Phloroglucinol derivatives, coumarins and an alkaloid from the roots of Evodia lepta Merr.

Two previously undescribed phloroglucinol derivatives [(±) evolephloroglucinols A and B], five unusual coumarins [evolecoumarins A and B and (±) evolecoumarins C-E], and one novel enantiomeric quinoline-type alkaloid [(±) evolealkaloid A], along with 20 known compounds, were isolated from the EtOH extract of the roots of Evodia lepta Merr. Their structures were elucidated by extensive spectroscopic analyses. The absolute configurations of the undescribed compounds were determined by X-ray diffraction or computational calculations. Their anti-neuroinflammatory effects were assayed. Among the identified compounds, compound 5a effectively reduced nitric oxide (NO) production with an EC50 value of 22.08 ± 0.46 µM. Hence, it could indeed inhibit the lipopolysaccharide (LPS)-induced Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome.

A bifunctional bortezomib-loaded porous nano-hydroxyapatite/alginate scaffold for simultaneous tumor inhibition and bone regeneration.

Treatments of osteolytic lesions due to malignant metastasis remain one of the major clinical challenges. The residual tumor cells after surgical resections and an acidic tumor microenvironment are unfavorable for osteogenic induction. Bortezomib (BTZ), a proteasome inhibitor used in chemotherapy, also has an osteogenic potential in concentration- and Ca2+-dependent manners. In this study, controlled delivery of BTZ in a novel bifunctional scaffold based on nano-hydroxyapatite (nHA) and sodium alginate (SA) nanocomposite, namely BTZ/nHA@SA, has been explored. By smartly adjusting microenvironments, a sustainable release of Ca2+ from nHA could be achieved, which was not only able to cross-link SA but also to regulate the switch between the dual functions of tumor inhibition and bone regeneration of BTZ to promote the osteogenic pathway. The freeze-dried BTZ/nHA@SA scaffold has excellent interconnectivity, is capable to promote the attachment and proliferation of mouse embryonic osteoblast precursor cells, as well as effectively induces breast cancer cell death in vitro. Furthermore, in vivo, studies using a mouse tumor model and a rabbit femoral defect model showed that the BTZ/nHA@SA scaffold could promote tumor ablation, and also enhance bone repair. Therefore, the BTZ/nHA@SA scaffold has unique dual functions of inhibiting tumor recurrence and promoting bone tissue regeneration simultaneously. This smart bi-functional scaffold offers a promising novel approach for oncological treatments by synchronously orchestrating tumor inhibition and tissue regeneration for the repair of neoplastic bone defects.

Hydroxysafflor Yellow A Exerts Neuroprotective Effect by Reducing Aß Toxicity Through Inhibiting Endoplasmic Reticulum Stress in Oxygen-Glucose Deprivation/Reperfusion Cell Model.

Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 µM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-ß peptides (Aß) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aß toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress.

Flavonoid-containing supplements for preventing acute respiratory tract infections: A systematic review and meta-analysis of 20 randomized controlled trials.

BACKGROUND: This systematic review and meta-analysis was conducted to investigate the efficacy and safety of flavonoid-containing supplements in preventing acute respiratory tract infection (ARTI). METHODS: Randomized controlled trials (RCTs) investigating the effects of flavonoid-containing supplements on ARTI prevention in the aspects of ARTI incidence, mean ARTI sick days, symptoms, bio-immune markers, and adverse effects were searched in 5 databases. Data were searched from inception to November 26, 2021. Stata 16.0 was used to perform the meta-analysis. RESULTS: Twenty RCTs (n = 4521) were included in this systematic review and meta-analysis. Pooled results showed that in the flavonoid-containing supplement group, the ARTI incidence and mean ARTI sick days were significantly decreased compared to those in the control group (RR = 0.81, 95% CI: 0.74-0.89, p < 0.001; WMD = -0.56, 95% CI: -1.04 to -0.08, p = 0.021; respectively). In 8 RCTs, flavonoids were singly used for interventions, ARTI incidence in the experimental group significantly decreased compared to that in the control group (RR = 0.85, 95% CI: 0.72-1.00, p = 0.047). In ten RCTs, flavonoid-containing mixtures were applied for interventions, and ARTI incidence in the experimental group significantly decreased compared to that in the control group (RR = 0.79, 95% CI: 0.71-0.89, p < 0.001). Furthermore, the ARTI incidence and mean ARTI sick days were significantly decreased in the experimental group compared to those in the control group in the flavan-3-ols subgroup (RR = 0.79, 95% CI: 0.67-0.92, p = 0.002; WMD = -2.75, 95% CI: -4.30 to -1.21, p < 0.001; respectively) and the multiple subclasses subgroup (RR = 0.75, 95% CI: 0.63-0.88, p = 0.001; WMD = -0.56, 95% CI: -1.11 to -0.01, p = 0.046; respectively). However, the bio-immune markers including interleukin-6, hypersensitive-c-reactive-protein, tumor necrosis factor-α, and interferon-γ did not differ between the flavonoid group and the control group. Moreover, in the flavonoid-containing supplement group, the incidence of adverse reactions did not increase compared to that in the control group (RR = 1.16, 95% CI: 0.78-1.73, p = 0.469). CONCLUSIONS: This systematic review and meta-analysis showed that flavonoid-containing supplements were efficacious and safe in preventing ARTIs. The most important limitations result from the small number of trials, poor quality of some included RCTs, differences in the composition and types of interventions, principal subclasses of flavonoids, methods of administration, and methodology. Moreover, only a few RCTs conducted independent verification of the flavonoid supplements used in the trial in terms of purity and potency, which may lead to a potential source of bias. Thus, larger and better-designed studies are needed to further verify this conclusion.

[Role of m 6A Reader YTHDC2 in Differentiation of Human Bone Marrow Mesenchymal Stem Cells].

OBJECTIVE: To study the regulatory effect of YTH domain-containing protein 2 (YTHDC2), a member of N 6-methyladenosine (m 6A) readers, on the osteogenic or adipogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). METHODS: YTHDC2 expression was knocked down by small interfering RNA (siRNA) in vitro. Osteogenic differentiation and adipogenic differentiation of hBMSCs were induced after YTHDC2 knockdown in order to study the changes in the differentiation phenotype of hBMSCs. Alkaline phosphatase staining (ALP staining) and alizarin red S staining were performed to examine osteogenic activity and calcium-nodular formation. Nile red staining was performed to examine lipid-droplet formation. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess the expression of osteogenesis and adipogenesis-related genes. RNA-sequencing was performed to identify the transcriptome changes after YTHDC2 knockdown and to explore the potential regulatory mechanism by which YTHDC2 regulated the diferentiation of hBMSCs. RESULTS: In this study, we found that siRNA-induced YTHDC2 knockdown resulted in increased ALP activity and calcium-nodular formation of hBMSCs during osteogenic differentiation, and significantly upregulated the expression of osteogenesis-related genes. In addition, the lipid-droplet formation capacity of hBMSCs was decreased during adipogenic differentiation. The expression of adipogenesis-related genes was significantly down-regulated. Gene-set enrichmen analysis of RNA-seq data showed that YTHDC2 was significantly correlated with ribosome function and mRNA-translation-related signaling pathways. CONCLUSION: The findings indicate that YTHDC2 knockdown can promote the osteogenic differentiation of hBMSCs and inhibit the adipogenic differentiation. YTHDC2 knockdown may cause changes in ribosome function.

Pharmacotherapy weight-loss interventions to prevent type 2 diabetes in overweight or obese adults and older adults: A protocol for systematic review and network meta-analysis.

BACKGROUND: Obesity is a worldwide problem and is associated with multiple negative health effects. Obesity also has a direct relationship with risk of diabetes. Several pharmacotherapy weight-reducing interventions have been employed to prevent type 2 diabetes (T2D) in overweight or obese adults and older adults. However, data with respect to comparative effectiveness are limited. To address this gap, in this study, evidence on benefits of anti-obesity agents for preventing diabetes will be systematically reviewed using a network meta-analysis. METHODS: We will perform an online systematic search for randomized controlled trials (RCTs) investigating 5 FDA-approved anti-obesity agents for preventing T2D in obese or overweight adults and older adults through electronic databases of PubMed, Embase, and the Cochrane Library from inception until December 31, 2020. Two independent reviewers will screen titles, abstracts, and full-texts of all potentially eligible trials. Two authors working independently will abstract data on trial-, participant- and intervention-related characteristics. The primary outcome will be incidence of T2D. Secondary outcomes will be achievement of normoglycaemia in patients with prediabetes, percentage of individuals achieving at least 5% or 10% weight loss of their baseline weight. We will conduct pairwise meta-analyses for all outcomes included in this study. To determine comparative efficacy of multiple interventions, network meta-analysis with a frequentist random-effects model will be performed. Moreover, subgroup analyses and sensitivity analyses will be performed to assess the robustness of our findings. To evaluate publication bias, the comparison-adjusted funnel plot will be utilized. Stata version 14.0 and RevMan version 5.3.3 will be used to perform all statistical analyses. RESULTS: This study will evaluate the effectiveness of weight-loss medications on T2D prevention in overweight or obese people. CONCLUSIONS: This study will generate meaningful findings for overweight or obese adults and older adults, clinicians, and policy-makers concerning the optimal anti-obesity pharmacotherapy to decrease risk of T2D. STUDY REGISTRATION NUMBER: INPLASY202110104.

The role of USP34 in the fixation of titanium implants in murine models.

Ubiquitin-specific protease 34 (USP34), a member of the ubiquitin-specific protease family, regulates osteogenic differentiation of bone marrow mesenchymal stem cells via bone morphogenetic protein signaling. This study aimed to investigate the role of USP34 in fixation of titanium implants in mouse models. Eight-week-old Usp34-knockout (Prx1-Cre;Usp34f/f ) mice and their Usp34 wild-type (Usp34f/f ) control littermates were used. Experimental titanium implants were inserted into the distal ends of femurs and the edentulous area of maxillae. Two and four weeks after surgery, samples of femur and maxilla were obtained, and micro-computed tomography scanning, histomorphometric analyses, and push-in tests were performed on the samples. Compared with controls, Prx1-Cre;Usp34f/f mice showed reduced bone volume for both femurs and maxillae; a decreased femoral bone-implant contact ratio (BIC) at 2 wk [mean (standard error of the mean): 62.17% (2.15%) vs. 44.06% (3.45%)] and 4 wk [72.46% (1.61%) vs. 64.53% (1.93%)]; decreases in femoral bone volume fraction (BV/TV) and push-in resistance; and lower BIC and BV/TV of the maxillae. Taken together, our data demonstrate that specific deletion of Usp34 in mesenchymal stem cells impairs fixation of titanium implants in mice.

Pyrroloquinoline quinone attenuates isoproterenol hydrochloride­induced cardiac hypertrophy in AC16 cells by inhibiting the NF­κB signaling pathway.

Pyrroloquinoline quinone (PQQ) is a naturally occurring redox co­factor that functions as an essential nutrient and antioxidant, and has been reported to exert potent anti­inflammatory effects. However, the therapeutic potential of PQQ for isoproterenol hydrochloride (Iso)­induced cardiac hypertrophy has not yet been explored, at least to the best of our knowledge. In the present study, the anti­inflammatory effects of PQQ were investigated in Iso­treated AC16 cells, a myocardial injury cellular model characterized by an increase in the apparent surface area of the cells and the activation of intracellular cardiac hypertrophy­associated proteins. The results revealed that pre­treatment with PQQ significantly inhibited the expression of cardiac hypertrophy marker proteins, such as atrial natriuretic peptide, brain natriuretic peptide and ß­myosin heavy chain. PQQ also inhibited the activation of the nuclear factor (NF)­κB signaling pathway in Iso­treated AC16 cells, thus inhibiting the nuclear translocation of NF­κB and reducing the phosphorylation levels of p65. On the whole, the findings of this study suggest that PQQ may be a promising therapeutic agent for effectively reversing the progression of cardiac hypertrophy.

Lorcaserin for prevention and remission of type 2 diabetes mellitus in people with overweight or obesity: protocol for a systematic review and meta-analysis.

INTRODUCTION: High body mass index (BMI) is associated with risk of diabetes. Lorcaserin is a selective 5-hydroxytryptamine 2C agonist which exerts robust benefits on long-term weight loss by suppressing appetite among adults with overweight or obesity. The magnitude of efficacy of lorcaserin for preventing and remitting type 2 diabetes mellitus (T2DM) among those people remains undefined. Therefore, we plan to conduct this systematic review and meta-analysis to aggregate data from all published studies with regard to the issue to acquire reliable evidence. METHODS AND ANALYSIS: We will search various databases for relevant trials published up to June 2019. Randomised controlled trials investigating the efficacy of lorcaserin for preventing and remitting T2DM among overweight and obese population will be included. A standardised data form will be used to complete data search and extraction in duplicate. All discrepancies will be resolved by consensus. The primary outcome will be incidence of T2DM in patients with pre-diabetes. Secondary outcomes will include achievement of normoglycaemia in people with pre-diabetes, remission of hyperglycaemia in patients with diabetes, the proportion of patients with weight loss of at least 5% or 10% and hypoglycaemia incident. Data synthesis and statistical analysis will be performed for each outcome with Stata V.14.0. ETHICS AND DISSEMINATION: Ethics approval is not required. Results of our study will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42019119136.

Epigallocatechin-3-gallate inhibits angiotensin II-induced cardiomyocyte hypertrophy via regulating Hippo signaling pathway in H9c2 rat cardiomyocytes.

Angiotensin II (AII) has been well known to induce cardiomyocyte hypertrophy. Epigallocatechin-3-gallate (EGCG) is the main active component of green tea and it has been shown to exhibit strong cardioprotective potential, although the underlying molecular mechanisms remain unclear. In this study, we investigated the role and mechanism of EGCG in preventing AII-induced cardiomyocyte hypertrophy using rat H9c2 cardiomyocytes cells. Reactive oxygen species assay, cell size, and mRNA expression of cardiac hypertrophy markers ANP and BNP were assessed in response to AII treatment. In addition, expression of proteins involved in Hippo signaling pathway were determined by western blot analysis. We found that AII treatment resulted in significant upregulation of ANP and BNP expression levels and increase in H9c2 cell size, which were markedly attenuated by EGCG treatment. Furthermore, our results suggested that EGCG inhibited AII-induced cardiac hypertrophy via regulating the Hippo signaling pathway. Therefore, EGCG may be an effective agent for preventing cardiac hypertrophy.

Graphene-Nanoparticle-Based Self-Healing Hydrogel in Preventing Postoperative Recurrence of Breast Cancer.

Hydrogel is an ideal scaffold in the fields of regenerative medicine and tumor therapy because of its biomimetic ability to modulate tissue microenvironment. Herein, we fabricated a new kind of self-healing hydrogel based on graphene nanoparticle and expanded its application in postoperative recurrence of breast cancer. First, a facile method was used to prepare self-healing hydrogel via Schiff-base linkage, which composed of chondroitin sulfate multialdehyde (CSMA), branched polyethylenimine (BPEI) and BPEI conjugated graphene (BPEI-GO). BPEI-GO was doped in the network and participated in Schiff-base reaction and stabilized the structure, as well as provided sustained drug delivery, and near-infrared laser (NIR)-triggered photothermal effect. The hydrogels exhibited excellent self-healing (∼100%) and improved mechanical properties (7,000 Pa). Further, in vitro breast cancer cell inhibition study showed enhanced cell killing efficiency with synergistic chemo-photothermal therapy. In the breast cancer postoperative recurrence prevention mice model, we found that combination of Doxorubicin (DOX) and photothermal therapy in CSMA/BPEI/BPEI-GO hydrogels group reduced tumor recurrence to 33.3%, compared with 66.7% for DOX-loaded hydrogels without NIR irradiation, 66.7% for local administration of free DOX, 100% for hydrogels with NIR irradiation, blank hydrogels, and blank control. This study suggests the great potential of CSMA/BPEI/BPEI-GO hydrogels for postoperative recurrence prevention of breast cancer.

Use of statins and the risk of delirium in critically ill and surgical patients: Protocol of a systematic review and meta-analysis.

BACKGROUND: The critically ill and surgical patients are at significant risk of delirium, which is associated with a high morbidity and mortality. The association between statin use and the incidence of delirium is still controversial. In this article, we will perform a systematic review and meta-analysis of published studies to evaluate the effectiveness of statins for the prophylaxis of delirium among critically ill and surgical patients. METHODS: We will conduct a systematic literature search in EMBASE, PubMed, and the Cochrane Library from inception date to October 2018 for randomized controlled trials (RCTs) and observational studies (either cohort or case-control studies) investigating the association between use of statins and delirium risk. The Cochrane Collaboration's tool for evaluating the risk of bias and Newcastle-Ottawa scale (NOS) will be used to assess the methodological quality of RCTs and observational studies, separately. The primary outcome will be the risk of incident delirium associated with statin use. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) will be calculated by a random-effects or fixed-effects model according to heterogeneity among included studies. Subgroup analyses, meta-regression method, and assessment of publication bias will be also performed. Statistical analyses will be conducted with RevMan (version 5.3.5) and Stata (version 14.0) software. In addition, the grading of recommendations assessment, development and evaluation (GRADE) approach will be applied to evaluate the quality of evidence. RESULTS: The study will provide a high-quality synthesis and evaluate the effectiveness of statins for delirium prevention among critically ill and surgical patients. CONCLUSIONS: The systematic review and meta-analysis will provide convincing evidence concerning the effect of statins against delirium in critically ill and surgical patients.

Pharmacologic interventions for preventing delirium in adult patients after cardiac surgery: Protocol of a systematic review and network meta-analysis.

BACKGROUND: Delirium is common in adult patients undergoing cardiac surgery and related to a high morbidity and mortality. Although a variety of pharmacologic interventions have been applied in delirium prevention, there is still uncertainty concerning which drug is optimal. Thus, we plan to conduct a systematic review and network meta-analysis (NMA) of published studies to assess the efficacy and safety of pharmacologic interventions for preventing delirium among those patients. METHODS: A systematic literature search will be conducted in Embase, PubMed, and the Cochrane Library. The primary outcome will be the incidence of postoperative delirium. Secondary outcomes will include all-cause mortality and length of hospital or intensive care unit stay. A frequentist NMA will be conducted using Stata version 14.0. The inconsistency between direct and indirect comparisons will be evaluated using a node splitting method. In addition, surface under the cumulative ranking area will be used to evaluate superiority of different treatments. RESULTS: The findings of our review will be submitted to a peer-reviewed publication. CONCLUSION: Our study will generate convincing evidence regarding the effectiveness and safety of different pharmacologic interventions for delirium prevention in cardiac surgery patients.