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Background There is growing evidence that pre-hospital use of metformin reduces mortality in patients with diabetes and sepsis; however, the effect of metformin on clinical outcomes in patients with diabetes and sepsis remains controversial. Therefore, there is a need for a systematic review and Meta-analysis of existing studies to further evaluate whether metformin can improve mortality and other clinical outcomes in patients with diabetes and sepsis. Objective To systematically evaluate the effects of pre-hospital metformin use on mortality, initial plasma lactate level and organ dysfunction in patients with diabetes and sepsis. Methods PubMed, Embase, Cochrane Library, Web of Science, Scopus, China Biomedical Literature Service System, Wanfang Data, CNKI and other databases were searched by computer for Chinese and English literature on the effects of pre-hospital metformin use on clinical outcomes in patients with sepsis and diabetes from inception to March 15, 2023. The test group (MET group) involved adult patients with diabetes and sepsis received pre-hospital metformin use, and the control group (NM group) involved adult patients with diabetes and sepsis who did not receive pre-hospital metformin use. After screening, data extraction and literature quality evaluation were conducted by two researchers, Meta-analysis was performed using RevMan 5.3 software. Results A total of 12 papers were included in this study, involving 12 320 patients with diabetes and sepsis, with Newcastle-Ottawa Scale (NOS) scores of 7-8. The results of Meta-analysis showed that the mortality rate (OR=0.61, 95%CI=0.46 to 0.80, P

Acute kidney injury (AKI) is a disease that is characterized by a rapid decline in renal function and has a relatively high incidence in hospitalized patients. Sepsis, renal hypoperfusion, and nephrotoxic drug exposure are the main causes of AKI. The major therapy measures currently include supportive treatment, symptomatic treatment, and kidney transplantation. These methods are supportive treatments, and their results are not satisfactory. Fortunately, many new treatments that markedly improve the AKI therapy efficiency are emerging. These include antioxidant therapy, ferroptosis therapy, anti-inflammatory therapy, autophagy therapy, and antiapoptotic therapy. In addition, the development of nanotechnology has further promoted therapeutic effects on AKI. In this review, we highlight recent advances in the development of nanocarriers for AKI drug delivery. Emphasis has been placed on the latest developments in nanocarrier modification and design. We also summarize the applications of different nanocarriers in AKI treatment. Finally, the advantages and challenges of nanocarrier applications in AKI are summarized, and several nanomedicines that have been approved for clinical trials to treat diverse kidney diseases are listed.

The kidneys play an irreplaceable role in metabolism and excretion. However, Acute Kidney Injury (AKI) often occurs due to high local concentrations of drugs, inflammation, and trauma. Activated optical probes with excellent detection performance can effectively identify biomarkers in the initial stage of AKI and play an important role in evaluating AKI and preventing the development of diseases. This article summarizes representative design strategies for molecular probes and special diagnostic applications. These molecular probes show great potential in basic research and clinical diagnosis, enabling enhanced images of tissue structure and biomarkers, as well as early diagnosis of AKI. In addition, the difficulties and challenges that optical probes may face in the development and application of AKI are also discussed in this article., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Current studies have demonstrated that disintegrin and metalloproteinase 17 (ADAM17) plays a critical role in the pathogenesis of sepsis. MicroRNA (miR)-145 is known to control immune responses as an anti-inflammatory modulatory molecule. However, a fundamental understanding of how miR-145 regulates ADAM17 and, more broadly, sepsis-induced inflammatory response remains unknown., Methods: We used western blotting and quantitative real-time PCR (qRT-PCR) to measure expression levels of ADAM17 and miR-145. Enzyme-linked immunosorbent assays (ELISA) were performed to measure cytokine production. To determine if ADAM17 is a target gene of miR-145, bioinformatics analyses and luciferase reporter assays were conducted. The impacts of ADAM17 and miR-145 on sepsis-induced inflammatory responses were accessed in vitro using human umbilical endothelial cells (HUVECs) treated with lipopolysaccharide (LPS). Sepsis-induced inflammatory response was measured in vivo using a polymicrobial septic mouse model induced by cecal ligation and puncture (CLP) with pre-injection of a miR-145 agomir., Results: In HUVECs treated with LPS, miR-145 expression was downregulated and miR-145 negatively regulated ADAM17 expression through direct binding to the ADAM17 transcript 3'-UTR. MiR-145 overexpression markedly reduced LPS-induced inflammatory cytokine production by targeting ADAM17 in HUVECs. In comparison to CLP-induced septic mice treated with a control agomir, treatment with a miR-145 agomir significantly reduced the expression of ADAM17, numerous downstream cytokines such as IL-6, TNF-α, IL-1β and MCP-1, and the endothelial injury factors ICAM-1, VCAM-1. The miR-145 agomir also alleviated acute lung and kidney injury and improved the survival rate of septic mice., Conclusions: This study showed that miR-145, by specifically targeting ADAM17, negatively regulates sepsis-induced inflammatory responses and vascular endothelial injury, and ultimately improved organ injury and survival during sepsis. The underlying mechanism for the regulation of ADAM17 expression by miR-145 and sepsis-induced inflammatory reactions may offer sepsis patients a novel therapeutic option., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background: A disintegrin and metalloproteinase 17 (ADAM17) is a proteolytic cleaving protein with a crucial function in the inflammatory responses, especially sepsis. But the clear role of ADAM17 in sepsis and the underlying mechanism remained unknown. In this study, we aim to determine the clinical association of ADAM17 -172A > G (rs12692386) promoter polymorphism with sepsis and to further explore the effect and mechanism of the early growth response 1 (EGR1)/ADAM17 pathway in inflammatory process during sepsis., Methods: A total of 477 sepsis patients and 750 controls were enrolled in this study to determine the association of ADAM17 -172A > G polymorphism with sepsis. The transcription factor binding to the promoter region of ADAM17 gene was predicted by bioinformatics analysis and verified by Chromatin Immunoprecipitation (ChIP) and luciferase assays. Quantitative real-time PCR and Western blot were performed to detect EGR1 and ADAM17 expression. Cytokine production was detected by enzyme-linked immunosorbent assay. The effect of EGR1/ADAM17 pathway on sepsis-induced inflammatory responses was evaluated in EGR1-silenced cells and endotoxemia mouse model., Results: The frequencies of non-survivors among the sepsis patients with the -172AG/GG genotypes and G allele were distinctly higher than those among patients with the AA genotype (53.9% vs. 39.7%, OR = 1.779, 95% CI = 1.119-2.829, P = 0.0142) and A allele (30.9% vs. 22.2%, OR = 1.570, 95% CI = 1.095-2.251, P = 0.0136). The Kaplan-Meier survival analysis indicated that the 28-day survival in septic patients with -172AG/GG genotypes of this functional ADAM17 promoter polymorphism was much worse than in the AA genotype carriers (log-rank = 5.358, P = 0.021). The results of in vitro lipopolysaccharide-stimulated and luciferase assays indicated that the -172 A-to-G variation could functionally upregulate promoter activity and transcription of ADAM17 gene via enhancing the binding affinity of its promoter region with the EGR1. The ChIP assay identified the direct interaction. Further studies demonstrated that inhibition of EGR1 significantly decreased ADAM17 expression and the pro-inflammatory cytokine secretion in vitro, and improved the survival and inflammatory response of sepsis mouse model., Conclusions: These results provided evidence that the ADAM17 -172A > G polymorphism functionally promoted ADAM17 expression and enhanced sepsis-induced inflammatory responses via the EGR1/ADAM17 pathway, which ultimately conferred susceptibility to sepsis mortality and poor prognosis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Micro/nanotextured topographies (MNTs) can modulate cell-biomaterial interactions mostly by their controllable geometrics. Among them, TiO 2 nanotubes, regarded as having a highly controllable nanoscale geometry, have been extensively investigated and applied and significantly affect diameter-dependent cell biological behaviors. In this study, we used five typical MNTs decorated with TiO 2 nanotubes with diameters of 30, 50, 70, 100 and 120 nm to explore the optimal nanotube diameter for improving the biofunctional properties and to more deeply understand the underlying mechanisms by which these MNTs affect osteogenic differentiation by revealing the effect of beta1-integrin/Hedgehog-Gli1 signaling on this process. The MNTs affected MG63 osteoblast-like cell spreading, osteogenic gene expression (BMP-2, Runx2 and ALP), mineralization and ALP activity in a diameter-dependent pattern, and the optimal TiO 2 nanotube diameter of 70 nm provided the best microenvironment for osteogenic differentiation as well as beta1-integrin/Hedgehog-Gli1 signaling activation. This enhanced osteogenic differentiation by the optimal-diameter TiO 2 nanotubes of 70 nm was attenuated via suppression of the beta1-integrin/ Hedgehog-Gli1 signaling, which indicated a significant role of this pathway in mediating the diameter-dependent osteogenic differentiation promotional effect of MNTs with different TiO 2 nanotube diameters. These results might provide deeper insights into the signal transduction mechanisms by which different nanoscale geometries influence cellular functions for biomaterial modification and biofunctionalization., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hedgehog-Gli1 signaling is evolutionarily conserved and plays an essential role in osteoblast proliferation and differentiation as well as bone formation. To evaluate the role of the Hedgehog-Gli1 pathway in the response of osteoblasts to hierarchical biomaterial topographies, human MG63 osteoblasts were seeded onto smooth, microstructured, and micro-/nanotextured topography (MNT) titanium to assess osteoblast proliferation and differentiation in terms of proliferative activity, alkaline phosphatase (ALP) production, and osteogenesis-related gene expression. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of Sonic hedgehog (Shh), Smoothened (Smo), and Gli1, and the protein levels were assayed by Western blotting. MG63 cells treated with the Smo inhibitor cyclopamine were seeded onto the titanium specimens, and the cell proliferation and differentiation were studied in the presence or absence of cyclopamine. Our results showed that compared to the smooth and microstructured surfaces, the MNTs induced a higher gene expression and protein production of Shh, Smo, and Gli1 as well as the activation of Hedgehog signaling. The enhanced proliferative activity, ALP production, and expression of the osteogenesis-related genes (bone morphogenetic protein-2, ALP, and runt-related transcription factor 2) enabled by the MNTs were significantly downregulated by the presence of cyclopamine to a similar level as those on the smooth and acid-etched microstructured surfaces in the absence of cyclopamine. This evidence explicitly demonstrates pivotal roles of Hedgehog-Gli1 signaling pathway in mediating the enhanced effect of MNTs on MG63 proliferation and differentiation, which greatly advances our understanding of the mechanism involved in the biological responsiveness of biomaterial topographies. These findings may aid in the optimization of hierarchical biomaterial topographies targeting Hedgehog-Gli1 signaling., Competing Interests: Disclosure The authors report no conflicts of interest in this work.