Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.

NQO1 Mediates Lenvatinib Resistance by Regulating ROS-induced Apoptosis in Hepatocellular Carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide. As a first-line drug for advanced HCC treatment, lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients, and the underlying mechanism remains largely unknown. The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC, explore the potential molecular mechanism, and propose combinatorial therapeutic targets for HCC management. METHODS: Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol. RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant (LR) cells. The upregulated genes were analyzed by GO and KEGG analyses. Then, qPCR and Western blotting were employed to determine the relative gene expression levels. Afterwards, the intracellular reactive oxygen species (ROS) and apoptosis were detected by flow cytometry. RESULTS: PLC-LR and Hep3B-LR were established. There was a total of 116 significantly upregulated genes common to both LR cell lines. The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities, and reactive oxygen species pathways. Notably, NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in LR cells, and was involved in the lenvatinib resistance. The high expression of NQO1 decreased the production of ROS induced by lenvatinib, and subsequently suppressed the apoptosis. The combination of lenvatinib and NQO1 inhibitor, dicoumarol, reversed the resistance of LR cells. CONCLUSION: The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels, thereby promoting lenvatinib resistance in HCC cells.

Protective Effects and Mechanism of Polysaccharides from Edible Medicinal Plants in Alcoholic Liver Injury: A Review.

Alcohol use accounts for a large variety of diseases, among which alcoholic liver injury (ALI) poses a serious threat to human health. In order to overcome the limitations of chemotherapeutic agents, some natural constituents, especially polysaccharides from edible medicinal plants (PEMPs), have been applied for the prevention and treatment of ALI. In this review, the protective effects of PEMPs on acute, subacute, subchronic, and chronic ALI are summarized. The pathogenesis of alcoholic liver injury is analyzed. The structure-activity relationship (SAR) and safety of PEMPs are discussed. In addition, the mechanism underlying the hepatoprotective activity of polysaccharides from edible medicinal plants is explored. PEMPs with hepatoprotective activities mainly belong to the families Orchidaceae, Solanaceae, and Liliaceae. The possible mechanisms of PEMPs include activating enzymes related to alcohol metabolism, attenuating damage from oxidative stress, regulating cytokines, inhibiting the apoptosis of hepatocytes, improving mitochondrial function, and regulating the gut microbiota. Strategies for further research into the practical application of PEMPs for ALI are proposed. Future studies on the mechanism of action of PEMPs will need to focus more on the utilization of multi-omics approaches, such as proteomics, epigenomics, and lipidomics.

Ultrasound-Microwave Combined Extraction of Novel Polysaccharide Fractions from Lycium barbarum Leaves and Their In Vitro Hypoglycemic and Antioxidant Activities.

Ultrasound-microwave combined extraction (UMCE), gradient ethanol precipitation, chemical characterization, and antioxidant and hypoglycemic activities of Lycium barbarum leaf polysaccharides (LLP) were systematically studied. The optimal conditions for UMCE of LLP achieved by response surface method (RSM) were as follows: microwave time of 16 min, ultrasonic time of 20 min, particle size of 100 mesh, and ratio of liquid to solid of 55:1. Three novel polysaccharide fractions (LLP30, LLP50, LLP70) with different molecular weights were obtained by gradient ethanol precipitation. Polysaccharide samples exhibited scavenging capacities against ABTS and DPPH radicals and inhibitory activities against α-glucosidase and α-amylase. Among the three fractions, LLP30 possessed relatively high antioxidant and hypoglycemic activities in vitro, which showed a potential for becoming a nutraceutical or a phytopharmaceutical for prevention and treatment of hyperglycemia or diabetes.

Effects of Se-enriched Chrysanthemum morifolium on lifespan and antioxidant defense-related gene expression of Drosophila melanogaster model.

Chrysanthemum morifolium is a well-known edible medicinal plant in Asia and some other regions. Content of selenium in Se-enriched C. morifolium (SeCM) is significantly higher than that in traditional C. morifolium (non-Se-enriched C. morifolium, TCM). In order to understand health effects of SeCM, its chemical composition, lifespan-prolonging activities, and impacts on antioxidant defense-related gene expressions of model organism D. melanogaster were systematically studied. A total of eight phenols, including luteolin-7-O-glucoside, linarin, luteolin, apigenin, diosmetin, acacetin, 3-caffeoylquinic acid and 4,5-dicaffeoylquinic acid, were identified in SeCM extract. Compared with TCM, SeCM exhibited superior antioxidant properties. Intake of SeCM dramatically reduced malondialdehyde level and increased activities of endogenous antioxidant enzymes in fruit flies. SeCM was able to upregulate gene expressions of Cu/Zn-superoxide dismutase, Mn-superoxide dismutase and hydrogen peroxide catalase, and extend lifespans of fruit flies. Comparatively high antioxidant capacities and lifespan-prolonging activities of SeCM might be attributed to its abundant phenols and selenium, which probably ameliorated accumulation of free radicals and susceptibility to oxidative stress. These findings provide clues on further exploitation and utilization of Se-enriched C. morifolium. PRACTICAL APPLICATIONS: Chrysanthemum morifolium has been used for nutraceutical and curative purposes in China for thousands of years. Se-enriched C. morifolium typically contains more selenium than traditional C. morifolium, and is widely consumed in Asia and some other regions. Selenium is an essential micronutrient for humans, and selenium deficiency may result in several diseases such as myocardial infarction. SeCM is one of important selenium supplements. In this study, SeCM was found to upregulate gene expressions of Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and hydrogen peroxide catalase, and extend lifespans of experimental animals. These results provide supporting information for developing SeCM-based functional foods with distinct health benefits.

Cancer metabolism and tumor microenvironment: fostering each other?

The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.

Chemical Structure, Hypoglycemic Activity, and Mechanism of Action of Selenium Polysaccharides.

Selenium polysaccharides (Se-polysaccharides) are one of important forms of organic Se, in which selenium (Se) and polysaccharides are joined by covalent bonds. In the present review, recent progress in chemical structure and hypoglycemic activity of Se-polysaccharides is summarized. In particular, the mechanism underlying hypoglycemic capacity of Se-polysaccharides is discussed, and the relationship between hypoglycemic activity and chemical structure is analyzed. Besides, strategies for further research into chemical structure and hypoglycemic activity of Se-polysaccharides are proposed. Hypoglycemic activity of Se-polysaccharides is closely related to their inhibitory effect on α-amylase and α-glucosidase, influence on insulin signal pathway especially IRS-PI3K-Akt signaling pathway, and protection capacity against oxidative stress.

Oxidative Stress Induced Osteocyte Apoptosis in Steroid-Induced Femoral Head Necrosis.

OBJECTIVE: To investigate the effect and mechanism of Glucocorticoids (GCs) induced oxidative stress and apoptosis on necrosis of the femoral head in patients and rats. METHODS: Eight patients with steroid-induced avascular necrosis of the femoral head (SINFH) and eight patients with developmental dysplasia of the hips (DDH) were enrolled in our study. In animal model, twenty male Sprague-Dawley rats were randomly divided into two groups (SINFH group and NS group). The SINFH model group received the methylprednisolone (MPS) injection, while control group was injected with normal saline (NS). MRI was used to confirm SINFH rat model was established successfully. Then, the rats were sacrificed 4 weeks later and femoral head samples were harvested. Histopathological staining was preformed to evaluate osteonecrosis. TUNEL staining was performed with 8-OHdG and DAPI immunofluorescence staining to evaluate oxidative injury and osteocyte apoptosis. Immunohistochemistry staining was used to detect Nox1, Nox2, and Nox4 protein expression. RESULTS: MRI showed signs of typical osteonecrosis of femoral head in SIHFH patients. Histopathological staining showed that the rate of empty lacunae in SINFH patients was significantly higher (56.88% ± 9.72% vs 19.92% ± 4.18%, T = -11.04, P < 0.001) than that in DDH patients. The immunofluorescence staining indicated that the TUNEL-positive cell and 8-OHdG-positve cell in SINFH patients were significantly higher (49.32% ± 12.95% vs 8.00% ± 2.11%, T = -7.04, P = 0.002, 54.6% ± 23.8% vs 9.75% ± 3.31%, T = -4.17, P = 0.003) compared to the DDH patients. The immunohistochemistry staining showed that the protein expression of NOX1, NOX2 and NOX4 in SINFH patients were significantly increased (64.50% ± 7.57% vs 37.58% ± 9.23%, T = -3.88, P = 0.018, 90.84% ± 2.93% vs 49.56% ± 16.47%, T = -5.46, P = 0.001, 85.46% ± 9.3% vs 40.69% ± 6.77%, T = -8.03, P = 0.001) compared to the DDH patients. In animal model, MRI showed signs of edema of femoral head in MPS group, which represents SINFH rat model was established successfully. Histological evaluation showed the rate of empty lacunae in MPS group was significantly higher (25.85% ± 4.68% vs 9.35% ± 1.99%, T = -7.96, P < 0.001) than that in NS group. The immunofluorescence staining indicated that the TUNEL-positive cell and 8-OHdG-positve cell (in MPS group were significantly increased (31.93% ± 1.01% vs 11.73% ± 1.16%, T = -32.26, P < 0.001, 47.59% ± 1.39% vs 22.07% ± 2.45%, T = -22.18, P < 0.001) compared to the NS group. The immunohistochemistry staining showed that the expression of NOX2 in MPS group was significantly increased (76.77% ± 8.34% vs 50.32% ± 10.84%, T = -4.74, P = 0.001) compare with NS group. CONCLUSION: Our findings indicated that GC-induced NOXs expression may be an important source of oxidative stress, which could lead to osteocyte apoptosis in the process of SINFH.

CaDHN3, a Pepper (Capsicum annuum L.) Dehydrin Gene Enhances the Tolerance against Salt and Drought Stresses by Reducing ROS Accumulation.

Dehydrins (DHNs) play an important role in abiotic stress tolerance in a large number of plants, but very little is known about the function of DHNs in pepper plants. Here, we isolated a Y1SK2-type DHN gene "CaDHN3" from pepper. To authenticate the function of CaDHN3 in salt and drought stresses, it was overexpressed in Arabidopsis and silenced in pepper through virus-induced gene silencing (VIGS). Sub-cellular localization showed that CaDHN3 was located in the nucleus and cell membrane. It was found that CaDHN3-overexpressed (OE) in Arabidopsis plants showed salt and drought tolerance phenotypic characteristics, i.e., increased the initial rooting length and germination rate, enhanced chlorophyll content, lowered the relative electrolyte leakage (REL) and malondialdehyde (MDA) content than the wild-type (WT) plants. Moreover, a substantial increase in the activities of antioxidant enzymes; including the superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ascorbate peroxidase (APX), and lower hydrogen peroxide (H2O2) contents and higher O2•- contents in the transgenic Arabidopsis plants. Silencing of CaDHN3 in pepper decreased the salt- and drought-stress tolerance, through a higher REL and MDA content, and there was more accumulation of reactive oxygen species (ROS) in the CaDHN3-silenced pepper plants than the control plants. Based on the yeast two-hybrid (Y2H) screening and Bimolecular Fluorescence Complementation (BiFC) results, we found that CaDHN3 interacts with CaHIRD11 protein in the plasma membrane. Correspondingly, the expressions of four osmotic-related genes were significantly up-regulated in the CaDHN3-overexpressed lines. In brief, our results manifested that CaDHN3 may play an important role in regulating the relative osmotic stress responses in plants through the ROS signaling pathway. The results of this study will provide a basis for further analyses of the function of DHN genes in pepper.

Obturator nerve impingement caused by an osteophyte in the sacroiliac joint: A case report.

BACKGROUND: Cases of obturator nerve impingement (ONI) caused by osteophytes resulting from bone hyperplasia on the sacroiliac articular surface have never been reported. This paper presents such a case in a patient in whom severe lower limb pain was caused by osteophyte compression of the sacroiliac joint on the obturator nerve. CASE SUMMARY: A 65-year-old Asian man presented with severe pain and numbness in his left lower limb, which became aggravated during walking and showed intermittent claudication. The physical examination revealed that the muscle strength of the left lower limb had decreased and that the passive knee flexion test result was positive. Computed tomography (CT) and 3D reconstruction showed a large osteophyte located in the anterior lower part of the left sacroiliac joint. The results of electrophysiological examination showed peripheral neuropathy. A CT-guided obturator nerve block significantly reduced the severity of pain in this patient. According to the above findings, ONI caused by the osteophyte in the sacroiliac joint was diagnosed. This patient underwent an operation to remove the bone spur and symptomatic treatment. After therapy, the patient's pain and numbness were significantly relieved. The last follow-up was performed 6 mo after the operation, and the patient recovered well without other complications, returned to work, and resumed his normal lifestyle. CONCLUSION: Osteophytes of the sacroiliac joint can cause ONI, which leads to symptoms including severe radiative pain in the lower limb in patients. The diagnosis and differentiation of this disease should attract the attention of clinicians. Surgical excision of osteophytes should be considered when conservative treatment is not effective.

Osteochondroma of the pubic symphysis causing hematuria: a case report and literature review.

BACKGROUND: Osteochondroma is the most common benign bone neoplasm and is sometimes referred to as osteocartilaginous exostosis. The symptoms caused by osteochondroma are rare, especially the urogenital complications. Therefore, this tumour is sometimes misdiagnosed. CASE PRESENTATION: This report described a 70-year-old woman with hematuria who was initially misdiagnosed with a bladder tumour in the outpatient department by a urologist. However, during cystoscopy, we found that the mass did not resemble a bladder tumor. Multidisciplinary approach with careful analysis of the imaging data suggested the diagnosis of osteochondroma. Open surgical excision of the mass was done and histology confirmed the diagnosis of benign osteochondroma. After 6 months of follow-up, the patient was still asymptomatic. CONCLUSIONS: This case illustrates that hematuria is caused by not only urogenital disease but also osteochondroma. We present this case to draw the attention of clinicians to osteochondroma of the pubic symphysis.

[Research on autophagy induced by two xanthone compounds in HepG2 cells].

To investigate the inhibitory effects of two xanthone compounds, 1-hydroxy-2,3,4,8-4 methoxy xanthone(here in after referred to as Fr15) and 1-hydroxy-2,3,4,6-4 methoxy xanthone(here in after referred to as Fr17), on the proliferation of hepatocellular carcinoma cells HepG2, and to further investigate their mechanism in combination with transcriptomics. Cell counting was used to detect the effects of two kinds of xanthone compounds Fr15 and Fr17(0, 0.03, 0.15, 0.3 mmoL·L~(-1)) on the proliferation of HepG2 cells; the effects of the two compounds Fr15 and Fr17 on HepG2 cell cycle were detected by flow cytometry; the changes of autophagosomes count in cells were observed under fluorescence microscope; the expression of autophagy marker proteins autophagy marker proteins SQSTM 1(p62) and microtubule associated protein 1 light chain 3 Ⅰ/Ⅱ(LC3 Ⅰ/Ⅱ) in the cells was detected by Western blot; the differentially expressed genes between the control group and the experimental group were analyzed by RNA-seq transcriptome sequencing; qRT-PCR was used to verify the differentially expressed genes in sequencing. The results showed that compounds Fr15 and Fr17 inhibited the proliferation of HepG2 cells with the increase of drug concentration and time. Flow cytometry showed that compounds Fr15 and Fr17 had little effect on HepG2 cell cycle. Fluorescence microscopy results showed that the number of autophagosomes in cells increased with the increase of drug concentration. Western blot showed that the expression of p62 protein was decreased and the expression of LC3-Ⅱ protein was significantly increased after drug addition. The results of RNA sequencing showed that 26 102 and 52 351 differentially expressed genes were obtained in Fr15 and Fr17 respectively. Analysis of KEGG showed that drug treatment had a great effect on autophagy pathway. qRT-PCR verified that 6 up-regulated genes were related to autophagy, and their trend was consis-tent with sequencing results, where all 6 genes showed an up-regulated trend. Two xanthone compounds Fr15 and Fr17 may inhibit proliferation of HepG2 cells by inducing autophagy.

The NAC transcription factor CaNAC064 is a regulator of cold stress tolerance in peppers.

NAC (NAM, ATAF1/2 and CUC2) proteins are plant-specific transcription factors (TFs) that are important in plant abiotic stress responses. In this study we isolated a NAC gene from Capsicum annuum leaves, designated as CaNAC064. We characterized the amino acid sequence of CaNAC064 and found that it contain conserved domains of the NAC family, including a highly conserved N-terminus domain and a highly variable C-terminus domain. Expression analysis showed that the 40C, 400C, salicylic acid (SA) and abscisic acid (ABA) treatments strongly induced the expression of CaNAC064 through silencing of CaNAC064 in pepper and overexpressing in Arabidopsis. CaNAC064-silenced pepper plants exhibited more serious wilting, higher MDA contents and chilling injury index, lower proline content, and more accumulation of ROS in the leaves after cold stress. The CaNAC064-overexpressing Arabidopsis plants exhibited lower MDA content, chilling injury index and relative electrolyte leakage content as compared to WT plants under cold stress. Transcriptional activation activity analysis indicated that CaNAC064 has transcriptional activation activity in the 691-1071 bp key region. We identified 45 proteins that putatively interact with CaNAC064 using the Yeast Two-Hybrid method. According to the Yeast Two-Hybrid and BIFC results, CaNAC064 interacted with low temperature-induced haplo-proteinase proteins in plant cell. These results suggested that CaNAC064 positively modulates plant cold-tolerance, laying the foundation for future investigations into the role of NACs as regulatory proteins of cold tolerance in plants.

CaDHN4, a Salt and Cold Stress-Responsive Dehydrin Gene from Pepper Decreases Abscisic Acid Sensitivity in Arabidopsis.

Dehydrins play an important role in improving plant resistance to abiotic stresses. In this study, we isolated a dehydrin gene from pepper (Capsicum annuum L.) leaves, designated as CaDHN4. Sub-cellular localization of CaDHN4 was to be found in the nucleus and membrane. To authenticate the function of CaDHN4 in cold- and salt-stress responses and abscisic acid (ABA) sensitivity, we reduced the CaDHN4 expression using virus-induced gene silencing (VIGS), and overexpressed the CaDHN4 in Arabidopsis. We found that silencing of CaDHN4 reduced the growth of pepper seedlings and CaDHN4-silenced plants exhibited more serious wilting, higher electrolyte leakage, and more accumulation of ROS in the leaves compared to pTRV2:00 plants after cold stress, and lower chlorophyll contents and higher electrolyte leakage compared to pTRV2:00 plants under salt stress. However, CaDHN4-overexpressing Arabidopsis plants had higher seed germination rates and post-germination primary root growth, compared to WT plants under salt stress. In response to cold and salt stresses, the CaDHN4-overexpressed Arabidopsis exhibited lower MDA content, and lower relative electrolyte leakage compared to the WT plants. Under ABA treatments, the fresh weight and germination rates of transgenic plants were higher than WT plants. The transgenic Arabidopsis expressing a CaDHN4 promoter displayed a more intense GUS staining than the normal growth conditions under treatment with hormones including ABA, methyl jasmonate (MeJA), and salicylic acid (SA). Our results suggest that CaDHN4 can protect against cold and salt stresses and decrease ABA sensitivity in Arabidopsis.

NADPH Oxidase Isoforms Are Involved in Glucocorticoid-Induced Preosteoblast Apoptosis.

Oxidative stress induced by long-term glucocorticoid (GC) use weakens the repair capacity of bone tissue. Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase (NOX) is a superoxide-generating enzyme that plays an important role in regulating bone metabolism. To clarify the role of nonphagocytic NOX isoforms in osteoblast reactive oxygen species (ROS) generation and apoptosis, dexamethasone was used to establish a high-dose GC environment in vitro. A dose-dependent increase in intracellular ROS generation was demonstrated, which was accompanied by increased osteoblastic MC3T3-E1 cell apoptosis. Addition of the ROS inhibitor NAC (N-acetyl-L-cysteine) or NOX inhibitor DPI (diphenyleneiodonium) reversed this effect, indicating that NOX-derived ROS can induce osteoblast apoptosis under high-dose dexamethasone stimulation. NOX1, NOX2, and NOX4 are NOX homologs recently identified in bone tissue. To clarify the NOX isoforms that play a role in osteoblast ROS generation, Nox1, Nox2, and Nox4 mRNA expression and NOX2 and NOX4 protein expression were analyzed. Nox1 and Nox4 mRNA expression was elevated in a dose-dependent manner after culture in 100 nM, 250 nM, 500 nM, or 1000 nM dexamethasone, and the increased expression of NOX1 mRNA was more significant compared with NOX4 mRNA. Small interfering RNAs (siRNAs) were used to confirm the role of NOX1 and NOX4 in ROS generation. To clarify the signaling pathway in ROS-induced osteoblast apoptosis, mitogen-activated protein kinase (MAPK) signaling molecules were analyzed. Phosphorylated ASK1 and p38 levels were significantly higher in the 1000 nM dexamethasone group, which NAC or DPI markedly attenuated. However, the total mRNA and protein levels of ASK1 and p38 between the dexamethasone group and control were not significantly different. This is related to ROS regulating the posttranslational modification of ASK1 and p38 in MC3T3-E1 cell apoptosis. Altogether, NOX1- and NOX4-derived ROS plays a pivotal role in high-dose dexamethasone-induced preosteoblast apoptosis by increasing phosphorylated ASK1 and p38 and may be an important mechanism in steroid-induced avascular necrosis of the femoral head (SANFH).

Fabrication of a cost effective and broadband self-powered photodetector based on Sb2Te3 and silicon.

The excellent conductive surface electronic states of topological insulators make them suitable candidates for the next generation optoelectronic devices. Moreover, their unique semiconducting properties are favorable for building heterojunctions with other semiconductors. Here, we fabricated a low cost and broadband self-powered photodetector based on Sb2Te3 and Si. The photolithography and thermal evaporation technique were combined to fabricate a series of asymmetric planar Sb2Te3 electrodes on the surface of an n-type silicon substrate. An obvious asymmetrical current voltage curve occurred under dark conditions, which is ascribed to the asymmetry of each electrode. During the photodetection test, self-powered photodetection was obtained upon 940 nm light irradiation. Moreover, the photodetector exhibited fast and broadband photodetection from 365 nm to 940 nm with a response time less than 40 ms.

[Correlation of the grades of histologic prostatic inflammation with the risk of prostate cancer in biopsy specimens from men with total PSA of 4－10 µg/L].

OBJECTIVE: To investigate the association of the grades of histologic prostatic inflammation (HPI) with prostate cancer in biopsy specimens for male patients with total serum PSA (tPSA) of 4－10 µg/L. METHODS: We performed prostate biopsy for 200 patients with tPSA of 4－10 µg/L from January 2015 to December 2017. We determined the location, extent and intensity of HPI and analyzed the correlation of the grades of HPI with the risk of prostate cancer. RESULTS: Of the 200 biopsy specimens, BPH was detected in 169 (84.5%) and PCa in 31 (15.5%). Statistically significant differences were found in the positive rates of PCa between grades 1, 2 and 3 HPI, which were 19.3%, 25.8% and 54.8% based on the location (P < 0.01), 77.4%, 19.4% and 3.2% based on the extent (P < 0.01), and 51.6%, 29.0% and 19.4% based on the intensity of the lesion (P < 0.01), but not in the positive rates of BPH (P > 0.05). Multivariate logistic regression analysis showed that the risk of PCa was correlated negatively with the location (95% CI: 0.052－0.407, OR = 0.113, P = 0.001, r = －2.078) and extent of HPI (95% CI: 0.068－0.819, OR = 0.231, P = 0.023, r = －1.526) but not correlated with its intensity (95% CI: 0.796－4.193, OR = 1.804, P = 0.215). The positive predictive value, negative predictive value, sensitivity and specificity of the combined application of the location and extent of HPI in differentiating PCa from BPH were 51.2%, 90.3%, 91.5% and 50.8%, respectively. CONCLUSIONS: The location and extent of HPI are negatively while its intensity is not correlated with the risk of PCa. The grading of HPI based on its location and extent could help reduce the repetition of prostate biopsy.

[Spatial Variation of Heavy Metals in Soils and Its Ecological Risk Evaluation in a Typical Carya cathayensis Production Area].

In recent years, the problem of soil pollution has become more and more serious. The problem of soil heavy metal pollution and its related human health risks has become a hot spot at home and abroad. Carya cathayensis is a unique high-grade woody nut and oil tree from China, and there are few reports on heavy metal pollution in Carya cathayensis plantation soils. Therefore, in order to study the spatial variability of heavy metals and the risk of pollution in Carya cathayensis soil and to promote the sustainable development of the Carya cathayensis industry, Lin'an, a typical Carya cathayensis plantation area, was selected for this study. A total of 188 soil samples were collected from the study area. We systematically studied the spatial heterogeneity of soil heavy metal content in the study area based on GIS technology, geostatistics, Moran's I, and other spatial analysis methods. The single factor pollution index method, the Nemerow comprehensive pollution index method, and the potential ecological risk assessment method were used to evaluate the heavy metal pollution in the study area. The results indicated that the mean content of soil cadmium (Cd), copper (Cu), zinc (Zn), lead (Pb), nickel (Ni), and chromium (Cr) were 0.37, 40.76, 87.61, 30.10, 28.33, 56.57 mg·kg-1, respectively. The average values of Cd and Cu were 1.33 and 2.87 times of the background values, respectively, and the average content of other heavy metals did not exceed the background values. The results of the single factor Nemerow pollution index and potential ecological risk assessment methods showed that heavy metals in the study area exceeded the soil background values in some samples, and the second grade standard of soil environmental quality was exceed for Cd, Cu, Zn, Pb, and Ni in 31.38%, 31.38%, 2.65%, 0.53%, and 17.02% of the samples, respectively. This indicated that the soils in the study area had different accumulation characteristics for Cd, Cu, Zn, Pb, Ni, and Cr, and the local soil had reached pollution levels for Cd, Cu, Zn, Pb, and Ni. Among them, Cd was the most serious, reaching the degree of strong ecological damage, followed by Cu. In general, the heavy metal contents indicated a moderate degree of ecological damage. Based on the analysis of the semi-variance function, the Cd, Cu, and Ni in the soil were best fit with exponential models, the Zn and Pb were better fit with the Gaussian model, and Cr was consistent with the spherical model. Cd, Cu, Pb, Ni, and Cr had the strong spatial autocorrelation, with Nugget/Sill ratios of 12.1%, 4.6%, 14.9%, 2.6%, and 11.2%, respectively, while the Nugget/Sill ratio of Zn was 48.8%, indicating a medium spatial autocorrelation. Moran's I and Kriging interpolation results found that the heavy metals Cd, Cu, Zn, Pb, Ni, and Cr all had obvious spatial distribution patterns and local spatial aggregation phenomena. The high values of heavy metals in soils were mainly found in Taiyang, Daoshi, Qingliangfeng, Heqiao, and Tuankou, and the probability of the risk for contamination by Cd and Cu was higher in the study area. The high values of Cd, Cu, Zn, Ni, and Cr were mainly related to mining, while Pb was closely related to the application of potassium.

Intra-articular platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: a meta-analysis.

PURPOSE: Platelet-rich plasma (PRP) and hyaluronic acid (HA) have been increasingly used in recent years to treat knee osteoarthritis (OA). However, whether PRP is superior to HA is controversial. METHODS: We conducted an electronic search of PubMed, Embase, ScienceDirect, and Cochrane library. The pooled data were analyzed using RevMan 5.1. RESULTS: Three prospective and ten randomized trials were identified. PRP injections reduced pain more effectively than HA injections in OA of the knee at 6 months (mean difference [MD]=-14.18; 95% confidence interval [CI]: -26.12 to -2.23; P=0.02; I2=95%) and 12 months (MD=-15.25; 95% CI: -22.17 to -8.32; P<0.01; I2=81%) of follow-up evaluated by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, while the VAS showed no significant difference at 3 months (MD=-0.98; 95% CI: -2.55 to 0.59; P=0.22; I2=90%) and 6 months (MD=-0.82; 95% CI: -1.80 to 0.16; P=0.1; I2=83%). Additionally, similar results were observed for the function recovery according to the WOMAC function score and EuroQol-visual analog scales. CONCLUSION: The intra-articular injection of PRP was not obviously superior to HA in knee OA. Due to the limited quality and data of the evidence currently available, more high-quality randomized controlled trials are required.

Contents of Heavy Metals in Chinese Edible Herbs: Evidence from a Case Study of Epimedii Folium.

Toxic heavy metal contamination in Chinese edible herbs has raised a worldwide concern. In this study, heavy metals in Epimedii Folium, an edible medicinal plant in China, were quantitatively analyzed. Variations of heavy metals in different species, in various organs (i.e., leaves, stems, and roots), in wild-growing and cultivated plants, and in 35 market samples of Epimedii Folium, were systematically investigated. In all of Epimedium samples, Hg (mercury) was not detectable (0.00 µg/g). Four species, Epimedium pubescens, Epimedium sagittatum, Epimedium brevicornu, and Epimedium wushanense, were found to contain Cu (copper) and Pb (lead). And contents of Cu and Pb in E. brevicornu were significantly higher than those in other species (P < 0.01). In wild-growing and cultivated Epimedium plants, Cd (cadmium) and As (arsenic) were not detectable, and concentrations of Cu and Pb in wild-growing plants were significantly higher than those in cultivated plants (P < 0.01). Cd was not detectable in leaves, roots, and stems, while organ specificity was apparent in the distribution of Cu, As, and Pb. And the highest levels of Cu and Pb were observed in roots and leaves, respectively. In Chinese markets, several samples of Epimedii Folium contained excessive Cu, Cd, As, and Pb beyond the national permissible limits. In summary, there was a large variation of heavy metals among Epimedii Folium samples, and Cu and Pb were the most important heavy metals contaminating the edible medicinal plant. Application of Epimedii Folium to drug and food industries will need to focus more on toxic heavy metal contamination.