Age-related bone diseases: Role of inflammaging.

Bone aging is characterized by an imbalance in the physiological and pathological processes of osteogenesis, osteoclastogenesis, adipogenesis, and chondrogenesis, resulting in exacerbated bone loss and the development of age-related bone diseases, including osteoporosis, osteoarthritis, rheumatoid arthritis, and periodontitis. Inflammaging, a novel concept in the field of aging research, pertains to the persistent and gradual escalation of pro-inflammatory reactions during the aging process. This phenomenon is distinguished by its low intensity, systemic nature, absence of symptoms, and potential for management. The mechanisms by which inflammaging contribute to age-related chronic diseases, particularly in the context of age-related bone diseases, remain unclear. The precise manner in which systemic inflammation induces bone aging and consequently contributes to the development of age-related bone diseases has yet to be fully elucidated. This article primarily examines the mechanisms underlying inflammaging and its association with age-related bone diseases, to elucidate the potential mechanisms of inflammaging in age-related bone diseases and offer insights for developing preventive and therapeutic strategies for such conditions.

Forskolin Enhances Antitumor Effect of Oncolytic Measles Virus by Promoting Rab27a Dependent Vesicular Transport System.

The measles vaccine virus strain (MV-Edm) serves as a potential platform for the development of effective oncolytic vectors. Nevertheless, despite promising pre-clinical data, our comprehension of the factors influencing the efficacy of MV-Edm infection and intratumoral spread, as well as the interactions between oncolytic viruses and specific chemotherapeutics associated with viral infection, remains limited. Therefore, we investigated the potency of Forskolin in enhancing the antitumor effect of oncolytic MV-Edm by promoting the Rab27a-dependent vesicular transport system. After infecting cells with MV-Edm, we observed an increased accumulation of cytoplasmic vesicles. Our study demonstrated that MV-Edm infection and spread in tumors, which are indispensable processes for viral oncolysis, depend on the vesicular transport system of tumor cells. Although tumor cells displayed a responsive mechanism to restrain the MV-Edm spread by down-regulating the expression of Rab27a, a key member of the vesicle transport system, over-expression of Rab27a promoted the oncolytic efficacy of MV-Edm towards A549 tumor cells. Additionally, we found that Forskolin, a Rab27a agonist, was capable of promoting the oncolytic effect of MV-Edm in vitro. Our study revealed that the vesicle transporter Rab27a could facilitate the secretion of MV-Edm and the generation of syncytial bodies in MV-Edm infected cells during the MV-Edm-mediated oncolysis pathway. The results of the study demonstrate that a combination of Forskolin and MV-Edm exerts a synergistic anti-tumor effect in vitro, leading to elevated oncolysis. This finding holds promise for the clinical treatment of patients with tumors.

Pharmacokinetics, Safety, and Tolerability of Tenapanor in Healthy Chinese and Caucasian Volunteers: A Randomized, Open-Label, Single-Center, Placebo-Controlled Phase 1 Study.

Background: Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects. Methods: This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio. Results: 59 healthy volunteers received tenapanor 10 mg (n = 12 Chinese), 30 mg (n = 12 Chinese), or 50 mg (n = 12 (Chinese), n = 11 (Caucasian)) or placebo (n = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean Cmax, AUC0-t, and AUC0-∞ of tenapanor-M1 increased with increasing dose level, and AUC0-t increased approximately dose proportionally. The Cmax accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred. Conclusion: Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783.

LncRNA AGAP2 antisense RNA 1 stabilized by insulin-like growth factor 2 mRNA binding protein 3 promotes macrophage M2 polarization in clear cell renal cell carcinoma through regulation of the microRNA-9-5p/THBS2/PI3K-Akt pathway.

BACKGROUND: Increasing evidence highlights the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of renal cell carcinoma (RCC). Here, we explored the mechanism of AGAP2-AS1 in the occurrence and development of clear cell RCC (ccRCC) involving IGF2BP3/miR-9-5p/THBS2. METHODS: The expressions of AGAP2-AS1, IGF2BP3, miR-9-5p, and THBS2 and their relationship were analyzed by bioinformatics. The targeting relationship between AGAP2-AS1 and miR-9-5p and between miR-9-5p and THBS2 was evaluated with their effect on cell biological behaviors and macrophage polarization assayed. Finally, we tested the effect of AGAP2-AS1 on ccRCC tumor formation in xenograft tumors. RESULTS: IGF2BP3 could stabilize AGAP2-AS1 through m6A modification. AGAP2-AS1 was highly expressed in ccRCC tissues and cells. The lentivirus-mediated intervention of AGAP2-AS1 induced malignant behaviors of ccRCC cells and led to M2 polarization of macrophages. In addition, THBS2 promoted M2 polarization of macrophages by activating the PI3K/AKT signaling pathway. AGAP2-AS1 could directly bind with miR-9-5p and promote the expression of THBS2 downstream of miR-9-5p. These results were further verified by in vivo experiments. CONCLUSION: AGAP2-AS1 stabilized by IGF2BP3 competitively binds to miR-9-5p to up-regulate THBS2, activating the PI3K/AKT signaling pathway and inducing macrophage M2 polarization, thus facilitating the development of RCC.

Expression of interferon regulatory factor family and its prognostic value in acute myeloid leukemia.

Aim: To elucidate the clinicopathological and prognostic values of interferon regulatory factor (IRF) family genes in acute myeloid leukemia (AML). Patients & methods: Differential expression analysis and survival analysis from several reliable databases were conducted and further validated using patients with AML. Results: The expression level of IRF1/2/4/5/7/8/9 in patients with AML was upregulated, while IRF3/6 expression was downregulated. High IRF1/7/9 expression indicated a worse overall survival rate. Conclusion: Overexpression of IRF1/7/9 may be associated with poor survival in patients with AML, suggesting that the IRF family may be a promising therapeutic target.

Dancing in local space: rolling hoop orbital amplification combined with local cascade nanozyme catalytic system to achieve ultra-sensitive detection of exosomal miRNA.

The exosomal miRNA (exo-miRNA) derived from tumor cells contains rich biological information that can effectively aid in the early diagnosis of disease. However, the extremely low abundance imposes stringent requirements for accurate detection techniques. In this study, a novel, protease-free DNA amplification strategy, known as "Rolling Hoop Orbital Amplification" (RHOA), was initially developed based on the design concept of local reaction and inspired by the childhood game of rolling iron ring. Benefiting from the local space constructed by the DNA orbital, the circular DNA enzyme rolls directionally and interacts efficiently with the amplification element, making it nearly 3-fold more productive than conventional free-diffusion amplification. Similarly, the localized cascade nanozyme catalytic system formed by bridging DNA probes also exhibits outperformed than free ones. Therefore, a localized energized high-performance electrochemiluminescence (ECL) biosensor was constructed by bridging cascading nanozymes on the electrode surface through DNA probes generated by RHOA, with an impressive limit of detection (LOD) of 1.5 aM for the detection of exosomal miRNA15a-5p and a stable linearity over a wide concentration range from 10- 2 to 108 fM. Thus, this work is a focused attempt at the localized reaction, which is expected to provide a reliable method for accurately detecting of exo-miRNAs.

Therapeutic Drug Monitoring and Pharmacokinetic Analysis of Cyclosporine in a Pediatric Patient with Hemophagocytic Lymphohistiocytosis Complicated by Diabetes Insipidus: A Grand Round.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease. Initial therapy is based on etoposide, dexamethasone, and cyclosporine (CSA). The pharmacokinetics (PKs) of CSA and other drugs are sometimes altered in patients with HLH complicated by diabetes insipidus (DI) but the precise mechanisms remain unknown. METHODS: In this study, the authors present a case of a 4-year-old boy with HLH complicated by DI. CSA concentrations were determined by enzyme multiplied immunoassay technique; noncompartmental PK analysis of the plasma concentration-time data was performed using PKSolver; and linear regression analysis was performed to determine linearity of relationship between urine output and C0 levels of CSA. RESULTS: Although C0 values of CSA were lower than the target levels, the patient was successfully treated and a good clinical outcome was achieved. Linear regression analysis showed a strong negative correlation between urine output and the serum trough concentration (C0) of CSA, pharmacokinetic analysis showed the main PK parameters of CSA as follows: C0, 50.2 mcg/L; peak concentration (Cmax), 723.4 mcg/L; area under the curve0-24, 7478.2 mcg·h/L; clearance, 0.77 L/h/kg, elimination half-life, 5.3 hours, and volume of distribution, 6.0 L/kg. CONCLUSIONS: To the best of the authors' knowledge, this is the first report of the CSA PK profile in a patient with HLH complicated by DI. The authors suppose that a large fluid output and input leads to extensive CSA distribution. These results suggest that the monitoring of the Cmax and area under the curve of CSA might be more clinically and pharmacokinetically significant than that of C0 in patients with HLH complicated by DI. This case highlights the importance of therapeutic drug monitoring and demonstrates PK parameters of CSA in a pediatric patient with HLH complicated by DI.

Preparation and Characterization of Graphene from Refined Benzene Extracted from Low-Rank Coal: Based on the CVD Technology.

Industrial preparation of graphene has been a research hotspot in recent years. Finding an economical and practical carbon source and reducing the cost of production and instrument is significant in industrial graphene production. Coal is a common carbon source. Efficient improvement and utilization in the cleaning of coal has recently been a popular research area. In this study, we developed a set of graphene preparation methods based on Anhui Huainan's low-rank gas coal (HNGC). Using self-built experimental equipment, benzene precursor was prepared from HNGC and used as carbon source to realize graphene growth. The quality of the graphene was characterized by a high-resolution microscope and Raman spectrometer. This study provides a new idea and method for the preparation of low-rank coal-based graphene.

Circular RNA circ_001842 plays an oncogenic role in renal cell carcinoma by disrupting microRNA-502-5p-mediated inhibition of SLC39A14.

Renal cell carcinoma (RCC) is a common urologic malignancy, and up to 30% of RCC patients present with locally advanced or metastatic disease at the time of initial diagnosis. Increasing evidence suggests that circular RNAs (circRNAs) serve as genomic regulatory molecules in various human cancers. Our initial in silico microarray-based analysis identified that circRNA circ_001842 was highly expressed in RCC. Such up-regulation of circ_001842 in RCC was experimentally validated in tissues and cell lines using RT-qPCR. Thereafter, we attempted to identify the role of circ_001842 in the pathogenesis of RCC. Through a series of gain- and loss-of function assays, cell biological functions were examined using colony formation assay, Transwell assay, annexin V-FITC/PI-labelled flow cytometry and scratch test. A high expression of circ_001842 in tissues was observed as associated with poor prognosis of RCC patients. circ_001842 was found to elevate SLC39A14 expression by binding to miR-502-5p, consequently resulting in augmented RCC cell proliferation, migration and invasion, as well as EMT in vitro and tumour growth in vivo. These observations imply the involvement of circ_001842 in RCC pathogenesis through a miR-502-5p-dependent SLC39A14 mechanism, suggesting circ_001842 is a potential target for RCC treatment.

The effect of soy intervention on insulin-like growth factor 1 levels: A meta-analysis of clinical trials.

A low insulin-like growth factor 1 (IGF-1) level is known to be associated with many disorders. Several studies have shown that soy consumption may influence IGF-1, but the findings remain inconclusive. In this work, we conducted a systematic review and meta-analysis to provide a more accurate estimation of the effect of soy consumption on plasma IGF-1. A comprehensive systematic search was performed in Scopus, Embase, Web of Science, and PubMed/MEDLINE databases from inception until October 2019. Eight studies fulfilled the eligibility criteria. The pooled weighted mean difference (WMD) of the eligible studies was calculated with random-effects approach. Overall, a significant increment in plasma IGF-1 was observed following soy intervention (WMD: 13.5 ng/ml, 95% CI: 5.2, 21.8, I2 = 97%). Subgroup analyses demonstrated a significantly greater increase in IGF-1, when soy was administered at a dosage of ≤40 g/day (WMD: 11.7 ng/ml, 95% CI: 10.9 to 12.6, I2 = 98%), and when the intervention duration was <12 weeks (WMD: 26.6 ng/ml, 95% CI: 9.1 to 44.1, I2 = 0.0%). In addition, soy intervention resulted in a greater increase in IGF-1 among non-healthy subjects (WMD: 36 ng/ml, 95% CI: 32.7 to 39.4, I2 = 84%) than healthy subjects (WMD: 9.8 ng/ml, 95% CI: 8.9 to 10.7, I2 = 90%). In conclusion, this study provided the first meta-analytical evidence that soy intake may increase IGF-1 levels, but the magnitude of the increase is dependent on the intervention dosage, duration, and health status of the participants.

Electronic Systems Diagnosis Fault in Gasoline Engines Based on Multi-Information Fusion.

The rapid development of electronic techniques in automobile has led to an increase of potential safety hazards, thus, a strong on-board diagnostic (OBD) system is desperately needed. To solve the problem of OBD insensitivity to manufacture errors or aging faults, the paper proposes a novel multi information fusion method. The diagnostic model is composed of a data fusion layer, feature fusion layer, and decision fusion layer. They are based on the back propagation (BP) neural network, support vector machine (SVM), and evidence theory, respectively. Algorithms are mainly focused on the reliability allocation of diagnostic results, which come from the data fusion layer and feature fusion layer. A fault simulator system was developed to simulate bias and drift faults of the intake pressure sensor. The real vehicle experiment was carried out to acquire data that are used to verify the availability of the method. Diagnostic results show that the multi-information fusion method improves diagnostic accuracy and reliability effectively. The study will be a promising approach for the diagnosis bias and drift fault of sensors in electronic control systems.

A novel P53/POMC/Gαs/SASH1 autoregulatory feedback loop activates mutated SASH1 to cause pathologic hyperpigmentation.

p53-Transcriptional-regulated proteins interact with a large number of other signal transduction pathways in the cell, and a number of positive and negative autoregulatory feedback loops act upon the p53 response. P53 directly controls the POMC/α-MSH productions induced by ultraviolet (UV) and is associated with UV-independent pathological pigmentation. When identifying the causative gene of dyschromatosis universalis hereditaria (DUH), we found three mutations encoding amino acid substitutions in the gene SAM and SH3 domain containing 1 (SASH1), and SASH1 was associated with guanine nucleotide-binding protein subunit-alpha isoforms short (Gαs). However, the pathological gene and pathological mechanism of DUH remain unknown for about 90 years. We demonstrate that SASH1 is physiologically induced by p53 upon UV stimulation and SASH and p53 is reciprocally induced at physiological and pathophysiological conditions. SASH1 is regulated by a novel p53/POMC/α-MSH/Gαs/SASH1 cascade to mediate melanogenesis. A novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. Our study demonstrates that a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype.

p53 regulates ERK1/2/CREB cascade via a novel SASH1/MAP2K2 crosstalk to induce hyperpigmentation.

We previously reported that three point mutations in SASH1 and mutated SASH1 promote melanocyte migration in dyschromatosis universalis hereditaria (DUH) and a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. However, the underlying mechanism of molecular regulation to cause this hyperpigmentation disorder still remains unclear. In this study, we aimed to investigate the molecular mechanism undergirding hyperpigmentation in the dyschromatosis disorder. Our results revealed that SASH1 binds with MAP2K2 and is induced by p53-POMC-MC1R signal cascade to enhance the phosphorylation level of ERK1/2 and CREB. Moreover, increase in phosphorylated ERK1/2 and CREB levels and melanogenesis-specific molecules is induced by mutated SASH1 alleles. Together, our results suggest that a novel SASH1/MAP2K2 crosstalk connects ERK1/2/CREB cascade with p53-POMC-MC1R cascade to cause hyperpigmentation phenotype of DUH.

Proteomic screening and identification of microRNA-128 targets in glioma cells.

Brain-enriched miR-128 is repressed in glioma cells, and could inhibit the proliferation of gliomas by targeting genes such as E2F3a and BMI1. To identify more targets of miR-128 in glioblastoma multiforme, the pulse stable isotope labeling with amino acids in cell culture (pSILAC) technique was used to test its impact on whole protein synthesis in T98G glioma cells. We successfully identified 1897 proteins, of which 1459 proteins were quantified. Among them, 133 proteins were downregulated after the overexpression of miR-128. Through predictions using various bioinformatics tools, 13 candidate target genes were chosen. A luciferase assay validated that 11 of 13 selected genes were potential targets of miR-128, and a mutagenesis experiment confirmed CBFB, CORO1C, GLTP, HnRNPF, and TROVE2 as the target genes. Moreover, we observed that the expression of CORO1C, TROVE2, and HnRNPF were higher in glioma cell lines compared to normal brain tissues and presented a tendency toward downregulation after overexpression of miR-128 in T98G cells. Furthermore, we have validated that CORO1C, TROVE2, and HnRNPF could inhibit glioma cell proliferation. In sum, our data showed that the integration of pSILAC and bioinformatics analysis was an efficient method for seeking the targets of miRNAs, and plentiful targets of miR-128 were screened and laid the foundation for research into the miR-128 regulation network.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) prevents apoptosis induced by hydrogen peroxide in basilar artery smooth muscle cells.

Cystic fibrosis transmembrane conductance regulator (CFTR) acts as a cAMP-dependent chloride channel, has been studied in various types of cells. CFTR is abundantly expressed in vascular smooth muscle cells and closely linked to vascular tone regulation. However, the functional significance of CFTR in basilar vascular smooth muscle cells (BASMCs) remains elusive. Accumulating evidence has shown the direct role of CFTR in cell apoptosis that contributes to several main pathological events in CF, such as inflammation, lung injury and pancreatic insufficiency. We therefore investigated the role of CFTR in BASMC apoptotic process induced by hydrogen peroxide (H2O2). We found that H2O2-induced cell apoptosis was parallel to a significant decrease in endogenous CFTR protein expression. Silencing CFTR with adenovirus-mediated CFTR specific siRNA further enhanced H2O2-induced BASMC injury, mitochondrial cytochrome c release into cytoplasm, cleaved caspase-3 and -9 protein expression and oxidized glutathione levels; while decreased cell viability, the Bcl-2/Bax ratio, mitochondrial membrane potential, total glutathione levels, activities of superoxide dismutase and catalase. The pharmacological activation of CFTR with forskolin produced the opposite effects. These results strongly suggest that CFTR may modulate oxidative stress-related BASMC apoptosis through the cAMP- and mitochondria-dependent pathway and regulating endogenous antioxidant defense system.

Effects of bacterial extracellular vesicles derived from oral and gastrointestinal pathogens on systemic diseases.

Oral microbiota and gastrointestinal microbiota, the two largest microbiomes in the human body, are closely correlated and frequently interact through the oral-gut axis. Recent research has focused on the roles of these microbiomes in human health and diseases. Under normal conditions, probiotics and commensal bacteria can positively impact health. However, altered physiological states may induce dysbiosis, increasing the risk of pathogen colonization. Studies suggest that oral and gastrointestinal pathogens contribute not only to localized diseases at their respective colonized sites but also to the progression of systemic diseases. However, the mechanisms by which bacteria at these local sites are involved in systemic diseases remain elusive. In response to this gap, the focus has shifted to bacterial extracellular vesicles (BEVs), which act as mediators of communication between the microbiota and the host. Numerous studies have reported the targeted delivery of bacterial pathogenic substances from the oral cavity and the gastrointestinal tract to distant organs via BEVs. These pathogenic components subsequently elicit specific cellular responses in target organs, thereby mediating the progression of systemic diseases. This review aims to elucidate the extensive microbial communication via the oral-gut axis, summarize the types and biogenesis mechanisms of BEVs, and highlight the translocation pathways of oral and gastrointestinal BEVs in vivo, as well as the impacts of pathogens-derived BEVs on systemic diseases.

Advances in Circular RNA in the Pathogenesis of Epilepsy.

Recent studies evidenced the involvement of circular RNA (circRNA) in neuroinflammation, apoptosis, and synaptic remodeling suggesting an important role for circRNA in the occurrence and development of epilepsy. This review provides an overview of circRNAs considered to be playing regulatory roles in the process of epilepsy and to be involved in multiple biological epilepsy-related processes, such as hippocampal sclerosis, inflammatory response, cell apoptosis, synaptic remodeling, and cell proliferation and differentiation. This review covers the current research status of differential expression of circRNA-mediated seizures, m6A methylation, demethylation-mediated seizures in post transcriptional circRNA modification, as well as the mechanisms of m5C- and m7G-modified circRNA. In summary, this article reviews the research progress on the relationship between circRNA in non-coding RNA and epilepsy.

Prognostic implications of cGAS and STING gene expression in acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the most threatening hematological malignances. cGAS-STING pathway plays an important role in tumor immunity and development. However, the prognostic role of cGAS-STING pathway in AML remains unknown. Firstly, The expression of cGAS and STING was analyzed by bioinformatics analysis. Subsequently, Bone marrow samples were collected from 120 AML patients and 15 healthy individuals in an independent cohort. The cGAS and STING expression was significantly elevated in AML patients compared with healthy controls. Patients with high cGAS and STING expression had a higher NRAS/KRAS mutation rate and lower complete remission (CR) rate. High cGAS and STING expression was significantly associated with lower overall survival (OS) and disease-free survival (DFS). Our findings revealed that the expression levels of cGAS and STING in AML are elevated. High expression of cGAS and STING correlated with worse OS and DFS and may be a useful biomarker for inferior prognosis in AML patients.

S defect-rich MoS2 aerogel with hierarchical porous structure: Efficient photocatalysis and convenient reuse for removal of organic dyes.

To avoid the difficulty of separating solids from liquids when reusing powder photocatalysts, 3D stereoscopic photocatalysts were constructed. In this study, three-dimensional S defect-rich MoS2 hierarchical aerogel was prepared by chemical cross-linking of functional ultrathin 2D MoS2. Its phase, micro-morphology and structure were characterized, and it was used in the study of photocatalytic degradation of organic pollutants. Of the samples tested, MS@CA-3 (i.e., defect-rich 3D MoS2 aerogel with a loading of 30 mg of defect-rich MoS2) exhibited the best photocatalytic activity due to its suitable load, good light transmission, and a degradation rate of up to 91.0% after 3 h. In addition, MS@CA-3 aerogel offers high recyclability and structural stability, and the degradation rate of the organic pollutant methylene blue decreases only 9.8% after more than ten cycles of photocatalytic degradation. It combines the high catalytic performance of S defect-rich 2D MoS2 and the convenient reusability of hierarchical porous aerogel. This study provides valuable data and a reference for the practical promotion and application of photocatalytic technology in the field of environmental remediation.

Tibial cortex transverse transport surgery improves wound healing in patients with severe type 2 DFUs by activating a systemic immune response: a cross-sectional study.

BACKGROUND: Tibial cortex transverse transport (TTT) surgery has become an ideal treatment for patients with type 2 severe diabetic foot ulcerations (DFUs) while conventional treatments are ineffective. Based on our clinical practice experience, the protective immune response from TTT surgery may play a role against infections to promote wound healing in patients with DFUs. Therefore, this research aimed to systematically study the specific clinical efficacy and the mechanism of TTT surgery. MATERIALS AND METHODS: Between June 2022 and September 2023, 68 patients with type 2 severe DFUs were enrolled and therapized by TTT surgery in this cross-sectional and experimental study. Major clinical outcomes including limb salvage rate and antibiotics usage rate were investigated. Ten clinical characteristics and laboratory features of glucose metabolism and kidney function were statistically analyzed. Blood samples from 6 key time points of TTT surgery were collected for label-free proteomics and clinical immune biomarker analysis. Besides, tissue samples from 3 key time points were for spatially resolved metabolomics and transcriptomics analysis, as well as applied to validate the key TTT-regulated molecules by RT-qPCR. RESULTS: Notably, 64.7% of patients did not use antibiotics during the entire TTT surgery. TTT surgery can achieve a high limb salvage rate of 92.6% in patients with unilateral or bilateral DFUs. Pathway analysis of a total of 252 differentially expressed proteins (DEPs) from the proteomic revealed that the immune response induced by TTT surgery at different stages was first comprehensively verified through multi-omics combined with immune biomarker analysis. The function of upward transport was activating the systemic immune response, and wound healing occurs with downward transport. The spatial metabolic characteristics of skin tissue from patients with DFUs indicated downregulated levels of stearoylcarnitine and the glycerophospholipid metabolism pathway in skin tissue from patients with severe DFUs. Finally, the expressions of PRNP (prion protein) to activate the immune response, PLCB3 (PLCB3, phospholipase C beta 3) and VE-cadherin to play roles in neovascularization, and PPDPF (pancreatic progenitor cell differentiation and proliferation factor), LAMC2 (laminin subunit gamma 2) and SPRR2G (small proline rich protein 2G) to facilitate the developmental process mainly keratinocyte differentiation were statistically significant in skin tissues through transcriptomic and RT-qPCR analysis. CONCLUSION: Tibial cortex transverse transport (TTT) surgery demonstrates favorable outcomes for patients with severe type 2 DFUs by activating a systemic immune response, contributing to anti-infection, ulcer recurrence, and the limb salvage rate for unilateral or bilateral DFUs. The specific clinical immune responses, candidate proteins, genes, and metabolic characteristics provide directions for in-depth mechanistic research on TTT surgery. Further research and public awareness are needed to optimize TTT surgery in patients with severe type 2 DFUs.