Marine-Derived Bisindoles for Potent Selective Cancer Drug Discovery and Development.

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.

The outcome of IV vitamin C therapy in patients with sepsis or septic shock: a meta-analysis of randomized controlled trials.

BACKGROUND: To update a meta-analysis of randomized controlled trials (RCTs) and further explore the outcome of IV vitamin C (IVVC) administration in sepsis or septic shock patients. METHODS: This study is a meta-analysis of RCTs. The RCTs of vitamin C therapy in sepsis or septic shock were searched in PubMed, EMBASE and Clinical Trials.gov from inception to January 16, 2023. We registered the protocol with PROSPERO (CRD42022354875). The primary outcome was delta Sequential Organ Failure Assessment (SOFA) score at 72-96 h. Two reviewers independently assessed RCTs according to eligibility criteria: (1) study type: RCT; (2) patient population: patients ≥ 18 years with sepsis or septic shock; (3) intervention: IVVC at any doses as monotherapy or combined with thiamine or and hydrocortisone compared with standard of care, no intervention or placebo (defined as control group); (4) the RCT described short-term mortality or SOFA score. Then, two authors independently extracted related information from RCTs. RESULTS: Eighteen RCTs (n = 3364 patients) were identified in this meta-analysis. There were significant effects in the delta SOFA score from baseline to 72-96 h (MD, - 0.62; 95% CI, - 1.00 to - 0.25; p = 0.001) and the duration of vasopressor use (MD, - 15.07; 95% CI, - 21.59 to - 8.55; p < 0.00001) with IVVC therapy. Treatment with IVVC was not shown to improve short-term mortality (OR, 0.89; 95% CI, 0.77 to 1.04; p = 0.14); nevertheless, dose at 25-100 mg/kg/d subgroup associated with a significant reduction in short-term mortality (OR, 0.80; 95% CI, 0.65 to 0.97; p = 0.03). An increase adverse event was observed in IVVC therapy (OR, 1.98; 95% CI, 1.06 to 3.68; p = 0.03). CONCLUSION: In this meta-analysis, IVVC in sepsis or septic shock patients significantly improved delta SOFA score and reduced the duration of vasopressor use, whereas it was not associated with reduction in short-term mortality and had higher adverse events.

Salidroside alleviates dexamethasone-induced inhibition of bone formation via transforming growth factor-beta/Smad2/3 signaling pathway.

Glucocorticoid-induced osteoporosis is the third epidemic osteoporosis following postmenopausal and senileosteoporosis. According to one study, salidroside made ovariectomized rats' bones strong. Salidroside's potential for treating glucocorticoid-induced osteoporosis remains unproven. This study aimed to investigate the protective effect and mechanism of salidroside on dexamethasone-induced osteogenic differentiation and bone formation in MC3T3-E1 cells and zebrafish. The study proved that salindroside had no harmful impact on MC3T3E1 cells. Salidroside significantly relieved dexamethasone-induced inhibition of ALP (alkaline phosphatase) activity and mineralization in MC3T3-E1 cells, and promoted osteogenic differentiation of cells. Salidroside increased the expression of osteopontin (OPN), runt-related transcription factor 2 (Runx2), osterix (Osx), transforming growth factor-beta (TGF-ß) proteins and promoted the phosphorylation of Smad2/3 in MC3T3-E1 cells treated with dexamethasone. In addition, the effect of salidroside in relieving dexamethasone-induced inhibition of osteogenic differentiation in MC3T3-E1 cells can be blocked by TGF-ß receptor type I/II inhibitor (LY2109761). At the same time, we found that salidroside significantly alleviated the inhibition of dexamethasone-induced bone formation in zebrafish and promoted the mineralization of zebrafish skulls. LY2109761 reversed the protective impact of salidroside on dexamethasone-mediated bone impairment in zebrafish. These findings suggested that salidroside alleviated dexamethasone-induced inhibition of osteogenic differentiation and bone formation via TGF-ß/Smad2/3 signaling pathway.

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids.

Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs.

Isolation, synthesis, and cytotoxicity evaluation of two impurities in nomegestrol acetate.

Nomegestrol acetate (NOMAc) is a synthetic progesterone analog and classified as a fourth-generation progestin. It has been approved in many countries for oral contraception, hormonal replacement therapy (HRT), and treatment of various gynecological disorders. There are several synthetic routes reported for the synthesis of NOMAc and they all share the very similar last three to five steps toward the conversion of 6-methylene to 6-methyl-6,7-unsaturated structure. Therefore the final product from different processing routes may have similar impurity profiles. In the analysis of NOMAc, we identified two impurities, impurity A (listed in EP 8.0) and impurity B (not specified in EP 8.0). Both impurities were further confirmed by synthesis. In addition, both impurities and NOMAc were evaluated for their in vitro cytotoxicities against L02 liver cells, mesenchymal stem cells, MCF-7 breast cancer cells, and C33A cervical cancer cells. These three analogs are not cytotoxic to the four cell lines at low concentrations (<20 µM). NOMAc and impurity A showed cytotoxicity to L02, MCF-7, and C33A cells at high concentrations, while impurity B did not show significant cytotoxicity to any of the cell lines tested.

[Systematic review of Shenqi Fuzheng Injection combined with chemotherapy for treatment of breast cancer].

Databases including China Biological Medicine database(CBM), Chinese scientific journals full-text database(VIP), China National Knowledge Infrastructure database(CNKI), WanFang Data, PubMed, and EMbase were searched from inception to March 2018 to collect the randomized controlled trials(RCTs) on Shenqi Fuzheng Injection combined with chemotherapy for the treatment of breast cancer. All included studies were critically appraised by two independent reviewers by following the cochrane systematic review method and using Revman 5.3 software and State 12.0 for data analysis. After screening, 20 RCTs involving 2 095 patients were included in the study. Meta-analysis showed that as compared with control group of chemotherapy alone, Shenqi Fuzheng Injection combined with chemotherapy could improve the clinical curative efficiency, the KPS score, and immune function indexes such as total T cells, Th cells and Ts cells; inhibit the decline of white blood cells(WBC), platelets in blood system, T-lymphocyte subsets such as CD3~+, CD4~+, CD4~+/CD8~+, alleviate myelosuppression and reduce the incidence of side effects such as gastrointestinal adverse reaction, liver and kidney dysfunction and abnormal electrocardiogram. The results revealed that for clinical breast cancer patients, Shenqi Fuzheng Injection combined with chemotherapy could significantly improve its clinical efficacy and reduce adverse reactions. However, the conclusions still need to be verified by high-quality, multi-center, large-sample, prospective, randomized and double-blind clinical trials. In conclusion, this study has systemically evaluated the efficacy and safety of Shenqi Fuzheng Injection combined with chemotherapy in treatment of breast cancer and provided the reference of evidence-based medicine for safe and effective clinical application of medicines.

[Systematic review on efficacy and safety of Danshen Chuanxiongqin Injection in treatment of acute cerebral infarction].

To systemically evaluate the therapeutic efficacy and safety of Danshen Chuanxiongqin Injection in treatment of acute cerebral infarction and provide the reference of evidence-based medicine for its clinical safety and effective drug use. Databases including CNKI, WanFang Data, SinoMed, the Cochrane Library, EMbase and PubMed were searched from inception to April 2018 to collect the randomized controlled trials (RCTs) on Danshen Chuanxiongqin Injection in the treatment of acute cerebral infarction. The quality of all included studies was evaluated by two independent reviewers following the cochrane systematic review method and using Revman5.3 software and State13.0 for Meta-analysis. A total of 30 RCTs involving 3 233 patients with acute cerebral infarction were included in the study after literature quality evaluation. Meta-analysis showed that as compared with the control group of conventional western medicine alone, Danshen Chuanxiongqin Injection combined with conventional western medicine can achieve better efficacy in treatment of acute cerebral infarction, increase the clinical total effective rate (RR=1.22, 95% CI [1.18, 1.27], P<0.000 01) and activities of daily living (MD=9.42, 95% CI [8.12, 10.72], P<0.000 01), and improve the degree of neurological impairment (MD=-3.99, 95% CI [-4.89, -3.07], P<0.000 01). Furthermore, the result showed that Danshen Chuanxiongqin Injection in the treatment of acute cerebral infarction can significantly decrease the whole blood high-shear viscosity, whole blood low-shear viscosity, plasma viscosity, fibrinogen level and other hemorheological indexes (P<0.01). This Meta-analysis demonstrated that Danshen Chuan xiongqin injection in the treatment of acute cerebral infarction is safe and effective, but lacks the large multicenter clinical randomized trials to support the treatment outcome.

Glutamine enteral therapy for critically ill adult patients: An updated meta-analysis of randomized controlled trials and trial sequential analysis.

BACKGROUND: The efficacy of supplemental enteral glutamine (GLN) in critical illness patients remains uncertainty. OBJECTIVE: Based on a recently published large-scale randomized controlled trials (RCTs) as regards the use of enteral GLN, we updated a meta-analysis of RCTs for further investigating the effects of enteral GLN administration in critically ill patients. METHODS: We searched RCTs reporting the impact of supplemental enteral GLN about clinical outcomes in adult critical illness patients from EMBASE, PubMed, Clinical Trials.gov, Scopus and Web of Science and subsequently registered the protocol in the PROSPERO (CRD42023399770). RCTs of combined enteral-parenteral GLN or parenteral GLN only were excluded. Hospital mortality was designated as the primary outcome. We conducted subgroup analyses of primary outcome based on specific patient populations, dosages and therapy regimens, and further performed trial sequential analysis (TSA) for clinical outcomes. RESULTS: Eighteen RCTs involving 2552 adult critically ill patients were identified. There were no remarkable influences on hospital mortality regardless of different subgroups (OR, 1.05; 95% CI, 0.85-1.30; p = 0.67), intensive care unit (ICU) length of stay (LOS) (MD, -0.07; 95% CI, -1.12 - 0.98; p = 0.89) and infectious complications (OR, 0.90; 95% CI, 0.75-1.10; p = 0.31) with enteral GLN supplementation. Additionally, the results of hospital mortality were confirmed by TSA. However, enteral GLN therapy was related to a reduction of hospital LOS (MD, -2.85; 95% CI, -5.27 to -0.43; p = 0.02). CONCLUSIONS: In this meta-analysis, it seems that enteral GLN supplementation is unlikely ameliorate clinical outcomes in critical illness patients except for the reduction of hospital LOS. Our data do not support enteral GLN supplementation used routinely in critical illness patients.

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis.

Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.

Investigation on the Energy-Absorbing Properties of Bionic Spider Web Structure.

In recent years, spider webs have received significant attention due to their exceptional mechanical properties, including strength, toughness, elasticity, and robustness. Among these spider webs, the orb web is a prevalent type. An orb web's main framework consists of radial and spiral threads, with elastic and sticky threads used to capture prey. This paper proposes a bionic orb web model to investigate the energy-absorbing properties of a bionic spider web structure. The model considers structural parameters such as radial line length, radial line cross-sectional diameter, number of spiral lines, spiral spacing, and spiral cross-sectional diameter. These parameters are evaluated to assess the energy absorption capability of the bionic spider web structure. Simulation results reveal that the impact of the radial line length and spiral cross-sectional diameter on the energy absorption of the spider web is more significant compared to the radial line cross-sectional diameter, the number of spiral lines, and spiral spacing. Specifically, within a radial line length range of 60-80 mm, the total absorbed energy of a spider web is inversely proportional to the radial line length of the web. Moreover, the number of spiral lines and spiral spacing of the spider web, when within the range of 6-10 turns and 4-5.5 mm, respectively, are proportional to the total energy absorbed. A regression equation is derived to predict the optimal combination of structural parameters for maximum energy absorption. The optimal parameters are determined as follows: radial line length of 63.48 mm, radial line cross-sectional diameter of 0.46 mm, ten spiral lines, spiral spacing of 5.39 mm, and spiral cross-sectional diameter of 0.48 mm.

Topological Design of a Hinger Bracket Based on Additive Manufacturing.

Topology optimization technology is often used in the design of lightweight structures under the condition that mechanical performance should be guaranteed, but a topology-optimized structure is often complicated and difficult to process using traditional machining technology. In this study, the topology optimization method, with a volume constraint and the minimization of structural flexibility, is applied to the lightweight design of a hinge bracket for civil aircraft. A mechanical performance analysis is conducted using numerical simulations to obtain the stress and deformation of the hinge bracket before and after topology optimization. The numerical simulation results show that the topology-optimized hinge bracket has good mechanical properties, and its weight was reduced by 28% compared with the original design of the model. In addition, the hinge bracket samples before and after topology optimization are prepared with additive manufacturing technology and mechanical performance tests are conducted using a universal mechanical testing machine. The test results show that the topology-optimized hinge bracket can satisfy the mechanical performance requirements of a hinge bracket at a weight loss ratio of 28%.

Identification of ALG3 as a potential prognostic biomarker in lung adenocarcinoma.

Background: The abnormal expression of Alpha-1,3-mannosyltransferase (ALG3) has been implicated in tumor promotion. However, the clinical significance of ALG3 in Lung Adenocarcinoma (LUAD) remains poorly understood. Therefore, we aimed to assess the prognostic value of ALG3 and its association with immune infiltrates in LUAD. Methods: The transcriptional expression profiles of ALG3 were obtained from the Cancer Genome Atlas (TCGA), comparing lung adenocarcinoma tissue with normal tissues. To determine the prognostic significance of AGL3, Kaplan-Meier plotter, and Cox regression analysis were employed. Logistic regression was utilized to analyze the association between ALG3 expression and clinical characteristics. Additionally, a receiver operating characteristic (ROC) curve and a nomogram were constructed. To explore the underlying mechanisms, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA) was conducted. The relationship between AGL3A mRNA expression and immune infiltrates was investigated using the tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB). Furthermore, an in vitro experiment was performed to assess the impact of ALG3 mRNA on lung cancer stemness abilities and examine key signaling pathway proteins. Results: Our results revealed the ALG3 mRNA and protein expression in patients with LUAD was much higher than that in adjacent normal tissues. High expression of ALG3 was significantly associated with N stage (N0, HR = 1.98, P = 0.002), pathological stage (stage I, HR = 2.09, P = 0.003), and the number of pack years (<40, HR = 2.58, P = 0.001). Kaplan-Meier survival analysis showed that high expression of ALG3 was associated with poor overall survival (P < 0.001), disease-free survival (P < 0.001), and progression-free interval (P = 0.007). Through multivariate analysis, it was determined that elevated ALG3 expression independently impacted overall survival (HR = 1.325, P = 0.04). The Tumor Immune Estimation Resource discovered a link between ALG3 expression and tumor-infiltrating immune cells in LUAD. Additionally, ROC analysis proved that ALG3 is a reliable diagnostic marker for LUAD (AUC:0.923). Functional pathways analysis identified that ALG3 is negatively correlated with FAT4. We performed qRT-PCR to assess that knockdown ALG3 expression significantly upregulated FAT4 expression. Spheroid assay and flow cytometry analysis results showed that downregulated of ALG3 inhibited H1975 cell line stemness. Western blot analysis revealed that decreased ALG3 inhibited the YAP/TAZ signal pathway. Conclusion: High expression of ALG3 is strongly associated with poor prognosis and immune infiltrates in LUAD.

Epimedin C Alleviates Glucocorticoid-Induced Suppression of Osteogenic Differentiation by Modulating PI3K/AKT/RUNX2 Signaling Pathway.

Secondary osteoporosis is triggered mostly by glucocorticoid (GC) therapy. Dexamethasone (DEX) was reported to inhibit osteogenic differentiation in zebrafish larvae and MC3T3-E1 cells in prior research. In this research, we primarily examined the protective impacts of epimedin C on the osteogenic inhibition impact of MC3T3-E1 cells and zebrafish larvae mediated by DEX. The findings illustrated no apparent toxicity for MC3T3-E1 cells after administering epimedin C at increasing dosages from 1 to 60 µM and no remarkable proliferation in MC3T3-E1 cells treated using DEX. In MC3T3-E1 cells that had been treated using DEX, we discovered that epimedin C enhanced alkaline phosphatase activities and mineralization. Epimedin C could substantially enhance the protein expression of osterix (OSX), Runt-related transcription factor 2 (RUNX2), and alkaline phosphatase (ALPL) in MC3T3-E1 cells subjected to DEX treatment. Additionally, epimedin C stimulated PI3K and AKT signaling pathways in MC3T3-E1 cells that had been treated using DEX. Furthermore, in a zebrafish larvae model, epimedin C was shown to enhance bone mineralization in DEX-mediated bone impairment. We also found that epimedin C enhanced ALPL activity and mineralization in MC3T3-E1 cells treated using DEX, which may be reversed by PI3K inhibitor (LY294002). LY294002 can also reverse the protective impact of epimedin C on DEX-mediated bone impairment in zebrafish larval. These findings suggested that epimedin C alleviated the suppressive impact of DEX on the osteogenesis of zebrafish larval and MC3T3-E1 cells via triggering the PI3K and AKT signaling pathways. Epimedin C has significant potential in the development of innovative drugs for the treatment of glucocorticoid-mediated osteoporosis.

A011, a novel small-molecule ligand of σ2 receptor, potently suppresses breast cancer progression via endoplasmic reticulum stress and autophagy.

Breast cancer has surpassed lung cancer to become the most commonly diagnosed cancer in women worldwide. Sigma-2 (σ2) receptor is considered to be a potential therapeutic target for breast cancer because of its high expression in breast cancer cells and low expression in normal breast cells. Many σ2 ligands have been reported to have excellent anticancer activity, but their mechanism of action has not been fully elucidated. We discovered that A011 had high affinity and selectivity for σ2 receptor, reduced proliferation in five cancer cell lines, and significantly inhibited the monoclonal formation ability of MCF-7 cells. Furthermore, A011 rapidly increased the levels of intracellular Ca2+ and reactive oxygen species and induced autophagy. Molecular pharmacology studies revealed that A011 induced endoplasmic reticulum stress, activated the PERK-eIF2α-CHOP pathway and inhibited the activation of the PI3K-Akt-mTOR pathway, leading to cell apoptosis. In an in vivo tumor model, A011 showed obvious anti-tumor activity and no significant toxicity. More importantly, our study demonstrated for the first time that endoplasmic reticulum stress is the main mechanism of anti-cancer effects for σ2 ligands, at least for A011. A011 may potentially be useful as a therapeutic agent for treating breast cancer.

Kaempferol Ameliorates the Inhibitory Activity of Dexamethasone in the Osteogenesis of MC3T3-E1 Cells by JNK and p38-MAPK Pathways.

Kaempferol has been reported to exhibit beneficial effect on the osteogenic differentiation in mesenchymal stem cells (MSC) and osteoblasts. In our previous study, dexamethasone (DEX) demonstrated inhibitory effect on MC3T3-E1 cells differentiation. In this study, we mainly explored the protective effect of kaempferol on the inhibitory activity of DEX in the osteogenesis of MC3T3-E1 cells. We found that kaempferol ameliorated the proliferation inhibition, cell cycle arrest, and cell apoptosis and increased the activity of alkaline phosphatase (ALP) and the mineralization in DEX-treated MC3T3-E1 cells. Kaempferol also significantly enhanced the expression of osterix (Osx) and runt-related transcription factor 2 (Runx2) in MC3T3-E1 cells treated with DEX. In addition, kaempferol attenuated DEX-induced reduction of cyclin D1 and Bcl-2 expression and elevation of p53 and Bax expression. Kaempferol also activated JNK and p38-MAPK pathways in DEX-treated MC3T3-E1 cells. Furthermore, kaempferol improved bone mineralization in DEX-induced bone damage in a zebrafish larvae model. These data suggested that kaempferol ameliorated the inhibitory activity of DEX in the osteogenesis of MC3T3-E1 cells by activating JNK and p38-MAPK signaling pathways. Kaempferol exhibited great potentials in developing new drugs for treating glucocorticoid-induced osteoporosis.

Effects of Anti-Diabetic Drugs on Fracture Risk: A Systematic Review and Network Meta-Analysis.

Purpose: Available data on the effects of anti-diabetic drugs on fracture risk are contradictory. Therefore, our study aimed to analyze all available data on the effects of anti-diabetic drugs on fracture risk in type 2 diabetes mellitus (T2DM) patients. Methods: Embase, Medline, ClinicalTrials.gov, and Cochrane CENTRAL were searched for relevant trials. All data analyses were performed with STATA (12.0) and R language (3.6.0). Risk ratio (RR) with its 95% confidence interval (CI) was calculated by combining data for the fracture effects of anti-diabetic drugs, including sodium-glucose co-transporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, meglitinides, α-glucosidase inhibitors, thiazolidinediones, biguanides, insulin, and sulfonylureas. Results: One hundred seventeen eligible randomized controlled trials (RCTs) with 221,364 participants were included in this study. Compared with placebo, trelagliptin (RR 3.51; 1.58-13.70) increased the risk of fracture, whereas albiglutide (RR 0.29; 0.04-0.93) and voglibose (RR 0.03; 0-0.11) decreased the risk of fracture. Other medications were comparable in terms of their effects on fracture risk, and no statistical significance was observed. In terms of fractures, voglibose (0.01%) may be the safest option, and trelagliptin (13.64%) may be the worst. Sensitivity analysis results were consistent with those of the main analysis. No statistically significant differences were observed in the regression coefficients of age (1.03; 0.32-2.1), follow-up duration (0.79; 0.27-1.64), and sex distribution (0.63; 0.15-1.56). Conclusions: We found varied results on the association between the use of anti-diabetic drugs and fracture risk. Specifically, trelagliptin raised the risk of fracture, whereas voglibose and albiglutide showed benefit with statistical difference. Other drugs were comparable in terms of their effects on fracture risk. Some drugs (omarigliptin, sitagliptin, vildagliptin, saxagliptin, empagliflozin, ertugliflozin, rosiglitazone, pioglitazone, and nateglinide) may increase the risk of fracture, while others (such as dulaglutide, exenatide, liraglutide, semaglutide, lixisenatide, linagliptin, alogliptin, canagliflozin, dapagliflozin, glipizide, gliclazide, glibenclamide, glimepiride, metformin, and insulin) may show benefits. The risk of fracture was independent of age, sex distribution, and the duration of exposure to anti-diabetic drugs. When developing individualized treatment strategies, the clinical efficacy of anti-diabetic drugs must be weighed against their benefits and risks brought about by individual differences of patients. Systematic Review Registration: This Systematic Review was prospectively registered on the PROSPERO (https://www.crd.york.ac.uk/PROSPERO/, registration number CRD42020189464).

Clinicopathological and prognostic value of long noncoding RNA SNHG7 in cancers: a meta-analysis and bioinformatics.

The long intergenic non-coding RNA SNHG7 has been reported to be abnormally expressed in many types of cancer, the results remain controversial. In this study, a meta-analysis was performed to evaluate the clinicopathologic and prognostic value of SNHG7 in cancers. Electronic databases of PubMed, Web of Science, Cochrane Library and Embase were used to search relevant studies. A combined hazard ratio (HR) and its corresponding 95% confidence interval (CI) were used to assess the association between SNHG7 expression and prognosis in cancer patients. Pooled odds ratio (OR) and 95% CI were calculated to elaborate the association between SNHG7 expression and clinicopathological features in cancers. Besides, the data from The Cancer Genome Atlas (TCGA) dataset was used to validate the results. In total, eighteen studies compromising 1303 participants were enrolled in this analysis. The pooled results showed increased SNHG7 expression could predict unfavorable overall survival (OS) (HR = 1.75, 95%CI = 1.52-2.02, P = 0.000). Analysis stratified by follow-up time, cancer types, analysis types, sample sizes and cut off further verified the prognostic value of SNHG7. Additionally, elevated SNHG7 expression was correlated with TNM stage (OR: 3.31, 95%CI = 2.29-4.80, P = 0.000), lymph node metastasis (OR = 3.32, 95%CI = 1.61-6.83, P = 0.004), and tumor differentiation (OR = 1.92, 95%CI = 1.22-3.03, P =0.005) in patients with cancers. Excavation of TCGA dataset valuated that SNHG7 was upregulated in some cancers and predicted worse OS, which partially confirmed our results in this meta-analysis.

The Impact of Glucagon-Like Peptide 1 Receptor Agonists on Bone Metabolism and Its Possible Mechanisms in Osteoporosis Treatment.

Diabetes mellitus and osteoporosis are closely related and have complex influencing factors. The impact of anti-diabetic drugs on bone metabolism has received more and more attention. Type 2 diabetes mellitus (T2DM) would lead to bone fragility, high risk of fracture, poor bone repair and other bone-related diseases. Furthermore, hypoglycemic drugs used to treat T2DM may have notable detrimental effects on bones. Thus, the clinically therapeutic strategy for T2DM should not only effectively control the patient's glucose levels, but also minimize the complications of bone metabolism diseases. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are novel and promising drug for the treatment of T2DM. Some studies have found that GLP-1RAs may play an anti-osteoporotic effect by controlling blood sugar levels, promoting bone formation and inhibiting bone resorption. However, in clinical practice, the specific effects of GLP-1RA on fracture risk and osteoporosis have not been clearly defined and evidenced. This review summarizes the current research findings by which GLP-1RAs treatment of diabetic osteoporosis, postmenopausal osteoporosis and glucocorticoid-induced osteoporosis and describes possible mechanisms, such as GLP-1R/MAPK signaling pathway, GLP-1R/PI3K/AKT signaling pathway and Wnt/ß-catenin pathway, that are associated with GLP-1RAs and osteoporosis. The specific role and related mechanisms of GLP-1RAs in the bone metabolism of patients with different types of osteoporosis need to be further explored and clarified.

Clinical Efficacy and Safety of Human Mesenchymal Stem Cell Therapy for Degenerative Disc Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Degenerative disc disease (DDD) can cause severe low back pain, which will have a serious negative impact on the ability to perform daily tasks or activities. For the past few years, mesenchymal stem cell (MSC) transplantation has emerged as a promising strategy for the treatment of DDD. However, the clinical efficacy of MSC in the treatment of DDD still lacks clinical evidence and is controversial. We conducted a meta-analysis with randomized controlled trials (RCTs) to evaluate the clinical efficacy and safety of MSC transplantation in patients with DDD. We searched major databases using terms from the database's inception through March 2021. The Cochrane bias risk assessment tool was used to assess quality. The analysis showed that MSC therapy could decrease visual analog scale (VAS) scores (SMD = -0.50, 95%CI = -0.68 ~ -0.33, P < 0.00001) and Oswestry Disability Index (ODI) scores (SMD = -0.27, 95%CI = -0.44 ~ -0.09, P = 0.003). The outcomes with subgroup analysis showed that MSC therapy could decrease VAS scores in 3 months (P = 0.001), 6 months (P = 0.01), 12 months (P = 0.02), and ≥24 months (P = 0.002) and ODI scores in ≥24 months (P = 0.006). Pooled analysis showed that MSC therapy has a higher ratio of patients at most thresholds but particularly at the MIC (minimally important change) (P = 0.0002) and CSC (clinically significant change) (P = 0.0002) in VAS and MIC (P = 0.0005) and CSC (P = 0.001) pain responders in ODI. Adverse events (AE) of treatment-emergent adverse events (TEAE), back pain, arthralgia, and muscle spasms were not statistically significant between the two groups. However, our further statistical analysis showed that MSC therapy may induce AE of TEAE related to study treatment (OR = 3.05, 95%CI = 1.11 ~ 8.40, P = 0.03). In conclusion, this study pooled the main outcomes and showed that MSC therapy could significantly decrease VAS and ODI scores in patients with DDD. Distinctly, the findings of this meta-analysis suggest a novel therapeutic strategy for patients with chronic low back pain (LBP) and lumbar dysfunction by DDD.

Therapeutic Evidence of Human Mesenchymal Stem Cell Transplantation for Cerebral Palsy: A Meta-Analysis of Randomized Controlled Trials.

Cerebral palsy (CP) is a kind of movement and posture disorder syndrome in early childhood. In recent years, human mesenchymal stem cell (hMSC) transplantation has become a promising therapeutic strategy for CP. However, clinical evidence is still limited and controversial about clinical efficacy of hMSC therapy for CP. Our aim is to evaluate the efficacy and safety of hMSC transplantation for children with CP using a meta-analysis of randomized controlled trials (RCTs). We conducted a systematic literature search including Embase, PubMed, ClinicalTrials.gov, Cochrane Controlled Trials Register databases, Chinese Clinical Trial Registry, and Web of Science from building database to February 2020. We used Cochrane bias risk assessment for the included studies. The result of pooled analysis showed that hMSC therapy significantly increased gross motor function measure (GMFM) scores (standardized mean difference (SMD) = 1.10, 95%CI = 0.66-1.53, P < 0.00001, high-quality evidence) and comprehensive function assessment (CFA) (SMD = 1.30, 95%CI = 0.71-1.90, P < 0.0001, high-quality evidence) in children with CP, compared with the control group. In the subgroup analysis, the results showed that hMSC therapy significantly increased GMFM scores of 3, 6, and 12 months and CFA of 3, 6, and 12 months. Adverse event (AE) of upper respiratory infection, diarrhea, and constipation was not statistically significant between the two groups. This meta-analysis synthesized the primary outcomes and suggested that hMSC therapy is beneficial, effective, and safe in improving GMFM scores and CFA scores in children with CP. In addition, subgroup analysis showed that hMSC therapy has a lasting positive benefit for CP in 3, 6, and 12 months.