Giant cell tumor of soft tissue involving thyroid gland: a case report and review of the literature.

BACKGROUND: Giant cell tumor of soft tissue is a low malignant uncommon neoplasm, with histologic features and immunophenotype similar to its bone counterpart. Primary giant cell tumor of soft tissue in the thyroid gland is considered an exceedingly rare entity. CASE PRESENTATION: We describe a case of primary thyroid giant cell tumor of soft tissue in a 69-year-old Chinese female patient. Neck ultrasonography showed a 19 mm × 12 mm × 5 mm nodule with heterogeneous echo and clear boundary located within the left thyroid. Histopathological examination revealed that the neoplasm was composed of two morphological components, mononuclear cells admixed with multinucleated osteoclast-like giant cells. Immunohistochemically, the tumor cells were positive for CD68 and vimentin, but were negative for epithelial membrane antigen, cytokeratin, and additional muscle markers. She underwent left unilateral thyroidectomy, and total thyroidectomy was performed for local recurrence 3 months later. The patient remained well without recurrence or metastasis following up for 12 months. CONCLUSION: The significance of this case lies in its rarity, the challenge of preoperative clinical diagnosis, and the differential diagnosis with other malignancies.

LncRNA CCRR Attenuates Postmyocardial Infarction Inflammatory Response by Inhibiting the TLR Signalling Pathway.

BACKGROUND: Timely and proper suppression of inflammation can effectively reduce myocardial injury and promote the postmyocardial infarction (post-MI) wound-healing process. We have previously found that cardiac conduction regulatory RNA (CCRR), a long noncoding RNA (lncRNA) transcribed by the gene located on chromosome 9, with abundant expression in the heart, elicits antiarrhythmic effects in heart failure, and this is a continuing study on the role of CCRR in MI. METHODS: CCRR was overexpressed in CCRR transgenic mice or after injection of adeno-associated virus-9 (AAV-9). MI surgery was performed, and cardiac function was assessed in vivo by echocardiography, followed by histologic analyses. Western blot analysis and qRT-PCR were performed to investigate the effects of CCRR on macrophages, cardiomyocytes, and cardiomyocytes cocultured with macrophages. Through microarray analysis and RNA-binding protein immunoprecipitation (RIP) and other related techniques were also employed to study the effects of CCRR on Toll-like receptor (TLR)2 and TLR4. RESULTS: We found that CCRR level was significantly decreased with increases in proinflammatory cytokines and activation of the TLR signalling pathway in the heart of the 3-day MI mice. CCRR overexpression downregulated TLR2 and TLR4 in MI and effectively inhibited the inflammatory responses in primary cardiomyocytes and macrophages cultured under hypoxic conditions. Downregulation of CCRR induced excessive inflammatory responses by activating the TLR signalling pathway. CCRR acted by suppressing TLR2 and TLR4 to inhibit the secretion of proinflammatory factors to reduce infarct size, thereby improving cardiac function. CONCLUSIONS: CCRR protected cardiomyocytes against MI injury by suppressing inflammatory response through targeting the TLR signalling pathway.

Effect of acupuncture on arthritic pathological injury in rats with type â ¡ collagen-induced rheumatoid arthritis. / é’ˆåˆºæ”¹å–„â ¡åž‹èƒ¶åŽŸè›‹ç™½è¯±å¯¼æ€§å ³èŠ‚ç‚Žå¤§é¼ ç‚Žæ€§ååº”çš„æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To observe the effect of acupuncture stimulation of "Yanglingquan"(GB34), "Zusanli"(ST36) and "Xuanzhong" (GB39) on arthritis index (AI), joint synovial membrane pathology, serum-related immunoinflammatory factors, and expressions of tumor suppressor gene mt-p53, nuclear factor kappa B (NF-κB) and peroxisome proliferator activated receptor gamma (PPARγ) in knee joint synovial tissue of rats with type Ⅱ collagen-induced arthritis (CIA), so as to explore its possible mechanisms underlying improvement of rheumatoid arthritis (RA). METHODS: Male SD rats were used in the present study. The CIA model was established by subcutaneous injection of collagen emulsion (200 µL/rat) in the tail root region on the first day and repeat (100 µL/rat) once on the 9th day. Eighteen successful CIA rats were randomized into model, medication and acupuncture groups, with 6 rats in each group. Other 6 normal rats were used as the normal control group. For rats of the medication group, leflunomide (1.9 mg/kg) was administrated by gavage, once a day, and for rats of the acupuncture group, manual acupuncture stimulation was applied to bilateral GB34, ST36, GB39 for 30 min, once a day, for 12 weeks. The arthritis index (AI) score (0-4 points) was evaluated once every week. The contents of IL-6, IL-17 and TNF-α in the serum were determined by ELISA. Histopathological changes of the ankle joint were observed by H.E. staining. The protein and mRNA expression levels of mt-p53, NF-κB p65, and PPARγ in the knee joint synovial tissue were determined by Western blot and quantitative real time PCR, separately. RESULTS: Compared with the normal control group, the AI scores at different time-points after modeling, contents of serum TNF-α, IL-6 and IL-17, expression levels of mt-p53, NF-κB p65, PPARγ proteins and mRNAs were significantly increased in the model group (P<0.01, P<0.05). In comparison with the model group, the AI scores at the 10th week in the medication group and at the 3rd, 9th and 10th week in the acupuncture group, contents of serum TNF-α, IL-6 and IL-17, and the expression levels of mt-p53 and NF-κB p65 proteins in both medication and acupuncture groups, as well as mt-p53 and NF-κB p65 mRNAs in the medication group were apparently decreased (P<0.01, P<0.05), while the expression levels of PPARγ protein in both medication and acupuncture group and PPARγ mRNA in the medication group were significantly up-regulated (P<0.05, P<0.01). No significant differences were found between the acupuncture and medication groups in down-regulating the AI score and serum TNF-α, IL-6 and IL-17 contents. The effect of acupuncture was weaker than that of medication in down-regulating the expression of mt-p53 and NF-κB p65 proteins and mRNAs and in up-regulating PPARγ mRNA (P<0.01). H.E. results showed ankle cartilage hyperplasia, reduced joint cavity, mild fibroproliferation and inflammatory cell infiltration in the surrounding soft tissue of the ankle joint in rats of the model group, which was milder in both medication and acupuncture groups. CONCLUSIONS: Acupuncture stimulation can improve the degree of joint inflammation and swelling in CIA rats, which may be related to its effects in inhibiting the overexpression of immunoinflammatory factors in serum and regulating expression of mt-p53, NF-κB p65, PPARγ mRNAs and proteins in the synovial tissue.

Oral micronized progesterone versus vaginal progesterone for luteal phase support in fresh embryo transfer cycles: a multicenter, randomized, non-inferiority trial.

STUDY QUESTION: Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer cycles? SUMMARY ANSWER: The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day. WHAT IS KNOWN ALREADY: LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass. STUDY DESIGN, SIZE, DURATION: This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11-12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group [35.3% versus 38.0%, absolute difference (AD): -2.6%; 95% CI: -9.0% to 3.8%, P-value for non-inferiority test: 0.010]. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: -6.4%; 95% CI: -12.6% to -0.1%, P-value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups. LIMITATIONS, REASONS FOR CAUTION: The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers. WIDER IMPLICATIONS OF THE FINDINGS: Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958. TRIAL REGISTRATION DATE: May 2018. DATE OF FIRST PATIENT'S ENROLMENT: November 2018.

The relationship between obstructive sleep apnea and risk of renal impairment in patients with hypertension, a longitudinal study.

OBJECTIVE: Association of obstructive sleep apnea (OSA) with renal damage is undetermined, especially in the population with hypertension, a high-risk group for chronic kidney disease. Therefore, we aimed to explore whether OSA is an independent risk factor for renal impairment in patients with hypertension, by considering the effects of gender, age, obesity and OSA severity. METHODS: The longitudinal observational study included patients with hypertension and suspected OSA without renal damage at baseline who visited Hypertension Center between January 2011 and December 2018, and followed up till renal outcomes, death, loss to follow-up, or May 31, 2022, using annual health check-ups, hospital readmission or out-patient visits. Main renal outcome was chronic kidney disease (CKD), defined as estimated glomerular filtration rate <60 ml/min per 1.73 m2 and/or positive proteinuria. Cox proportional hazard models were used to evaluate the association, and repeated after propensity score matching. Sensitivity analysis were performed by excluding those with primary aldosteronism. RESULTS: 7961 patients with hypertension were included with 5022 ones with OSA, and 82% were followed up. During median follow-up of 3.42 years, 1486 patients developed CKD. Per 1000 person-year incidence of CKD was 56.72 in OSA group. In Cox regression analysis, OSA and severe OSA group respectively showed 1.21 (95% CI: 1.08-1.35) and 1.27 (95% CI: 1.09-1.47) fold risk for CKD in total, compared with non-OSA group. Overall results remained consistent in propensity score matching and sensitivity analysis. CONCLUSION: OSA is independently associated with higher risk of chronic kidney disease in hypertension.

Metabolomics analysis of the potential mechanism of Yi-Guan-Jian decoction to reverse bone loss in glucocorticoid-induced osteoporosis.

BACKGROUND: Glucocorticoid-induced osteoporosis (GIOP) is a disease in which long-term use of glucocorticoid causes bone loss, deterioration of bone microstructure and fracture. Currently, clinical drugs targeting this disease have certain side effects. There is still a need to find effective drugs with fewer side effects. The theory of traditional Chinese medicine suggests that YGJ has therapeutic effect on GIOP, but it has not been explained. Therefore, this study aims to explore the protective effect of YGJ on GIOP mouse models and elucidate the underlying mechanism through LC-MS-based metabolomics analysis. METHODS: The general condition of 8 week age male C57BL/6J mice was recorded after 8 weeks of treatment with dexamethasone (DEX) and YGJ. Bone-related parameters and bone morphology were determined by Micro-CT. HE staining was used to observe the pathological changes of bone tissue. Serum levels of bone metabolism markers were detected by ELISA. Liver metabolomics analysis was conducted to search for the significant markers of anti-GIOP of YGJ and the metabolic pathway affecting it. RESULTS: After treatment, YGJ significantly reversed the weight loss caused by DEX; increase the number of bone trabecular in ROI region, significantly improve the bone-related parameters of GIOP mice, and increase the levels of alkaline phosphatase and osteocalcin. In the study of metabolic mechanism, YGJ reversed 24 potential markers in GIOP mice. These included cortisol, 3-hydroxybutyric acid, taurine, esculin and uric acid, which are closely associated with osteoporosis. Topological analysis results showed that YGJ had the most significant effect on taurine and hypotaurine metabolism, with - log10 (P) > 2.0 and Impact > 0.4. CONCLUSIONS: Yi-Guan-Jian decoction can increase bone density and improve bone microstructure by regulating the levels of alkaline phosphatase and osteocalcin and reverse bone loss in GIOP mouse model. The underlying metabolic mechanism may be related to taurine and hypotaurine metabolic pathway.

Effects of Zishen Yutai Pills on in vitro Fertilization-Embryo Transfer Outcomes in Patients with Diminished Ovarian Reserve: A Prospective, Open-Labeled, Randomized and Controlled Study.

OBJECTIVE: To explore the effects of Zishen Yutai Pills (ZYPs) on the quality of oocytes and embryos, as well as pregnancy outcomes in patients with diminished ovarian reserve (DOR) receiving in vitro fertilization-embryo transfer (IVF-ET). The possible mechanisms, involving the regulation of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), were also investigated. METHODS: A total of 120 patients with DOR who underwent their IVF-ET cycle were randomly allocated to 2 groups in a 1:1 ratio. The patients in the treatment group (60 cases) received ZYPs from the mid-luteal phase of the former menstrual cycle by using gonadotropin-releasing hormone (GnRH) antagonist protocol. The patients in the control group (60 cases) received the same protocol but without ZYPs. The primary outcomes were the number of oocytes retrieved and high-quality embryos. Secondary outcomes included other oocyte or embryo indices as well as pregnancy outcomes. Adverse events were assessed by comparison of the incidence of ectopic pregnancy, pregnancy complications, pregnancy loss, and preterm birth. Contents of BMP15 and GDF9 in the follicle fluids (FF) were also quantified with enzyme-linked immunosorbent assay. RESULTS: Compared with the control group, the numbers of oocytes retrieved and high-quality embryos were significantly increased in the ZYPs group (both P<0.05). After treatment with ZYPs, a significant regulation of serum sex hormones was observed, including progesterone and estradiol. Both hormones were up-regulated compared with the control group (P=0.014 and 0.008), respectively. No significant differences were observed with regard to pregnancy outcomes including implantation rates, biochemical pregnancy rates, clinical pregnancy rates, live birth rates, and pregnancy loss rates (all P>0.05). The administration of ZYPs did not increase the incidence of adverse events. The expressions of BMP15 and GDF9 in the ZYPs group were significantly up-regulated compared with the control group (both P<0.05). CONCLUSIONS: ZYPs exhibited beneficial effects in DOR patients undergoing IVF-ET, resulting in increments of oocytes and embryos, and up-regulation of BMP15 and GDF9 expressions in the FF. However, the effects of ZYPs on pregnancy outcomes should be assessed in clinical trials with larger sample sizes (Trial reqistration No. ChiCTR2100048441).

Design, synthesis and biological characteristics of pyrazolo[3,4-d]pyrimidine derivatives as potential VEGFR-2 inhibitors.

Aim: Several VEGFR-2 inhibitors with the structure of [3,4-d]pyrimidine and based on sorafenib were designed and synthesized. Materials & methods: Cytotoxic activity was evaluated by MTT, wound healing and clone formation assays. Cell cycle and apoptosis were analyzed by flow cytometry. Molecular simulation and western blot were also applied. Results: Among them, II-1 significantly inhibited tumor cellular activity (IC50 = 5.90 ± 0.05 µM on HepG2 cells) compared with sorafenib (IC50 = 9.05 ± 0.54 µM on HepG2 cells). Molecular docking demonstrated that II-1 and sorafenib have the same hydrogen binding. Finally, the protein expression of phosphorylated VEGFR-2 was substantially reduced after II-1 treatment. Conclusion: Compound II-1 can inhibit VEFGR-2 activation and is an effective antitumor agent in liver cancer cells.

Identification of Gene Modules and Hub Genes Associated with Sporisorium scitamineum Infection Using Weighted Gene Co-Expression Network Analysis.

Sporisorium scitamineum is a biotrophic fungus responsible for sugarcane smut disease. To investigate the key genes involved in S. scitamineum infection, we conducted RNA sequencing of sugarcane sprouts inoculated with S. scitamineum teliospores. A weighted gene co-expression network analysis (WGCNA) showed that two co-expressed gene modules, MEdarkturquoise and MEpurple-containing 66 and 208 genes, respectively-were associated with S. scitamineum infection. The genes in these two modules were further studied using Gene Ontology (GO) enrichment analysis, pathogen-host interaction (PHI) database BLASTp, and small secreted cysteine-rich proteins (SCRPs) prediction. The top ten hub genes in each module were identified using the Cytohubba plugin. The GO enrichment analysis found that endoplasmic reticulum-related and catabolism-related genes were expressed during S. scitamineum infection. A total of 83 genes had homologs in the PHI database, 62 of which correlated with pathogen virulence. A total of 21 proteins had the characteristics of small secreted cysteine-rich proteins (SCRPs), a common source of fungal effectors. The top ten hub genes in each module were identified, and seven were annotated as Mig1-Mig1 protein, glycosyl hydrolase, beta-N-acetylglucosaminidase, secreted chorismate mutase, collagen, mRNA export factor, and pleckstrin homology domain protein, while the remaining three were unknown. Two SCRPs-SPSC_06609 and SPSC_04676-and three proteins-SPSC_01958, SPSC_02155, and SPSC_00940-identified in the PHI database were also among the top ten hub genes in the MEdarkturquoise and MEpurple modules, suggesting that they may play important roles in S. scitamineum infection. A S. scitamineum infection model was postulated based on current findings. These findings help to deepen the current understanding of early events in S. scitamineum infection.

Renieramycin T Inhibits Melanoma B16F10 Cell Metastasis and Invasion via Regulating Nrf2 and STAT3 Signaling Pathways.

As one of marine tetrahydroisoquinoline alkaloids, renieramycin T plays a significant role in inhibiting tumor metastasis and invasion. However, the effect of renieramycin T on inflammation-related tumor metastasis and invasion is still unknown, and its mechanisms remain unclear. Here we established an inflammation-related tumor model by using the supernatant of RAW264.7 cells to simulate B16F10 mouse melanoma cells. The results indicate that renieramycin T suppressed RAW264.7 cell supernatant-reduced B16F10 cell adhesion to a fibronectin-coated substrate, migration, and invasion through the matrigel in a concentration-dependent manner. Moreover, Western blot results reveal that renieramycin T attenuated the phosphorylation of STAT3 and down-regulated the expression of Nrf2. Together, the above findings suggest a model of renieramycin T in suppressing B16F10 cancer cell migration and invasion. It may serve as a promising drug for the treatment of cancer metastasis.

Association of Polycystic Ovary Syndrome Phenotypes With Adverse Pregnancy Outcomes After In-Vitro Fertilization/Intracytoplasmic Sperm Injection.

Objective: This study aims to evaluate the association between polycystic ovary syndrome (PCOS) phenotypes and adverse perinatal outcomes, comparing the characteristics, ovarian response, and assisted reproductive outcomes in patients with various PCOS phenotypes after in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Methods: This study comprised 6,732 patients who underwent the first cycle of IVF/ICSI treatment in our outpatient department from January 2017 to July 2018. Propensity score matching (PSM) was used in PCOS and non-PCOS groups to balance the influence of intergroup confounding factors. After the PSM procedure, 1,186 patients were included in the two groups, and the PCOS patients were further divided into four PCOS phenotype groups based on the Rotterdam criteria. Results: Patients with various PCOS phenotypes had similar rates of biochemical pregnancy, clinical pregnancy, and live birth (all P-values > 0.05). The overall incidence of adverse pregnancy outcomes (including ectopic pregnancy, miscarriage, preterm birth) was significantly higher in PCOS phenotype A and D groups than in the control group (44% and 46.4% vs. 28.7%, P = 0.027). The rates of hypertensive disorder of pregnancy (HDP) were significantly higher in PCOS phenotype A and C groups than in the control group (9.3% and 12.5% vs. 3.1%, P = 0.037). After adjustment for potential confounders, the differences in adverse pregnancy outcomes persisted (P = 0.025). Conclusions: The overall incidence of adverse pregnancy outcomes is higher in women with PCOS phenotypes A and D than in women with non-PCOS.

Overexpression of Sugarcane ScDIR Genes Enhances Drought Tolerance in Nicotiana benthamiana.

Dirigent proteins (DIRs) are known to function in lignin biogenesis and to be involved in stress resistance in plants. However, the sugarcane DIRs have not been functionally characterized. In this study, we investigated the DIR-protein-encoding genes in Saccharum spp. (ScDIR) by screening collections of sugarcane databases, monitoring the responses of these genes to drought stress by real-time quantitative PCR, and identifying their heterologous expression in tobacco. Of the 64 ScDIRs identified, four belonging to the DIR-b/d (ScDIR5 and ScDIR11) and DIR-c (ScDIR7 and ScDIR40) subfamilies showed a significant transcriptional response when subjected to drought stress. ScDIR5, ScDIR7, and ScDIR11 are localized in the cell membrane, whereas ScDIR40 is found in the cell wall. The overexpression of these ScDIR genes in tobacco generally increased the drought tolerance of the transgenic lines, with ScDIR7 conferring the highest degree of drought tolerance. The characterization of the physiological and biochemical indicators (superoxide dismutase, catalase, malondialdehyde, and H2O2) confirmed that the ScDIR-overexpressing lines outperformed the wild type. These results demonstrated that specific ScDIRs in sugarcane respond and contribute to tolerance of drought stress, shedding light on potential means of improving drought tolerance in this crop.

Engineering vascularized dermal grafts by integrating a biomimetic scaffold and Wharton's jelly MSC-derived endothelial cells.

Tissue engineering aims to generate functional tissue constructs with the necessary scaffold properties for cell colonization and the establishment of a vascular network. However, treatment of tissue defects using synthetic scaffolds remains a challenge mainly due to insufficient and slow vascularization. Our previous study developed a macroporous silk fibroin scaffold with a nanofibrous microstructure, and demonstrated that the nanofibrous structure can promote the viability of endothelial cells (ECs) and guide cell migration. Further studies are needed to clarify the effect of scaffold microstructures on cell-mediated vascularization. Here, we investigated the efficacy of EC-seeded nanofibrous scaffolds in improving vascularization in vivo. ECs derived from induced human Wharton's Jelly mesenchymal stem cells served as a potential source for cell transplantation. The cell-seeded scaffolds were implanted into dermal defects of SD rats, demonstrating that the multiscale hierarchical design significantly improved the capacity of transplanted cells to promote and accelerate neovascularization and dermal reconstruction via enhancing cell infiltration, collagen deposition and growth factor expression. Our findings provide new insight into the development of degradable macroporous composite materials with 3D microstructures as tissue engineering scaffolds with enhanced vascularization functions, and also provide new treatment options for cell transplantation.

The flavonoid Astragalin shows anti-tumor activity and inhibits PI3K/AKT signaling in gastric cancer.

Gastric cancer is a common malignant cancer, which is one of the most affected cancers by PI3K/AKT signaling. Here, we investigated the anti-tumor role of Astragalin, a natural flavonoid compound, in gastric cancer and explored the underlying molecular mechanism. Three well-established gastric cancer cell lines and xenograft mouse model were used to examine the anti-tumor effect of Astragalin by using CCK-8, transwell assays, and Western blot. Tumor burden of xenograft mice with Astragalin administration was monitored and determined during and at end of the experiments. Astragalin could effectively inhibit cell viability of gastric cancer cells and possessed good anti-tumor activity in xenograft mice. In addition, astragalin induced the expression of apoptotic signaling proteins, suppressed the migration and invasion cancer cells, and inhibited the PI3K/AKT signaling pathway significantly. In contrast, epidermal growth factor stimulation was able to block the anti-tumor activity of Astragalin. In conclusion, astragalin exerts its anticancer activities through inhibiting PI3K/AKT signaling, which highlights its potential for the treatment of gastric cancer.

Angiogenesis effects of 4-methoxy benzyl alcohol on cerebral ischemia-reperfusion injury via regulation of VEGF-Ang/Tie2 balance.

Angiogenesis facilitates the formation of microvascular networks and promotes neurological deficit recovery after cerebral ischemia-reperfusion injury (CIRI). This study investigated the angiogenesis effects of 4-methoxy benzyl alcohol (4-MA) on CIRI. The angiogenesis effects of 4-MA and the potential underlying mechanisms were assessed based on a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model and a hind limb ischemic (HLI) mouse model. Immunofluorescence was conducted to detect microvessel density, and Western blotting and polymerase chain reaction were performed to determine the expression of angiogenesis-promoting factors. In addition, we investigated whether the angiogenesis effects of 4-MA caused damage to the blood-brain barrier (BBB). After treatment with 4-MA (20 mg/kg) for 7 days, the neurological deficits recovered and microvessel density in the cerebral cortex increased in the MCAO/R rats. Additionally, 4-MA also regulated the expression of angiogenesis factors, with an increase in vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) expression and a decrease in angiopoietin 1 (Ang-1), Ang-2, and Tie-2 expression in both MCAO/R rats and HLI mice. Moreover, 4-MA increased the expression of angiogenesis-promoting factors without exacerbating BBB cascade damage in MCAO/R rats. Our results indicated that 4-MA may contribute to the formation of microvascular networks, thus promoting neurological deficit recovery after CIRI.

Dually acid- and GSH-triggered bis(ß-cyclodextrin) as drugs delivery nanoplatform for effective anticancer monotherapy.

The intrinsic poor solubility and limited load capacity of ß-cyclodextrins (ß-CDs) results in reduced bioavailability, rendering the material unsuitable in complex biological environments. In this work, a pair of ß-CDs was methylated and covalently linked with acid-sensitive acylhydrazone and GSH-sensitive disulfide bonds to ensure a precise drug release pattern. The hydrophobic anticancer drug doxorubicin (Dox) was encapsulated inside the hydrophobic core of bis(ß-CD) via hydrophobic association with loading capacity of 24% in weight and a hydrodynamic size of about 100 nm. When exposed to acidic and reductive environments, the acylhydrazone and disulfide bonds were found to be cleaved, resulting in Dox release. Using fluorescence imaging and flow cytometry analysis, the designed bis(ß-CD) were determined to activate the drug release behavior by specific intracellular stimuli (pH and GSH). In vivo studies demonstrated specific drug delivery characteristics and controlled drug release behaviors in the tumor sites, giving rise to high antitumor activity and low toxicity. Taken in concert, this dual stimuli-responsive bis(ß-CD) with superior amphiphilicity and biocompatibility features showed great potential for future clinical applications.

Monoclonal Antibodies, Small Molecule Inhibitors and Antibody-drug Conjugates as HER2 Inhibitors.

Overexpression of human epidermal growth factor receptor (HER)-2 is found in a variety of cancers, often portending poor clinical outcomes. Therefore, HER2 is an attractive target for treatment. This review describes the research progress of HER2 targeted inhibitors in recent years. Excellent reviews are available, so we focus on the development, mechanisms of action, and structure-activity relationships of different types of inhibitors, including monoclonal antibodies, small molecule inhibitors, and antibody-drug conjugates (ADCs). In addition, the differences among them are compared.

A nanoprobe for ratiometric imaging of glutathione in living cells based on the use of a nanocomposite prepared from dual-emission carbon dots and manganese dioxide nanosheets.

A ratiometric fluorescence assay for glutathione (GSH) was developed. The novel assay is based on a nanoprobe composed of manganese dioxide nanosheets (MnO2 NS) and dual-emission carbon dots (de-CDs) with intrinsic GSH-response property. After construction of the nanoprobe, two emission peaks of de-CDs were suppressed to varying degrees by MnO2 NS. The suppression was relieved and the two emission peaks recovered proportionally when MnO2 NS was decomposed by GSH, thus realizing the ratiometric assay for micromolar GSH. The intrinsic responsiveness of de-CDs to millimolar GSH broadens the analytical range of the nanoprobe. An appropriate precursor, calcon-carboxylic acid, was screened out to synthesize de-CDs via one-step hydrothermal treatment. The de-CD@MnO2 NS nanoprobe can measure GSH concentrations through the fluorescence intensity ratio between 435 and 516 nm excited at 365 nm. The range of response was from 1 µM to 10 mM and the detection limit reached 0.6 µM (3σ criterion). Benefiting from its good biocompatibility, the proposed nanoprobe has excellent applicability for intracellular GSH imaging.Graphical abstract Schematic representation of glutathione (GSH) ratiometric detection. The nanoprobe is prepared from dual-emission carbon dots (de-CDs) and manganese dioxide nanosheets (MnO2 NS). GSH removes quenching effect by decomposing MnO2 NS and induces intrinsic response of de-CDs, which realizes ratiometric detection.

Topographic cues reveal filopodia-mediated cell locomotion in 3D microenvironment.

In cell-material interactions, the formation and functioning of filopodia have been demonstrated to be very sensitive to topographic cues. However, substrate-exploring functions of filopodia in a 3D microenvironment remain elusive. In this study, the silk fibroin film with a micropillar structure was prepared to reveal a filopodial-mediated cell response to 3D topographic cues. The micropillars provided a confined space for cell spreading by a simplified 3D structure, allowing initial cells to settle on the bottom of substrates rather than on the top of micropillars. Shortly after cell adhesion, the authors describe how cells transform from a filopodia-rich spherical cell state to a lamellipodia-dominated state that enables cell to climb along micropillars and spread on the top of the micropillars. The authors found that filopodia not only served as sensors for pathfinding but also provided nucleation scaffolds for the formation and orientation of minilamellipodia on the micropillar substrate. On the route of long filopodial extension following micropillars, all three functional filopodial adhesions have the ability to form veil-like minilamellipodium, simply by tethering the filopodium to the micropillars. Stable filopodia contacts consistently stimulated the local protrusion of a lamellipodium, which ultimately steered cell migration. Their results suggest the filopodia-mediated cell locomotion in the 3D microenvironment using a filopodia-to-minilamellipodium transformation mechanism.

Anti-neuroinflammatory effect of 3,4-dihydroxybenzaldehyde in ischemic stroke.

BACKGROUND: Increasing evidence from human and animal studies suggests that cerebral ischemic diseases are associated with nerve dysfunction and neuroinflammation. Therefore, alleviating neuroinflammation is a potential way to treat ischemic stroke. Gastrodia elata Blume (GEB) is a traditional Chinese medicine used to treat central nervous system diseases and related conditions, such as vertigo, headache, epilepsy. We have previously shown that GEB has a protective effect in ischemic stroke, and that the underlying mechanism is related to anti-neuroinflammation. 3,4-Dihydroxybenzaldehyde (DBD) is a phenolic component of GEB and may be responsible for the neuroprotective effect of GEB; however, the detailed molecular mechanisms underlying the effects of DBD are unknown. METHODS: The anti-neuroinflammatory effect of DBD and the potential mechanisms underlying it were assessed. We using a rat model of middle cerebral artery occlusion/reperfusion and lipopolysaccharide-treated BV2 microglial cells. RESULTS: DBD (10 mg/kg) significantly decreased infarct volume. Additionally, it alleviated neurological deficits in the rats by inhibiting microglia activation. DBD (0.01, 0.1, and 1 µM) also significantly decreased the levels of inflammatory mediators and cytokines such as tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, prostaglandin E2. Furthermore, phenotypic analysis of the BV2 cells showed that DBD significantly down-regulated the expression of M1 marker but significantly up-regulated the expression of M2 marker. Moreover, it suppressed nuclear factor (NF)-κB activation and inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase, and extracellular signal-regulated protein kinases 1/2. CONCLUSIONS: The neuroprotective and anti-inflammatory effects of DBD are associated with selective modulation of microglia polarization and reduction in the production of inflammatory mediators and cytokines through inhibition of MAPK and NF-κB activation. These findings suggest that DBD may be a potential treatment for ischemic stroke and other neuroinflammatory diseases.