Adipocyte­rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator­activated receptor gamma/ABCG2 in epithelial ovarian cancer.

The effects of adipocyte­rich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyte­rich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARM­associated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro. Specifically, the peroxisome proliferator­activated receptor Î³ (PPARγ) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPARγ and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPARγ, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPARγ, using DDP, a nude mouse model injected with OVCAR3­shPPARγ cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPARγ. Expression of PPARγ/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPARγ improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPARγ. The present study showed that the introduction of ARM­educated PPARγ attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.

A better method to evaluate the reliability of echocardiography for assessment of pulmonary hypertension: comparison of tricuspid regurgitant spectrum quality grading and tricuspid valve regurgitation degree.

Background: Transthoracic echocardiography (TTE) is recommended as the most important noninvasive screening tool for the diagnosis of pulmonary hypertension (PH), sonographers usually measure the volume of regurgitant flow rather than evaluating the spectral quality, so physicians will determine whether the ultrasound measurements of pulmonary arterial systolic pressure (US-PASP) are reliable based on the volume of tricuspid regurgitation (TR). Therefore, for the first time, we grade the quality of TR spectrum (TRS) based on its integrity and clarity, aiming to assess clinical application value of different tricuspid regurgitant spectrum quality grades (TR-SQG), and investigate whether the accuracy of US-PASP is more trustworthy than TR. Methods: We retrospectively analyzed 108 patients with chronic thromboembolic PH (CTEPH) to compare the correlation and agreement between US-PASP and right heart catheterization measurements of PASP (RHC-PASP). TR area (TRA) and TRS were measured in each patient, and TR-SQG was performed. Results: The correlation coefficients between US-PASP and RHC-PASP were r=0.622 (P<0.001), r=0.754 (P<0.001), r=0.595 (P<0.001) in mild, moderate, severe TR, and r=0.301 (P=0.135), r=0.747 (P<0.001), r=0.739 (P<0.001), r=0.828 (P<0.001) in TR-SQG I-IV, respectively. Bland-Altman analysis revealed the mean biases of 5.05, 3.06, 7.62 mmHg in mild, moderate, severe TR, and -16.47, -8.07, 1.82, 6.09 mmHg in TR-SQG I-IV, respectively. In mild TR with the TR-SQG III and IV, the correlation coefficients between US-PASP and RHC-PASP were r=0.779 (P<0.001), intraclass correlation coefficient (ICC) =0.774, paired t-test P=0.160, respectively; and the consistency was significantly higher than that of mild TR without considering TR-SQG. In moderate TR with the TR-SQG III and IV, the r=0.749, ICC =0.746, paired t-test P=0.298 between US-PASP and RHC-PASP. Conclusions: The US-PASP with TR-SQG III or IV is trustworthy, and its accuracy and consistency are better than those predicted by the traditional severity of TR. The establishment of the ultrasound evaluation system of TR-SQG helps clinicians to judge whether the US-PASP is accurate, credible, and reliable.

Inhibition of ATM promotes PD-L1 expression by activating JNK/c-Jun/TNF-α signaling axis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer. Anti-PD-1/PD-L1 treatment for advanced TNBC is still limited to PD-L1-positive patients. Ataxia telangiectasia mutated (ATM) is a switch molecule for homologous recombination and repair. In this study, we found a significant negative correlation between ATM and PD-L1 in 4 TNBC clinical specimens by single-cell RNA sequencing (scRNA-seq), which was confirmed by immunochemical staining in 86 TNBC specimens. We then established ATM knockdown TNBC stable cell lines to perform in vitro studies and animal experiments, proving the negative regulation of PD-L1 by ATM via suppression of tumor necrosis factor-alpha (TNF-α), which was confirmed by cytokine array analysis of TNBC cell line and analysis of clinical specimens. We further found that ATM inhibits TNF-α via inactivating JNK/c-Jun by scRNA-seq, Western blot and luciferase reporter assays. Finally, we identified a negative correlation between changes in phospho-ATMS1981 and PD-L1 levels in TNBC post- and pre-neoadjuvant therapy. This study reveals a novel mechanism by which ATM negatively regulates PD-L1 by downregulating JNK/c-Jun/TNF-α in TNBC, shedding light on the wide application of immune checkpoint blockade therapy for treating multi-line-resistant TNBC.

Observation of robust edge mode and in-gap corner mode in Kagome surface-wave photonic crystals.

Recent theory has demonstrated that Kagome photonic crystals (PCs) support first-order and second-order topological phenomena. Here, we extend the topological physics of the Kagome lattice to surface electromagnetic waves and experimentally show a Kagome surface-wave PC. Under the protection of first-order and second-order topologies, both robust edge modes and in-gap corner modes are observed. The robust transport of edge modes is demonstrated by high transmission through the waveguide with a sharp bend. The localized corner mode is found at the corner with one isolated rod when a triangle-shaped sample is constructed. Our work not only shows a platform to mimic the topological physics in classical wave systems, but also offers a potential application in designing high-performance photonic devices.

Yangjing capsule improves oligoasthenozoospermia by promoting nitric oxide production through PLCγ1/AKT/eNOS pathway.

Background: Oligoasthenozoospermia is an important factor leading to male infertility. Yangjing capsule (YC), a traditional Chinese preparation, displays beneficial effects on male infertility. However, whether YC could improve oligoasthenozoospermia remains unclear. Methods: In this study, we aimed to explore the effect of YC in the treatment of oligoasthenozoospermia. Male Sprague-Dawley (SD) rats were treated with 800 mg/kg ornidazole once daily for 30 days to induce in vivo oligoasthenozoospermia; primary Sertoli cells were treated with 400 µg/mL ornidazole for 24 h to induce in vitro oligoasthenozoospermia. Results: We found that YC improved the testicle and epididymis weight, sperm concentration, sperm progressive motility, serum testosterone, fertility rate and testis morphology in ornidazole-exposed rats and enhanced cell survival in ornidazole-stimulated primary Sertoli cells. YC also inhibited the ornidazole-caused decrease in nitric oxide (NO) generation and the phosphorylation of phospholipase C γ1 (PLCγ1), AKT, and eNOS in vivo and in vitro in oligoasthenozoospermia. Furthermore, the knockdown of PLCγ1 blunted the beneficial effects of YC in vitro. Conclusion: Collectively, our data suggested that YC protected against oligoasthenozoospermia by promoting NO levels through the PLCγ1/AKT/eNOS pathway.

The Protective Effects of Bushen Daozhuo Granule on Chronic Non-bacterial Prostatitis.

Background: Chronic non-bacterial prostatitis (CNP), one of the most common chronic diseases in urology, leads to pain in the prostate and dysuria, critically affecting the physical or mental health of patients. However, there are no standard treatment approaches for the treatment of CNP in the clinic. Although the clinical application of Bushen Daozhuo granule (BSDZG) offers hope to CNP patients in China, the mechanisms of BSDZG in treating CNP are still not entirely clear. Hence, we aimed to investigate the novel therapeutic mechanisms of BSDZG on CNP. Methods: In this study, we first assayed the prostate index of rats and then determined the anti-inflammatory and anti-apoptotic effects of BSDZG on CNP in vivo and in vitro by employing ELISA kits and TUNEL staining. Next, we investigated whether the anti-inflammatory and anti-apoptotic mechanisms of BSDZG on prostate protein-induced rats and lipopolysaccharide (LPS) induced RWPE-1 cells were related to the AKT, p38 MAPK, and NF-κB pathways with the help of Western blot. Finally, the influence of BSDZG on the interaction between the p38 MAPK and NF-κB pathway in LPS-induced RWPE-1 cells was explored by adopting dehydrocorydaline (DHC, p38 MAPK activator) with the help of ELISA kits and Western blot. Results: In vivo, BSDZG effectively reduced the prostate index. In vivo and in vitro, BSDZG dramatically declined the level of two pro-inflammatory cytokines, TNF-α and IL-1ß, as well as the apoptosis rate. Moreover, in vivo and in vitro, BSDZG memorably upregulated the expression level of p-AKT, and substantially downregulated the expression level of p-p38 MAPK and NF-κB2. The activation of p38 MAPK significantly reversed the moderation effects of BSDZG on the level of TNF-α and IL-1ß, as well as the expression level of p-p38 MAPK and NF-κB2 in vitro. Conclusion: To sum up, the in vivo and in vitro therapeutic mechanisms of BSDZG on CNP were reflected as the anti-inflammation and anti-apoptosis that was formed by inhibiting the level of pro-inflammatory cytokines, TNF-α and IL-1ß, to regulate the AKT, p38 MAPK, and NF-κB pathways, and the anti-inflammatory effect of BSDZG was realized by suppressing the p38 MAPK pathway to inhibit the downstream NF-κB pathway.

Astragaloside IV attenuates IL-1ß-induced intervertebral disc degeneration through inhibition of the NF-κB pathway.

BACKGROUND: Intervertebral disc degeneration (IDD) is the main cause of low back pain. Patients with low back pain may experience significant socio-economic burdens and decreased productivity. Previous studies have shown that inflammation is one of the main causes of IDD. Astragaloside IV (AS IV), a traditional Chinese medicine, has been reported to have therapeutic effects on many inflammation-related diseases; however, the effectiveness of AS IV as the treatment for IDD has not been studied. METHODS: Nucleus pulposus (NP) cells from patients with IDD were used for the experiments. Cell counting kit 8 (CCK8) was used to evaluate the effect of AS IV on the viability of NP cells (NPCs). To mimic IDD in vitro, NPCs were divided into the following groups: control group, interleukin 1ß (IL-1ß) group, and AS IV + IL-1ß group. To analyse the effect of AS IV on IL-1ß-induced IDD, Western blotting, RT-qPCR, flow cytometry, and immunofluorescence assays were performed. To evaluate the effect of AS IV in vivo, a rat model of puncture-induced IDD was established. RESULTS: AS IV effectively alleviated IL-1ß-induced inflammation, apoptosis, and extracellular matrix degeneration in NPCs. We also observed that AS IV decreased the IL-1ß-induced phosphorylation of inhibitor of kappa B-alpha (p-IκBα) in the cytosol, and reduced nuclear translocation of NF-κB p65, indicating that AS IV inhibited the NF-κB pathway. Using the puncture-induced rat IDD model, our results showed that AS IV had a protective effect against the progression of IDD, suggesting that AS IV could alleviate IDD in vivo. CONCLUSIONS: Our results demonstrated that AS IV effectively alleviated IDD in vivo and in vitro, indicating that it could be used as a therapeutic to treat IDD.

Antibacterial and antioxidant films based on HA/Gr/TA fabricated using electrospinning for wound healing.

Prevention of bacterial contamination, maintenance of redox balance in the environment, and acceleration of wound healing are key requirements for wound dressing. In the present study, hyaluronic acid (HA)/graphene (Gr)-electrospun fibre films loaded with polyphenolic tannic acid (TA) were prepared using electrospinning. The antioxidant activity of the films was then examined to determine whether they contained optimal TA concentrations for subsequent research. Following that, the surface morphology and physicochemical properties of the films were determined and in vitro experiments were conducted to assess their biocompatibility and antibacterial activity. Finally, the in vivo effects of the electrostatically spun fibre films on infected wound healing in mouse models were observed. The HA/Gr/TA-electrospun fibre film with 0.3% w/v TA concentration displayed the best antioxidant activity and better mechanical, water-absorption, water-retention, and degradation properties than the film without TA. In addition, it displayed superior antibacterial activity and biocompatibility, as well acceleration of infected wound healing, than the film without TA. Therefore, the HA/Gr/TA-electrospun fibre film is a promising alternative option for wound dressings.

[Effect of Lingnan Chen's acupuncture on postmenopausal osteoporosis and serum GH and IGF-1].

OBJECTIVE: To compare the therapeutic effect on postmenopausal osteoporosis (PMOP) between Lingnan Chen's needling technique and calcitriol soft capsules and investigate the effect mechanism in view of serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1). METHODS: Seventy patients of PMOP were randomized into an observation group (35 cases, 4 cases dropped off ) and a control group (35 cases, 3 cases dropped off ). The patients of both groups were treated with calcium carbonate D3 tablets orally (600 mg each time, once daily). In the observation group, acupuncture was delivered at Shenshu (BL 23), Pishu (BL 20), Guanyuan (CV 4), Sanyinjiao (SP 6), etc. with the specific reinforcing-reducing technique and qi-conducting technique of Lingnan Chen's acupuncture, once every two days, three times a week. In the control group, calcitriol soft capsules were taken orally, 0.25 µg each time, twice a day. The intervention measures of two groups all lasted 12 weeks. Before and after treatment, the bone mineral density (BMD), the levels of serum GH and IGF-1 were assessed in two groups. Before treatment and 4, 8 and 12 weeks after treatment, TCM symptoms score and the MOS item short form health survey (SF-36) score were evaluated and the therapeutic effects were compared between groups. RESULTS: In both within-group and between-group comparisons, the difference in BMD was not significant before and after treatment (P>0.05). After treatment, the levels of serum GH and IGF-1 were increased in the observation group (P<0.05), and higher than the control group (P<0.05). After 4, 8 and 12 weeks of treatment, the scores of TCM symptoms were reduced in both groups compared with those before treatment (P<0.05), and the score in the observation group was lower than that in the control group (P<0.05). After 4, 8 and 12 weeks of treatment, except the score of general health 4 weeks after treatment in the control group, the scores of the other domains in SF-36 were increased in both groups compared with those before treatment (P<0.05). After 12 weeks of treatment, except the score for the general health and social functions, the scores of the other domains of SF-36 in the observation group were all higher than those in the control group (P<0.05). The total effective rate was 83.9% (26/31) in the observation group, higher than 59.4% (19/32) in the control group (P<0.05). CONCLUSION: Lingnan Chen's needling technique is effective on postmenopausal osteoporosis. This therapy may relieve the symptoms of osteoporosis and improve the quality of life, better than calcitriol soft capsules, and the effect mechanism may be related to the up-regulation of serum GH and IGF-1 in the patients.

Sex Hormones Had Mediation in the Connection Between Certain Blood Routine Parameters and Bone Loss.

To investigate the association between blood routine (BRT) parameters and bone loss as well as the possible mechanism of this association with bone loss in the middle- aged and elderly patients. A total of nine hundred and ninety-eight subjects (the total) aged≥40 years in General Hospital of Southern Theater Command of People's Liberation Army from March 2015 to January 2018 were enrolled in a cross-sectional studyPatients were divided into two groups as "at least osteopenia group" (including osteopenia, osteoporosis, and severe osteoporosis) and "normal group" according to the diagnosis standard of OP. The above indicators were analyzed and compared between the two groups. Binary multivariate logistic regression analysis was carried out to explore the association between BRT parameters and risk of bone loss in the subjects Mediation Effect was conducted to test endocrine variables as mediators in the correlation of BRT parameters with the bone loss for the possible mechanisms. There were 669 cases in the at least osteopenia group and 329 in the normal group. RBC, Hb, HCT and MCHC were all positively correlated with BMD of lumbar spine(L1-4), left femoral neck and left femur, along with lymph positively correlated with BMD of left femoral neck and left femur, respectively. Eosinophils(Eo) was positively correlated with BMD of L1-L4 and RDW-SD together with RDW-CV were both negatively correlated with BMD of left femoral neck and left femur. By binary multivariate logistic regression, only Hb was associated with bone loss and the OR value was 0.478 as protective factor for BMD. Estradiol (E2) and testosterone (T) had partial mediating effect on the association of BRT parameters with the risk of bone loss. The mediating effect of E2 on the relationship between WBC and bone loss accounted for 46.35% of the total effect, and that of T on the relationship between RBC, Hb, HCT, MCHC and bone loss accounted for 27%, 18.3%, 31.1% and 26.8%, respectively. Bone loss in the middle-aged and elderly population is accompanied with the change of BRT parameters and the erythrocyte indices tend to be more obvious especially the Hb, which indicates anemia had a potential connection with bone loss. Sex hormone, especially T, is an important mediating variable in the association between blood routine parameters and bone loss.

Regulating DNA methylation could reduce neuronal ischemia response and apoptosis after ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is an important pathophysiological condition that can cause cell injury and large-scale tissue injury in the nervous system. Previous studies have shown that epigenetic regulation may play a role in the pathogenesis of IRI. METHODS: In this study, we isolated mouse cortical neurons and constructed an oxygen-glucose deprivation/reoxygenation (OGD) model to explore the change in DNA methylation and its effect on the expression of corresponding genes. RESULTS: We found that DNA methylation in neurons increased with hypoxia duration and that hypermethylation of numerous promoters and 3'-untranslated regions increased. We performed Gene Ontology enrichment analysis to study gene function and Kyoto Encyclopedia of Genes and Genomes pathway analysis to identify the pathways associated with gene regulation. The results showed that hypermethylation-related genes expressed after OGD were related to physiological pathways such as neuronal projection, ion transport, growth and development, while hypomethylation-related genes were related to pathological pathways such as the external apoptosis signaling pathway, neuronal death regulation, and regulation of oxidative stress. However, the changes in DNA methylation were specific for certain genes and may have been related to OGD-induced neuronal damage. Importantly, we integrated transcription and DNA methylation data to identify several candidate target genes, including hypomethylated Apoe, Pax6, Bmp4, and Ptch1 and hypermethylated Adora2a, Crhr1, Stxbp1, and Tac1. This study further indicated the effect of DNA methylation on gene function in brain IRI from the perspective of epigenetics, and the identified genes may become new targets for achieving neuroprotection in the brain after IRI.

Ideal nodal rings of one-dimensional photonic crystals in the visible region.

Three-dimensional (3D) artificial metacrystals host rich topological phases, such as Weyl points, nodal rings, and 3D photonic topological insulators. These topological states enable a wide range of applications, including 3D robust waveguides, one-way fiber, and negative refraction of the surface wave. However, these carefully designed metacrystals are usually very complex, hindering their extension to nanoscale photonic systems. Here, we theoretically proposed and experimentally realized an ideal nodal ring in the visible region using a simple 1D photonic crystal. The π-Berry phase around the ring is manifested by a 2π reflection phase's winding and the resultant drumhead surface states. By breaking the inversion symmetry, the nodal ring can be gapped and the π-Berry phase would diffuse into a toroidal-shaped Berry flux, resulting in photonic ridge states (the 3D extension of quantum valley Hall states). Our results provide a simple and feasible platform for exploring 3D topological physics and its potential applications in nanophotonics.

Electroacupuncture Alleviates Inflammation of Dry Eye Diseases by Regulating the α7nAChR/NF-κB Signaling Pathway.

PURPOSE: We tried to investigate whether electroacupuncture (EA) can reduce inflammation of dry eye disease (DED) by regulating α7nAChR and inhibiting the NF-κB signaling pathway. METHODS: Healthy New Zealand white rabbits were treated with scopolamine hydrobromide (Scop) for 21 consecutive days to establish the DED animal model. After 21 days, EA, fluorometholone (Flu), and α7nAChR antagonist (α-BGT) treatments were performed, and the Scop injection was continued until day 35. During treatment, the fluorescence staining of the corneal epithelium and the level of tear flow were observed. The influence of EA on the LG pathology and inflammatory factors ACh, α7nAChR, and NF-κB was detected using the LG histopathology, transmission electron microscopy (TEM), cytokine protein chip technology, enzyme-linked immunosorbent assay (ELISA), and Western blot. RESULTS: The EA stimulation can reduce the corneal epithelial damage and repair epithelial cell ultrastructure, promote the tear secretion, relieve the LG atrophy and decrease lipid droplet accumulation in LG acinar cell, and reduce the levels of inflammatory cytokines (i.e., IL-1, MIP-1b, TNF-α, and IL-8) in the LG. The protective effect of EA on the inflammation and the ocular surface is similar to the corticosteroid Flu. EA and Flu can upregulate the expression of the α7nAChR and downregulate the expression of NF-κB. The α7nAChR antagonist α-BGT can reverse the protective effect of EA on the LG and the inhibitory effect on the NF-κB pathway and the expression of inflammatory factors but cannot affect the expression of Flu on the NF-κB pathway and inflammatory factors. CONCLUSION: These results prove that EA can alleviate DEDs by stimulating the acupoints around the eyes. These beneficial effects are related to the upregulation of α7nAChR and the downregulation of NF-κB in the LG. The protective effect of LG is mediated through the anti-inflammatory pathway mediated by α7nAChR. EA can reduce the NF-κB P65 nuclear transcription and reduce inflammatory factors by regulating α7nAChR. This expression indicates that the α7nAChR/NF-κB signaling pathway may serve as a potential therapeutic target for EA to treat DEDs.

Roles and mechanisms of adipokines in drug resistance of tumor cells.

The drug resistance of cancer cells has become one of the biggest obstacles of effective anticancer treatments. Adipocytes produce plenty of cytokines (also known as adipokines), which remarkably affect the drug resistance exhibited by cancer cells. Different adipokines (leptin, visfatin, resistin, adiponectin, Interleukin 6, and tumor necrosis factor α) can induce drug resistance in different cancer cells by various functional mechanisms. This phenomenon is of great interest in pharmacological anti-cancer studies since it indicates that in the cancers with adipocyte-rich microenvironment, all adipokines join together to assist cancer cells to survive by facilitating drug resistance. Studies on adipokines contribute to the development of novel pharmacological strategies for cancer therapy if their roles and molecular targets are better understood. The review will elucidate the roles and the underlying mechanisms of adipokines in drug resistance, which may be of great significance for revealing new strategies for cancer treatment.

Alteration of mRNA 5-Methylcytosine Modification in Neurons After OGD/R and Potential Roles in Cell Stress Response and Apoptosis.

Epigenetic modifications play an important role in central nervous system disorders. As a widespread posttranscriptional RNA modification, the role of the m5C modification in cerebral ischemia-reperfusion injury (IRI) remains poorly defined. Here, we successfully constructed a neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) model and obtained an overview of the transcriptome-wide m5C profiles using RNA-BS-seq. We discovered that the distribution of neuronal m5C modifications was highly conserved, significantly enriched in CG-rich regions and concentrated in the mRNA translation initiation regions. After OGD/R, modification level of m5C increased, whereas the number of methylated mRNA genes decreased. The amount of overlap of m5C sites with the binding sites of most RNA-binding proteins increased significantly, except for that of the RBM3-binding protein. Moreover, hypermethylated genes in neurons were significantly enriched in pathological processes, and the hub hypermethylated genes RPL8 and RPS9 identified by the protein-protein interaction network were significantly related to cerebral injury. Furthermore, the upregulated transcripts with hypermethylated modification were enriched in the processes involved in response to stress and regulation of apoptosis, and these processes were not identified in hypomethylated transcripts. In final, we verified that OGD/R induced neuronal apoptosis in vitro using TUNEL and western blot assays. Our study identified novel m5C mRNAs associated with ischemia-reperfusion in neurons, providing valuable perspectives for future studies on the role of the RNA methylation in cerebral IRI.

IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells.

The inflammatory milieu in tumor modulates the resistance to the conventional antitumoral therapies. Interleukin-6 (IL-6), a pleiotropic pro-inflammatory cytokine and a crucial mediator of tumor development, has been targeted as a therapeutic strategy to overcome chemoresistance in the treatment of tumors. The protein levels and nuclear translocation of HIFs (hypoxia-inducible factors), such as HIF-1α, are linked to the drug resistance of tumor cells. However, whether IL-6 promotes the nuclear translocation of HIF-1α and the related mechanism remain to be investigated. We applied two ovarian cancer (OvCa) cell lines, A2780 cells and SKOV3 cells for the in vivo and in vitro studies. We found that IL-6 up-regulates the HIF-1α expression via the signal transducer and activator of transcription 3 (STAT3) signaling under hypoxia in either endogenous or exogenous way, and then we proved that IL-6 enhances the transcriptional activity of HIF-1α via the STAT3 signaling. Further mechanism research revealed that IL-6 promotes the nuclear translocation of HIF-1α through the STAT3 signaling under hypoxia. Proliferation assay and apoptosis assay were applied and proved that IL-6 enhances the chemoresistance of OvCa cells against cisplatin through the upregulation of HIF-1α via the STAT3 signaling in vitro. The In vivo studies confirmed the effect of IL-6 in increasing the chemoresistance of OvCa cells against cisplatin through the IL-6/STAT3/HIF-1α loop in the animal models. Our data elucidates the explicit mechanism of IL-6/STAT3/HIF-1α loop in OvCa and also provides new insights into the development of different approaches for the inflammation-induced and hypoxia-induced resistance in tumor therapies.

Risk Interval of Complete Blood Counts May be Closely Associated with Bone Mineral Density in the Elderly Chinese Population.

BACKGROUND: Accumulating research suggests that hematopoiesis and bone metabolism are interconnected. Several studies have investigated the partial indexes of peripheral blood counts related to bone mineral density (BMD). The aim of this study was to investigate the associations between all of the parameters, especially the risk interval of complete blood counts (CBC) and BMD in a sample of elderly subjects aged >70 years. METHODS: Three hundred and eighty-six subjects aged > 70 years in our hospital were enrolled in a cross-sectional study and underwent BMD measurement along with a CBC test. Patients were divided into two groups: "at least osteopenia" (T-score < -1) and a normal group (T-score ≥ -1). The clinicopathological characteristics, CBC parameters, and BMD were analyzed between the two groups. We performed a supervised discretization (using a conditional inference tree algorithm) to find the risk interval for the continuous variables, especially for CBC parameters, and bootstrap multivariable logistic regression to estimate the odds of CBC parameters associated with BMD. RESULTS: A total of 248 subjects were included in the study and divided into the normal (n = 43) and "at least osteopenia" groups (n = 205). Subjects in the "at least osteopenia" group had varying degrees of decreases in white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (Hb), mean corpuscular hemoglobin concentration (MCHC), hematocrit (HCT), platelet volume distribution width (PDW) mean platelet volume (MPV), eosinophils, and lymphocytes, and had increases in platelets (PLTs). MCHC, WBC, RBC, PDW, MPV, Hb, and lymphocytes were successfully divided into two (low and high) intervals. Bootstrap logistic regression showed that low levels of body mass index (BMI) [(11.88, 23.53); OR: 4.07; p < 0.0001], lymphocytes [(0.54, 2.3); OR: 3.95; p < 0.0001] and PDW [(8.5, 12.7); OR: 2.44; p < 0.0001] along with being female and older age [(72, 97); OR: 2.16; p < 0.0001] were significantly associated with BMD as risk factors. CONCLUSIONS: The elderly with BMD loss tended to show an abnormal sign in the CBC test. Low levels of lymphocytes and PDW may contribute to the evaluation of osteoporosis risk in the elderly. Bone remodeling and hematopoiesis may have stronger associations and interactions than has been previously recognized.

Deep vein thrombosis in a nonobstructive azoospermia male taking tamoxifen: a rare case report.

Tamoxifen is used for male infertility and nonobstructive azoospermia (NOA). Although thrombosis complication of tamoxifen on the treatment of breast cancer has been reported repeatedly, there was no literature about the thrombosis complication of tamoxifen treatment on NOA. A 32-year-old man was admitted to hospital for severe swelling of left lower limb, with difficulty walking. He had been diagnosed with NOA 5 months ago and had been taking tamoxifen 20 mg daily for 4 months continuously. After admission, the patient was finally diagnosed of deep vein thrombosis (DVT) with elevated D-dimer level and Doppler ultrasound of the deep venous system. After a series of effective treatments, especially the operation of percutaneous venous thromboembolism aspiration, the patient recovered rapidly and the abnormal laboratory results of coagulopathy returned to normal. Clinicians should warn about the possibility of thromboembolic complications with tamoxifen when treating male infertility.

Yangjing Capsule Can Improve the Function of the Testicular Angiogenesis through Activating VEGFA/eNOS Signaling Pathway.

BACKGROUND: The testicular microcirculation was an important aspect of testicular physiology and it offered a stable environment for the transport of nutrients and secretary products in the testis. Yangjing capsule (YC), a traditional Chinese compound herbal prescription, has been proved as an effective drug to ameliorate spermatogenesis, promote testosterone synthesis in vivo, and cure spermatogenesis in clinical practice. OBJECTIVE: This study was aimed at understanding the potential mechanisms of YC exerting angiogenic effects in the mouse spermatogenesis dysfunction model induced by cyclophosphamide (CP) and MLTC-1 cells. MATERIALS AND METHODS: Balb/c mice were randomly divided into five groups: control, CP, CP plus YC (630 mg/kg), CP plus YC (1260 mg/kg), and CP plus YC (2520 mg/kg). After 30 days, mice were sacrificed and the expressions of endothelial marker CD34+, angiogenic marker VEGFA, VEGFR1, VEGFR2, and eNOS in the testes of the mice were examined; moreover, Leydig cell line MLTC-1 cells were cultured and treated with different concentrations of YC extracts (YCE), and the expressions of VEGFA, VEGFR1, VEGFR2, and eNOS, as well as the secretion of NO, were evaluated. RESULTS: We observed that YC significantly increased the expressions of VEGFA, VEGFR1, VEGFR2, and eNOS in testes of CP-treated mice; moreover, YCE has led to increased expressions of VEGFA, VEGFR1, VEGFR2, and eNOS and secretion of NO in MLTC-1 in vitro. These data suggested that the YC might be an alternative treatment for the dysfunction of testicular microcirculation by promoting the angiogenesis in the testis.