Breviscapine attenuates lead­induced myocardial injury by activating the Nrf2 signaling pathway.

The present study investigated the therapeutic potential of breviscapine (Bre) in mitigating lead (Pb)-induced myocardial injury through activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway. Rat cardiomyocytes (H9C2 cells) were exposed to Pb to model Pb poisoning, and various parameters, including cell viability, apoptosis and reactive oxygen species (ROS) production, were assessed using Cell Counting Kit-8, flow cytometry and 2',7'-dichlorfluoresceindiacetate assays, respectively. Additionally, a rat model of Pb poisoning was established in which blood Pb levels were measured using a graphite furnace atomic absorption spectrophotometer, and alterations in myocardial tissue, oxidative stress markers, inflammatory indicators, protein expression related to apoptosis and the Nrf2 pathway were evaluated via histopathology, ELISA and western blotting. The results showed that Bre treatment enhanced cell viability, decreased apoptosis, and reduced ROS production in Pb-exposed H9C2 cells. Moreover, Bre modulated oxidative stress markers and inflammatory factors while enhancing the expression of proteins in the Nrf2 pathway. In a rat model, Bre mitigated the lead-induced increase in blood Pb levels and myocardial injury biomarkers, and reversed the downregulation of Nrf2 pathway proteins. In conclusion, the current findings suggested that Bre mitigates Pb-induced myocardial injury by activating the Nrf2 signaling pathway, highlighting its potential as a therapeutic agent for protecting the heart from the harmful effects of Pb exposure. Further research is required to elucidate the exact mechanisms and explore the clinical applicability of Bre in mitigating Pb-induced myocardial damage.

Primary synovial sarcoma of the thyroid gland: a CARE compliant case report and literature review.

Rationale: Synovial sarcoma is a subtype of soft tissue sarcoma. Synovial sarcoma in the head and neck region is relatively unusual. Primary synovial sarcoma of the thyroid gland (PSST) is first reported in 2003 by Inako Kikuchi. PSST is extremely rare with only 15 cases documented globally. PSST shows rapid disease progression and a relatively poor prognosis. However, diagnosis and therapy are challenging for clinical surgeons. In this article, we reported the 16th PSST case and reviewed the PSST cases globally for further clinical application. Patient concerns: The patient was referred to us because of gradually worsened dyspnea and dysphagia for 20 days. Physical examination showed a 5 × 4 cm mass with a clear boundary and good mobility. Contrast-enhanced ultrasonography (CEUS) and computed tomography (CT) showed a mass in the isthmus of the thyroid gland. The imageology diagnosis tends to be a benign thyroid nodule. Diagnosis: After surgery, histopathology, immunohistochemistry, and fluorescence, in situ hybridization indicated the mass to be primary synovial sarcoma of the thyroid gland with no local and distant metastasis. Interventions: The patient underwent total thyroidectomy and dissected the lymph nodes in the central compartment. This patient received postoperative chemotherapy (a combination of ifosfamide and epirubicin for five cycles). Patients tolerated chemotherapy well. No recurrence was found during the 9-month follow-up. Lessons: Although PSST is an extremely rare disease, we should raise our awareness when we encounter a rapidly growing, cystic-solid mixed thyroid mass with neck compression symptoms to avoid misdiagnosis. Intraoperatively, surgeons should refine surgical procedures to avoid capsular rupture and tumor local implantation metastasis. Intraoperative frozen section pathology is necessary sometimes, especially when the diagnosis could not be established before surgery.

Development of a responsive probe for colorimetric and fluorescent detection of bisulfite in food and animal serum samples in 100% aqueous solution.

Bisulfite (HSO3-) has the functions of bleaching, antiseptic, antioxidant, inhibiting bacterial growth, and controlling enzymatic reactions in food. However, long-term consumption of foods containing excessive amounts of bisulfite can be harmful to health. In addition, large doses of sulfur dioxide (SO2) can cause diarrhea, hypotension, allergic and asthmatic reactions in susceptible individuals. Therefore, it is urgent and essential to explore some rapid, reliable, and convenient tools to detect HSO3- in food and SO2 gas. Herein, we exploited a fluorescent probe, NPO, to detect HSO3- in 100 % aqueous solution. The probe has the advantages of easy synthesis, excellent water solubility, significant colorimetric change, good selectivity, high sensitivity, and fast response (within 1 min). Probe NPO was successfully applied for testing strips to visualize the behavior of HSO3- and SO2 gas. Moreover, the probe has been used to monitor the behavior of HSO3- in real food samples and animal serum samples.

Deficit irrigation and leaf removal modulate anthocyanin and proanthocyanidin repartitioning of Cabernet Sauvignon (Vitis vinifera L.) grape and resulting wine profile.

BACKGROUND: In monsoonal climates, grape anthocyanin and proanthocyanidin (PA) accumulations are unsatisfactory for producing optimal wine. Agronomical practices are often considered to be effective means for regulating fruit components. However, there is a lack of quantitative information on the effects of deficit irrigation (DI), basal leaf removal (LR) or their combination of deficit irrigation and leaf removal (DILR) on the characteristics of anthocyanin and PA compositions and their implications on the resulting wine quality. In this study, the dynamics of grape anthocyanin and PA accumulation were investigated in DI, LR and DILR during grape ripening, and the resulting wine profile was assessed. RESULTS: The contents of reducing sugar and total anthocyanins in Cabernet Sauvignon berries were significantly increased by DI, LR and DILR, while titratable acidity, total flavan-3-ols and tannins levels were generally decreased. Notably, the levels of 3'5'-substituted anthocyanins, such as malvidin and its derivatives significantly increased, and 3'-substituted anthocyanins decreased in both grape and wine under DI and DILR strategies. Skin PAs were sensitive to water deficits, whereas they were insensitive to LR. In resulting wine, PAs content and the proportion of 3'-hydroxylated PAs, such as (+)-catechin, (-)-epicatechin and (-)-epicatechin-3-O-gallate units were significantly decreased under DI and DILR, while molecular mass and the proportion of 3'5'-hydroxylated units of PAs were increased in response to DILR. CONCLUSION: The DILR was the most favorable for the repartitioning of anthocyanin and PA metabolites, and promoted the accumulation of tri-substituted forms contributing a higher color intensity, mouthfeel persistence, structure, and astringency of wine. This information provides an important strategy for modulating the anthocyanin and PA compositions by agricultural practices and achieving the desired quality of grapes and wines in monsoonal climates. © 2021 Society of Chemical Industry.

Assessing MicroRNA-375 Levels in Type 2 Diabetes Mellitus (T2DM) Patients and Their First-Degree Relatives with T2DM.

PURPOSE: The pancreatic islet specific microRNA-375 (miR-375) is overexpressed in type 2 diabetes mellitus (T2DM) patients suppressing the glucose-induced insulin secretion. Thus, miR-375 may serve as a biomarker for the early prediction of T2DM among high-risk individuals. We conducted this clinical study to assess the significance of miR-375 among type 2 diabetes mellitus (T2DM) patients and their first-degree relatives. PATIENTS AND METHODS: We included 56 Han Chinese individuals (N: NGT = 21, T2DM = 10, FD-NGT =13 and FD-T2DM = 12) who received medical health check-ups from January 2018 to September 2018 at The Third Hospital of Yunnan Province, China. They were categorized as normal glucose tolerance (NGT), T2DM, first-degree relatives with normal glucose tolerance (FD-NGT) and first-degree relatives with T2DM (FD-T2DM). OGTT, C-peptide and Insulin tests were performed to confirm the diagnosis. The miR-375 levels were determined by Quantitative real-time RT-PCR (qRT-PCR). RESULTS: The OGTT test showed a significant difference in T2DM and FD-T2DM groups compared with NGT and FD-NGT (p< 0.05). Similar results were observed during C-peptide and insulin tests. Interestingly, the 2-hour insulin test showed FD-NGT group having a significantly higher mean ± standard error of (64.240 ± 12.775) compared to NGT (28.836 ± 10.875). Assessment of miR-375 expression levels in 4 groups showed a significant up-regulation in T2DM and FD-T2DM compared with NGT and FD-NGT groups. A slight increase in miRNA expression was observed in FD-NGT compared with NGT group but was not statistically significant. CONCLUSION: The OGTT, C-peptide and insulin tests revealed a statistically significant difference in T2DM and FD-T2DM compared with NGT and FD-NGT groups. A significantly higher miR-375 expression was also observed in T2DM and FD-T2DM groups compared with NGT and FD-NGT and thus, miR-375 may serve as a stable biomarker for the early prediction of T2DM among high-risk individuals.

LncRNA HOTAIRM1 knockdown inhibits cell glycolysis metabolism and tumor progression by miR-498/ABCE1 axis in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a major contributor of cancer-related mortality. Long non-coding RNAs (lncRNAs) are indicated to participate in the pathogenesis of NSCLC. OBJECTIVE: In this research, the effects of lncRNA HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1) on NSCLC progression and underlying mechanism were revealed. METHODS: The expression levels of HOTAIRM1 and microRNA-498 (miR-498) were detected by quantitative real time polymerase chain reaction (qRT-PCR) in NSCLC tissues, cells or exosomes. The protein expression of CD63, CD81, hexokinase 2 (HK2) and ATP binding cassette subfamily E member 1 (ABCE1) was determined by western blot. Cell viability, apoptosis, migration and invasion were investigated by cell counting kit-8 (CCK-8), flow cytometry, transwell migration and invasion assays, respectively. Cell glycolysis metabolism was revealed by glucose uptake and lactate production assays and western blot analysis. The binding relationship between miR-498 and HOTAIRM1 or ABCE1 was predicted by DIANA-LncBase v2 and starBase online database, and identified by dual-luciferase reporter assay. The effects of HOTAIRM1 on NSCLC growth in vivo were revealed by in vivo tumor formation assay. RESULTS: HOTAIRM1 expression was dramatically upregulated, whereas miR-498 expression was significantly downregulated in NSCLC tissues cells or exosomes as compared to control groups. Mechanistically, HOTAIRM1 knockdown repressed cell viability, migration, invasion and glycolysis metabolism, whereas induced cell apoptosis in NSCLC; however, miR-498 inhibitor hindered these effects. Functionally, HOTAIRM1 functioned as a sponge of miR-498 and miR-498 targeted ABCE1. In addition, HOTAIRM1 silencing inhibited NSCLC growth in vivo by downregulating ABCE1 and upregulating miR-498 expression. CONCLUSIONS: HOTAIRM1 knockdown repressed cell glycolysis metabolism and tumor development by reducing ABCE1 expression through sponging miR-498 in NSCLC, which provided a theoretical basis for further studying NSCLC progression.

1-Aminocyclopropane-1-Carboxylate Deaminase-Producing Plant Growth-Promoting Rhizobacteria Improve Drought Stress Tolerance in Grapevine (Vitis vinifera L.).

Plant growth-promoting rhizobacteria (PGPRs) that produce 1-aminocyclopropane-1-carboxylate (ACC) deaminase are capable of reducing limits to plant growth due to water-deficient conditions. Here, seven PGPR strains that can produce ACC deaminase were successfully obtained from the rhizosphere soil of grapevine (Vitis vinifera L.) in arid regions of China. The strains belonged to three different genera: Pseudomonas, Enterobacter, and Achromobacter, according to their 16S rDNA sequencing analysis. A drought tolerance experiment revealed two PGPR strains (DR3 and DR6) with exceptionally high phosphate solubilization, nitrogen fixation, indoleacetic acid (IAA), and exopolysaccharides secretion potential. Both strains were selected for use in a pot experiment to evaluate their growth-promoting effects on grapevines under drought conditions. Each of these two PGPRs and their mixed inoculation into grapevines were expected to alleviate the comprehensive growth inhibition of grapevines caused by drought stress. The mixed inoculation was hypothesized to elicit the best growth-promoting effects. Inoculation with the PGPRs not only enhanced the root-adhering soil/root tissue ratios and soil aggregate stability, but it also increased the nitrogen and phosphorus levels in the soil and plant leaves. Further, inoculation with PGPRs significantly altered the plant height, biomass of shoot and root organs, relative water contents, and net photosynthetic rate of leaves, enabling grapevines to better cope with drought. Moreover, the contents of IAA, abscisic acid, and malondialdehyde in these grapevines under drought stress were significantly changed by PGPRs. They indirectly affected biochemical and physiological properties of grapevines to alleviate their drought stress. Taken together, these results demonstrate that the DR3 and DR6 PGPRs might be useful for effectively weakening the growth inhibition caused by drought in grapevines. The strains might also be applied as effective bioinoculants to maintain the quality of wine grapes.

Cyclin E: a potential treatment target to reverse cancer chemoresistance by regulating the cell cycle.

The cyclin family plays important roles in regulating the proliferative cycle of mammalian cells. Among the members of this family, cyclin E regulates multiple downstream molecules, such as the retinoblastoma susceptibility gene (RB1) and the transcription factor E2F, by interacting with cyclin-dependent kinases (CDKs) and plays an important role in the cell cycle transition from G1 to S phase. Over the years, studies have shown that cyclin E is closely related to the chemotherapy resistance of tumor cells and that its expression in tumor cells is closely related to prognosis. The dysregulated expression of cyclin E has a definite effect not only on the cell cycle regulation of tumor cells but also on the presence of low-molecular-weight cyclin E (LMW-E) and other cyclins that render tumor cells resistant. In addition, many studies in recent years have confirmed that chemotherapy resistance mediated by cyclin E can be reversed. For example, the combination of a cyclin-dependent kinase inhibitor (CKI) with anticancer drugs or the therapeutic targeting of related genes improves chemotherapy resistance by reducing the level or activity of cyclin E in tumor cells. This review summarizes the specific processes by which cyclin E regulates the cell cycle, its relationship to chemotherapy resistance in cancer, and its potential as a clinical therapeutic target to reverse chemotherapy resistance.

Exosomes: A Potential Therapeutic Tool Targeting Communications between Tumor Cells and Macrophages.

Exosomes comprise extracellular vesicles (EVs) with diameters between 30 and 150 nm. They transfer proteins, RNA, and other molecules from cell to cell, playing an important role in the interactions between cells. The tumor microenvironment (TME) has been found to contain various cells and molecules that have an important impact on tumor development. In the TME, macrophages have been found to have an important relationship with tumor cells, with tumors recruiting and inducing macrophages to become tumor-associated macrophages (TAMs), which promote tumor development. Recently, exosomes have been found to play a critical role in the interaction between tumor cells and macrophages. Thus, in this review, we summarize the roles and mechanisms of exosomes in the interaction between tumor cells and macrophages and the potential methods by which exosomes are used to target the communication between tumor cells and macrophages to treat cancer.

Natural Prenylchalconaringenins and Prenylnaringenins as Antidiabetic Agents: α-Glucosidase and α-Amylase Inhibition and in Vivo Antihyperglycemic and Antihyperlipidemic Effects.

Inhibition of α-glucosidase and α-amylase decreases postprandial blood glucose levels and delays glucose absorption, making it a treatment strategy for type 2 diabetes. This study examined in vivo and in vitro antidiabetic activities of natural prenylchalconaringenins 1 and 2 and prenylnaringenins 3 and 4, found in hops and beer. 3'-Geranylchalconaringenin (2) competitively and irreversibly inhibited α-glucosidase (IC50 = 1.08 µM) with activity 50-fold higher than that of acarbose (IC50 = 51.30 µM) and showed moderate inhibitory activity against α-amylase (IC50 = 20.46 µM). Docking analysis substantiated these findings. In addition, compound 2 suppressed the increase in postprandial blood glucose levels and serum levels of total cholesterol and triglycerides in streptozotocin-induced diabetic mice. Taken together, these results suggest that 2 has dual inhibitory activity against α-glucosidase and α-amylase and alleviates diabetic hyperglycemia and hyperlipidemia, making it a potential functional food ingredient and drug candidate for management of type 2 diabetes.

Inhibitory activity evaluation and mechanistic studies of tetracyclic oxindole derivatives as α-glucosidase inhibitors.

α-Glucosidase inhibitors are known to prevent the digestion of carbohydrates and reduce the impact of carbohydrates on blood glucose. Three series of tetracyclic oxindole derivatives were designed, synthesized and evaluated for α-glucosidase inhibitory activity in vitro. Compound 6t exhibited the most potent inhibitory activity with IC50 0.7 µM and was about 170 times as active as acarbose (IC50 = 115.8 µM). The kinetic analysis of compound 6t revealed it inhibited α-glucosidase in an irreversible and mixed manner. Fluorescence spectra indicated that 6t directly bound to α-glucosidase. Docking simulation showed the existence of potential H-bonding, van der Waals, Pi and Sigma-Pi interactions between 6t and α-glucosidase.

Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway.

Epalrestat is a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy. This study assumed that epalrestat had a protective effect on diabetic peripheral nerve injury by suppressing the expression of aldose reductase in peripheral nerves of diabetes mellitus rats. The high-fat and high-carbohydrate model rats were established by intraperitoneal injection of streptozotocin. Peripheral neuropathy occurred in these rats after sustaining high blood glucose for 8 weeks. At 12 weeks after streptozotocin injection, rats were intragastrically administered epalrestat 100 mg/kg daily for 6 weeks. Transmission electron microscope revealed that the injuries to myelinated nerve fibers, non-myelinated nerve fibers and Schwann cells of rat sciatic nerves had reduced compared to rats without epalrestat administuation. Western blot assay and immunohistochemical results demonstrated that after intervention with epalrestat, the activities of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase gradually increased, but aldose reductase protein expression gradually diminished. Results confirmed that epalrestat could protect against diabetic peripheral neuropathy by relieving oxidative stress and suppressing the polyol pathway.

Synthesis, α-glucosidase inhibitory and molecular docking studies of prenylated and geranylated flavones, isoflavones and chalcones.

Three series of prenylated and/or geranylated flavonoids were synthesized and evaluated for their α-glucosidase inhibitory activity. The 3',5'-digeranylated chalcone (16) was identified as a new α-glucosidase inhibitor whose activity (IC50=0.90 µM) was 50-fold more than that of acarbose (IC50=51.32 µM). Molecular docking studies revealed the existence of strong hydrophobic interaction and H-bonding between compound 16 and α-glucosidase's active site. The inhibitory mode analysis showed that 16 exhibited a competitive inhibitory mode.

miR21 is Associated with the Cognitive Improvement Following Voluntary Running Wheel Exercise in TBI Mice.

Recent evidences revealed that the alteration of microRNAs (miRNAs) might be associated with neuroplasticity induced by voluntary running wheel (RW) exercise in mice suffered from traumatic brain injury (TBI). In the present study, we explored the possible role of miR21 involved in the cognitive improvement following voluntary RW in TBI mice. Firstly, in situ hybridization and quantitative real-time PCR (qRT-PCR) were employed to determine the hippocampal expression and location of miR21 in TBI mice with or without spontaneous RW. Either miR21-mimics/plenti-miR21 or miR21-agomir/miR21-sponge was employed to regulate the miR21 expression in vivo and in vitro. Acquisition of spatial learning and memory retention was assessed by Morris Water Maze (MWM) test. Golgi stain was also performed to evaluate the alteration of hippocampal dendrite. Our finding confirmed that the elevated miR21 level in hippocampal post-TBI was significantly reduced by spontaneous RW. Overexpression of miR21 in TBI mice with spontaneous RW induced deteriorations in spatial learning and memory retention by significant decreases in the somata size and branch points of the hippocampus neurons. In vitro transduction with miR21 also reduced the neurite extension and the area of cultured hippocampal neuron. However, miR21 down-regulation reversed these effects. The present data strongly suggest that miR21 is an important molecule that has been involved in neuroprotection induced by voluntary RW exercise post-TBI.

Design, synthesis and docking study of novel tetracyclic oxindole derivatives as α-glucosidase inhibitors.

A series of novel tetracyclic oxindole derivatives were synthesized via tandem Suzuki coupling-Michael addition reaction catalyzed by palladium. Twenty derivatives were designed and synthesized in 6-8 steps in 8-20% overall yields. Their structures were confirmed by (1)H, (13)C NMR and LC/MS. These compounds were evaluated for α-glucosidase inhibitory activity in vitro. Compounds 7c, 7d, 7e, 7g, 7h, and 7i exhibited IC50 values of 32.3, 12.1, 15.7, 29.0, 16.0, and 4.8 µM, respectively, with potency all higher than that of the control standard acarbose (IC50=115.8 µM). Molecular docking studies revealed the existence of potential hydrogen bonding and hydrophobic interaction between the enzyme and the active compound 7i.

Elevated glucose-6-phosphate dehydrogenase expression in the cervical cancer cases is associated with the cancerigenic event of high-risk human papillomaviruses.

The most important etiologic agent in the pathogenesis of cervical cancers (CCs) is human papillomavirus (HPV), while the mechanisms underlying are still not well known. Glucose-6-phosphate dehydrogenase (G6PD) is reported to elevate in various tumor cells. However, no available references elucidated the correlation between the levels of G6PD and HPV-infected CC until now. In the present study, we explored the possible role of G6PD in the pathology of CC induced by HPV infection. Totally 48 patients with HPV + CC and another 63 healthy women enrolled in the clinical were employed in the present study. Overall, prevalence of cervical infection with high-risk-HPV (HR-HPV) type examined was HPV-16, followed by HPV-18. The expressions of G6PD in CC samples were also detected by immunohistochemistry (IHC), qRT-PCR, and Western blot. Regression analysis showed elevated G6PD level was positively correlated with the CC development in 30-40 aged patients with HR-HPV-16/18 infection. The HPV16 + Siha, HPV18 + Hela, and HPV-C33A cell lines were employed and transfected with G6PD deficient vectors developed in vitro. MTT and flow cytometry were also employed to determine the survival and apoptosis of CC cells after G6PD expressional inhibition. Our data revealed that G6PD down-regulation induced poor proliferation and more apoptosis of HPV18 + Hela cells, when compared with that of HPV16 + Siha and HPV-C33A cells. These findings suggest that G6PD expressions in the HR-HPV + human CC tissues and cell lines play an important role in tumor growth and proliferation.