This study aimed to assess the safety of SGLT2 inhibitors in type 2 diabetes, chronic kidney disease, and chronic heart failure considering the number needed to treat (NNT).Methods: Data were ...obtained from 10 morbidity-mortality trials and were pooled to calculate the NNTs. The number needed to treat to benefit (NNTB) is used to express beneficial outcomes, whereas the number needed to treat to be harmed (NNTH) is used for harmful outcomes. The eight safety outcomes of interest were fracture, diabetic ketoacidosis, amputation, urinary tract infection, genital infection, acute kidney injury, severe hypoglycemia, and volume depletion.A total of 10 trials involving 76319 patients were included in this meta-analysis. The mean follow-up was 2.35 years. SGLT2 inhibitors play a positive role in acute kidney injury and severe hypoglycemia, with the corresponding mean NNTBs being 157 and 561, respectively. SGLT2 inhibitors significantly increased the risk of diabetic ketoacidosis, genital infection, and volume depletion, with the corresponding mean NNTHs being 1014, 41, and 139. It was found that the safety of SGLT2 inhibitors was the same in three diseases and five SGLT2 inhibitors.SGLT2 inhibitors have a positive impact on acute kidney injury and severe hypoglycemia, but they increase the incidence of diabetic ketoacidosis, genital infection, and volume depletion.
PD-1 and CTLA-4 antibodies offer great hope for cancer immunotherapy. However, many patients are incapable of responding to PD-1 and CTLA-4 blockade and show low response rates due to insufficient ...immune activation. The combination of checkpoint blockers has been proposed to increase the response rates. Besides, antibody drugs have disadvantages such as inclined to cause immune-related adverse events and infiltration problems. In this study, we developed a cyclic peptide C25 by using Ph.D.-C7C phage display technology targeting LAG-3. As a result, C25 showed a relative high affinity with human LAG-3 protein and could effectively interfere the binding between LAG-3 and HLA-DR (MHC-II). Additionally, C25 could significantly stimulate CD8+ T cell activation in human PBMCs. The results also demonstrated that C25 could inhibit tumor growth of CT26, B16 and B16-OVA bearing mice, and the infiltration of CD8+ T cells was significantly increased while FOXP3+ Tregs significantly decreased in the tumor site. Furthermore, the secretion of IFN-γ by CD8+ T cells in spleen, draining lymph nodes and especially in the tumors was promoted. Simultaneously, we exploited T cells depletion models to study the anti-tumor mechanisms for C25 peptide, and the results combined with MTT assay confirmed that C25 exerted anti-tumor effects via CD8+ T cells but not direct killing. In conclusion, cyclic peptide C25 provides a rationale for targeting the immune checkpoint, by blockade of LAG-3/HLA-DR interaction in order to enhance anti-tumor immunity, and C25 may provide an alternative for cancer immunotherapy besides antibody drugs.
Cyclic peptide C25 targeting LAG-3 was developed by phage display bio-panning. C25 binds to LAG-3 and is capable of preventing the binding of LAG-3 to HLA-DR. C25 exhibits significant anti-tumor activity dependent on CD8+ T cells activation. Surprisingly, it can also lead to the reduction of Tregs in tumor microenvironment. Display omitted
BackgroundImmunotherapy has achieved remarkable advances via a variety of strategies against tumor cells that evade immune surveillance. As important innate immune cells, macrophages play important ...roles in maintaining homeostasis, preventing pathogen invasion, resisting tumor cells and promoting adaptive immune response. CD47 is found to be overexpressed on tumor cells and act as a don’t eat me’ signal, which contributes to immune evasion. Macrophages mediated phagocytosis via blockade CD47/SIRPα (signal regulatory protein alpha) interaction was proved to induce effective antitumor immune response.MethodsA novel peptide pep-20, specifically targeting CD47 and blocking CD47/SIRPα interaction, was identified via high-throughput phage display library bio-panning. The capability to enhance the macrophage-mediated phagocytosis activities and antitumor effects of pep-20 were investigated. The mechanism of pep-20 to induce T-cell response was explored by ex vivo analysis and confirmed via macrophage depleting strategy. The structure-activity relationship and D-amino acid substitution of pep-20 were also studied. The antitumor effects and mechanism of a proteolysis resistant D-amino acid derivate pep-20-D12 combined with irradiation (IR) were also investigated.ResultsPep-20 showed remarkable enhancement of macrophage-mediated phagocytosis to both solid and hematologic tumor cells in vitro, and inhibited tumor growth in immune-competent tumor-bearing mice. Furthermore, pep-20 promoted macrophages to mobilize the antitumor T-cell response with minimal toxicity. Furthermore, systemic administration of the derivate pep-20-D12 showed robust synergistic antitumor efficacy in combination with IR.ConclusionIn summary, these results demonstrated that CD47/SIRPα blocking peptides, pep-20 and its derivate, could serve as promising candidates to promote macrophages-mediated phagocytosis and immune response in cancer immunotherapy.
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Aerogel with porous structure and ultra-light weight is a potential sorbent for solving oils or organic solvents pollution. Herein, a type of flexible mesoporous aerogel was ...fabricated though a simple ambient pressure drying using methyltrimethoxysilane/dodecyltrimethoxysilane (MTMS/DTMS) as precursors and distilled water as solvent. The as-synthesized aerogel exhibits superhydrophobicity with water contact angle of 163° and low density of 0.102 g/cm3. Moreover, the aerogel can selectively separate oils and water-insoluble organic solvents on and under water, and the sorption capacities can reach up to 7.98–13.4 times its own weight. More importantly, the obtained aerogel is capable of separate surfactant-free and surfactant-stabilized oil-in-water emulsions with high separation efficiency of greater than 98.4%. In addition, the aerogel is highly resistant toward corrosive aqueous solutions (acidic, alkaline, salty solutions), harsh temperature environments (−30 and 160 °C), and mechanical abrasion. Due to eco-friendly fabrication process, low cost, and outstanding oil/water separation performance, the developed aerogel have potential application in oils or organic pollutants sorption and water purification.
Seed germination is susceptible to external environmental factors, especially salt stress. Suaeda liaotungensis is a halophyte with strong salt tolerance, and the germination rate of brown seeds ...under 1000 mM NaCl treatment still reached 28.9%. To explore the mechanism of salt stress response during brown seed germination in Suaeda liaotungensis, we conducted transcriptomic analysis on the dry seeds (SlD), germinated seeds under the control condition (SlG_C), and salt treatment (SlG_N). Transcriptome analysis revealed that 13314 and 755 differentially expressed genes (DEGs) from SlD vs. SlG_C and SlG_C vs. SlG_N were detected, respectively. Most DEGs were enriched in pathways related to transcription regulation and hormone signal transduction, ROS metabolism, cell wall organization or biogenesis, and carbohydrate metabolic process in two contrasting groups. Compared with the control condition, POD and CAT activity, H2O2, soluble sugar, and proline contents were increased during germinated seeds under salt stress. Furthermore, functional analysis demonstrated that overexpression of SlNAC2 significantly enhanced salt tolerance during the germination stage in Arabidopsis. These results not only revealed the tolerant mechanism of brown seed germination in response to salinity stress but also promoted the exploration and application of salt-tolerant gene resources of Suaeda liaotungensis.
Pulmonary hypertension (PH) is a lethal vascular disease with limited therapeutic options. The mechanistic connections between alveolar hypoxia and PH are not well understood. The aim of this study ...was to investigate the role of mitotic regulator Polo-like kinase 1 (PLK1) in PH development.
Mouse lungs along with human pulmonary arterial smooth muscle cells and endothelial cells were used to investigate the effects of hypoxia on PLK1. Hypoxia- or Sugen5416/hypoxia was applied to induce PH in mice. Plk1 heterozygous knockout mice and PLK1 inhibitors (BI 2536 and BI 6727)-treated mice were checked for the significance of PLK1 in the development of PH.
Hypoxia stimulated PLK1 expression through induction of HIF1α and RELA. Mice with heterozygous deletion of Plk1 were partially resistant to hypoxia-induced PH. PLK1 inhibitors ameliorated PH in mice.
Augmented PLK1 is essential for the development of PH and is a druggable target for PH.
•The metabonome of chicken breast was dominated by 30 metabolites.•Glutamate, lactate, taurine, 5′-IMP increased in wooden breast (WB) samples.•WB-affected fillets possessed a unique biochemical ...signature.
The objective was to characterize the effect of wooden breast (WB) myodegeneration on the metabolite profile of chicken meat by 1H NMR and multivariate data analysis. The results displayed that the metabonome of chicken breast consisted predominantly of 30 metabolites, including amino acids, organic acids, carbohydrates, alkaloids, nucleosides and their derivatives. WB-affected samples showed higher leucine, valine, alanine, glutamate, lysine, lactate, succinate, taurine, glucose, and 5′-IMP levels, but lower histidine, β-alanine, acetate, creatine, creatinine, anserine and nicotinamide adenine dinucleotide levels compared to normal fillets (p < 0.05). In conclusion, results indicated that WB-affected fillets possessed a unique biochemical signature. This unique profile could identify candidate biomarkers for diagnostic utilization and provide mechanistic insight into biochemical processes leading to WB myopathy in commercial broiler chickens.
Tea tree oil (TTO), a volatile essential oil, has been widely used as an antimicrobial agent. However, the mechanism underlying TTO antifungal activity is not fully understood. In this study, a ...comprehensive metabolomics survey was undertaken to identify changes in metabolite production in
cells treated with TTO. Significant differences in 91 metabolites were observed, including 8 upregulated and 83 downregulated metabolites in TTO-treated cells. The results indicate that TTO inhibits primary metabolic pathways through the suppression of the tricarboxylic acid (TCA) cycle and fatty acid metabolism. Further experiments show that TTO treatment decreases the activities of key enzymes in the TCA cycle and increases the level of hydrogen peroxide (H
O
). Membrane damage is also induced by TTO treatment. We hypothesize that the effect of TTO on
is achieved mainly by disruption of the TCA cycle and fatty acid metabolism, resulting in mitochondrial dysfunction and oxidative stress.
The appointed-time leader-following consensus problem for second-order multi-agent systems with external disturbance on directed graphs is addressed. A distributed controller based on the cumulative ...position difference and cumulative velocity difference is proposed, which does not require prior knowledge of external disturbances. It is shown that the proposed controller guarantees the prescribed performance of the controlled systems, namely, to keep the cumulative position difference within a predefined boundary envelope. Furthermore, by employing a novel performance function, it is ensured that the position tracking error converges to an arbitrarily small expected region within the appointed time. Different from most existing finite/fixed-time control methods, here the settling time and the convergence region can both be predefined, which are also independent of initial conditions and the system parameters. Finally, the theoretical results are verified by simulations.
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