmannia/chemistry* ; Chemometrics ; Mass Spectrometry/methods* ; Quality Control ; Principal Component Analysis ; Plant Extracts

This study aims to investigate the effect of Chaijin Jieyu Anshen Formula on the neuroinflammation of rats with insomnia complicated with depression through the regulation of triggering receptor expressed on myeloid cells 2(TREM2)/complement protein C1q signaling pathway. Rats were randomly divided into a normal group, a model group, a positive drug group, as well as a high, medium, and low-dose groups of Chaijin Jieyu Anshen Formula, with 10 rats in each group. Except for the normal group, the other groups were injected with p-chlorophenylalanine and exposed to chronic unpredictable mild stress to establish the rat model of insomnia complicated with depression. The sucrose preference experiment, open field experiment, and water maze test were performed to evaluate the depression in rats. Enzyme-linked immunosorbent assay was employed to detect serum 5-hydroxytryptamine(5-HT), dopamine(DA), and norepinephrine(NE) levels. Hematoxylin and eosin staining and Nissl staining were used to observe the damage in nucleus accumbens neurons. Western blot and immunofluorescence were performed to detect TREM2, C1q, postsynaptic density 95(PSD-95), and synaptophysin 1(SYN1) expressions in rat nucleus accumbens, respectively. Golgi-Cox staining was utilized to observe the synaptic spine density of nucleus accumbens neurons. The results show that, compared with the model group, Chaijin Jieyu Anshen Formula can significantly increase the sucrose preference as well as the distance and number of voluntary activities, shorten the immobility time in forced swimming test and the successful incubation period of positioning navigation, and prolong the stay time of space exploration in the target quadrant test. The serum 5-HT, DA, and NE contents in the model group are significantly lower than those in the normal group, with the above contents significantly increased after the intervention of Chaijin Jieyu Anshen Formula. In addition, Chaijin Jieyu Anshen Formula can alleviate pathological damages such as swelling and loose arrangement of tissue cells in the nucleus accumbens, while increasing the Nissl body numbers. Chaijin Jieyu Anshen Formula can improve synaptic damage in the nucleus accumbens and increase the synaptic spine density. Compared to the normal group, the expression of C1q protein was significantly higher in the model group, while the expression of TREM2 protein was significantly lower. Compared to the model group, the intervention with Chaijin Jieyu Anshen Formula significantly downregulated the expression of C1q protein and significantly upregulated the expression of TREM2. Compared with the model group, the PSD-95 and SYN1 fluorescence intensity is significantly increased in the groups receiving different doses of Chaijin Jieyu Anshen Formula. In summary, Chaijin Jieyu Anshen Formula can reduce the C1q protein expression, relieve the TREM2 inhibition, and promote the synapse-related proteins PSD-95 and SNY1 expression. Chaijin Jieyu Anshen Formula improves synaptic injury of the nucleus accumbens neurons, thereby treating insomnia complicated with depression.
Animals ; Male ; Rats ; Nucleus Accumbens/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Depression/complications* ; Membrane Glycoproteins/genetics* ; Rats, Sprague-Dawley ; Sleep Initiation and Maintenance Disorders/complications* ; Neurons/metabolism* ; Receptors, Immunologic/genetics* ; Signal Transduction/drug effects* ; Synapses/metabolism*

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

As global greenhouse gases continue rising, the urgency of more ambitious action is clearer than ever before. China is the world's biggest emitter of greenhouse gases and one of the countries affected most by climate change. The evidence about the impacts of climate change on the environment and human health may encourage China to take more decisive action to mitigate greenhouse gas emissions and adapt to climate impacts. This article aimed to review the evidence of environmental damages and health risks posed by climate change and to provide a new science-based perspective for the delivery of sustainable development goals. Over recent decades, China has experienced a strong warming pattern with a growing frequency of extreme weather events, and the impacts of climate change on China's environment and human health have been consistently observed, with increasing O ₃ air pollution, decreases in water resources and availability, land degradation, and increased risks for both communicable and non-communicable diseases. Therefore, China's climate policy should target the key factors driving climate change and scale up strategic measures to curb carbon emissions and adapt to inevitable increasing climate impacts. It provides new insights for not only China but also other countries, particularly developing and emerging economies, to ensure climate and environmental sustainability whilst pursuing economic growth.
Climate Change ; China ; Humans ; Greenhouse Gases ; Air Pollution ; Sustainable Development ; Environment

BACKGROUND: Lead is a persistent inorganic environmental pollutant with global implication for human health. Among the diseases associated with lead exposure, the damage to the central nervous system has received considerable attention. It has been reported that long-term lead exposure increases the risk of meningioma; however, the underlying mechanism remains poorly understood. Clinical studies have indicated that loss-of-function and mutations in the neurofibromin-2 (NF2) gene play a crucial role in promoting meningioma formation. METHODS: The effect of Pb on meningioma were tested in-vitro and in-vivo. Two human meningioma cell lines were used in this study, including NF2-wildtype IOMM-Lee cell and NF2-null CH157-MN cell. Cell viability, cell cycle and cell size were examined after Pb exposure. The expression of Merlin, mammalian sterile 20-like kinases 1 and 2 (MST1/2) and Yes-associated protein (YAP) from these two meningioma cells were analyzed by Western blot. A xenograft mouse model was constructed by subcutaneous injection of IOMM-Lee meningioma cells. RESULTS: This study demonstrated that treatment with lead induce dose-dependent proliferation in IOMM-Lee cell (with an EC₅₀ value of 19.6 µM). Moreover, IOMM-Lee cell exhibited augmented cell size in conjunction with elevated levels of phosphorylated histone H3, indicative of altered cell cycle progression resulting from lead exposure. However, no significant change was observed in the CH157-MN cell. Additionally, the Merlin-Hippo signaling pathway was inactivated with decreased Merlin and phosphorylation levels of MST1/2 and YAP, leading to increased YAP nuclear translocation in IOMM-Lee cells. However, there was no change in the Merlin-Hippo signaling pathway in CH157-MN cells after lead treatment. The administration of Pb resulted in an acceleration of the subcutaneous IOMM-Lee meningioma xenograft growth in mice. CONCLUSIONS Overall, the current study elucidates the potential mechanism by which lead exposure promotes the proliferation of meningioma with NF2 expression for the first time.
Meningioma/genetics* ; Neurofibromin 2/genetics* ; Humans ; Cell Proliferation/drug effects* ; Animals ; Signal Transduction/drug effects* ; Mice ; Hippo Signaling Pathway ; Lead/adverse effects* ; Cell Line, Tumor ; Protein Serine-Threonine Kinases/genetics* ; Meningeal Neoplasms ; Environmental Pollutants/adverse effects* ; Female