Serological response and immune-related adverse events following COVID-19 vaccination in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

With the popularity of Coronavirus disease 2019 (COVID-19) vaccine and the development of vaccination strategies, the impact of COVID-19 vaccine on cancer patients receiving immune checkpoint inhibitors (ICIs) is still unclear. In the systematic review and meta-analysis of patients with ICIs, we assessed the serological response of cancer patients receiving COVID-19 vaccine, and explored the risk of immune related adverse events (irAEs). We searched PubMed, EMBASE and Cochrane Library as of 10 June 2023, and included cancer patients who received ICIs and COVID-19 vaccine. The systematic review and meta-analysis include cohort study, cross-sectional study and case report. The outcome included the serological response, Spike-specific T-cell response, irAEs and rare adverse events. When possible, the data were analysed by random effect analysis, and the statistical heterogeneity was assessed by Q-test and I2 statistics. We explored the sources of heterogeneity through L'Abbe plots, Galbraith radial plots, and sensitivity analysis. The publication bias was evaluated by Egger's, Begg's linear regression test and funnel plot, and the impact of publication bias was further analysed by trim and fill method. 27 studies were eligible (19 cohort studies, 1 cross-sectional study and 7 case reports), involving 8331 patients (with 4724 receiving ICIs). Most studies used mRNA vaccine (BNT162b2 or mRNA-1273). Compared with cancer patients receiving chemotherapy, cancer patients receiving ICIs were significantly more likely to have seroconversion (RR = 1.05, 95%CI 1.01-1.10, P = 0.02). There were no statistically significant differences in seroconversion rates when comparing cancer patients receiving ICIs with controls without cancer (RR = 0.95, 95% CI 0.89-1.01, P = 0.09) or with cancer patients receiving targeted therapy (RR = 1.05, 95% CI 0.79-1.39, P = 0.75). The incidence of irAEs in patients receiving ICIs before and after COVID-19 vaccination was (21.96%, 95%CI 16.66%-28.94%) and (14.88%, 95%CI 8.65%-25.57%), respectively. The most common irAEs were endocrine abnormalities, skin disorders, etc. The certainty of evidence was low in cancer patients with ICIs, compared with those receiving chemotherapy, and very low versus controls without cancer. Cancer patients treated with ICIs seem to be able to receive COVID-19 vaccine safely without increasing the incidence of irAEs.

Application of the TaqMan ARMS-PCR Approach for Genotyping Drug-Induced Hearing Loss Using Dried Blood Samples.

A single nucleotide variant in mitochondrial DNA (mtDNA) 1555A>G is associated with drug-induced hearing loss. For the 1555A>G mutation site, 1555A wild-type and 1555G mutant-type plasmids were constructed, respectively. In this study, a PCR method based on the TaqMan amplification refractory mutation system was proposed to detect mtDNA 1555A>G. A common upstream primer, a common TaqMan probe, and two downstream allele-specific primers with mismatched bases were designed. One-step amplification and detection of the wild-type and mutant type at the 1555 site were realized for the deafness-related gene through two reactions. Based on this detection method, the minimum detection limit of the wild-type and mutant type detection systems for plasmids was 50 copies/µL. The minimum sensitivity for the detection of nucleic acids in real dried blood spot (DBS) samples was 0.1 ng/µL. In the normal DBS DNA sample, the detection limit of the mutation abundance reached 0.78%. The specificity of the detection method was 100%, and the coefficient of variation was less than 3.36%. This approach was validated using clinical DNA extracted from 113 DBS samples of newborns. Additionally, it showed 100% agreement with bi-directional Sanger sequencing. It can be used as an optional method for the clinical detection of deafness-related genes.

The integration of single-cell and bulk RNA-seq atlas reveals ERS-mediated acinar cell damage in acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a clinically common acute abdominal disease, whose pathogenesis remains unclear. The severe patients usually have multiple complications and lack specific drugs, leading to a high mortality and poor outcome. Acinar cells are recognized as the initial site of AP. However, there are no precise single-cell transcriptomic profiles to decipher the landscape of acinar cells during AP, which are the missing pieces of jigsaw we aimed to complete in this study. METHODS: A single-cell sequencing dataset was used to identify the cell types in pancreas of AP mice and to depict the transcriptomic maps in acinar cells. The pathways' activities were evaluated by gene sets enrichment analysis (GSEA) and single-cell gene sets variation analysis (GSVA). Pseudotime analysis was performed to describe the development trajectories of acinar cells. We also constructed the protein-protein interaction (PPI) network and identified the hub genes. Another independent single-cell sequencing dataset of pancreas samples from AP mice and a bulk RNA sequencing dataset of peripheral blood samples from AP patients were also analyzed. RESULTS: In this study, we identified genetic markers of each cell type in the pancreas of AP mice based on single-cell sequencing datasets and analyzed the transcription changes in acinar cells. We found that acinar cells featured acinar-ductal metaplasia (ADM), as well as increased endocytosis and vesicle transport activity during AP. Notably, the endoplasmic reticulum stress (ERS) and ER-associated degradation (ERAD) pathways activated by accumulation of unfolded/misfolded proteins in acinar cells could be pivotal for the development of AP. CONCLUSION: We deciphered the distinct roadmap of acinar cells in the early stage of AP at single-cell level. ERS and ERAD pathways are crucially important for acinar homeostasis and the pathogenesis of AP.

PLOD3 facilitated T cell activation in the colorectal tumor microenvironment and liver metastasis by the TNF-α/ NF-κB pathway.

BACKGROUND: Colorectal cancer (CRC) has been the third most prevalent cancer worldwide. Liver metastasis is the critical factor for the poor prognosis of CRC. Here, we investigated the expression and role of PLOD3 in CRC. METHODS: Different liver metastasis models were established by injecting PLOD3 stable knockdown or overexpression CT26 or MC38 mouse CRC cells into the spleen of mice to verify the tumorigenicity and metastasis ability in vivo. RESULTS: We identified PLOD3 is significantly overexpressed in liver metastasis samples of CRC. High expression of PLOD3 was significantly associated with poor survival of CRC patients. The knockdown of PLOD3 exhibited remarkable inhibition of proliferation, migration, and invasion in CRC cells, while the opposite results could be found in different PLOD3-overexpressed CRC cells. Stable knockdown of PLOD3 also significantly inhibited liver metastasis of CRC cells in different xenografts models, while stable overexpression of PLOD3 promotes liver metastasis and tumor progression. Further studies showed that PLOD3 facilitated the T cell activation in the tumor microenvironment and affected the TNF-α/ NF-κB pathway. CONCLUSIONS: This study revealed the essential biological functions of PLOD3 in colon cancer progression and metastasis, suggesting that PLOD3 is a promising translational medicine target and bioengineering targeting PLOD3 overcomes CRC liver metastasis.

Novel Water-Splitting Electrolyzer Design Incorporating a Gas Diffusion Electrode and a Gel Membrane for Highly Efficient Hydrogen Production.

Advancements in cost-effective, high-performance alkaline water-splitting systems are crucial for the hydrogen industry. While the significance of electrode material design has been widely acknowledged, the practical implementation of these advancements remains challenging. In this study, we focused on the holistic design of the electrolysis system and successfully developed a novel alkaline water-splitting electrolyzer. The unique configuration of our electrolyzer allows the designed NiFe-LDH/carbon cloth gas diffusion anode to interact solely with the PVA-based gel membrane and air, enabling the direct discharge of oxygen into the gas phase. This innovative feature accelerates anode bubble overflow, reduces gas interference, and decreases the system impedance by minimizing electrode spacing. As a result, by utilizing the NiFeSn-alloy/nickel mesh cathode, our electrolyzer achieves a high current density of 308 mA cm-2 at a cell voltage of 2.0 V and demonstrates exceptional stability over 1000 h.

Ultra-efficient Ru and Nb Co-Modified CeO2 Catalysts for Catalytic Oxidation of 1,2-Dichloroethane.

The oxidation of chlorinated volatile organic compounds on CeO2 is hindered by its high susceptibility to chlorine poisoning, resulting in a reduced efficiency and stability. In this study, Ru- and Nb-co-modified CeO2 catalysts were designed to achieve excellent activity, stability, and CO2 selectivity in the catalytic oxidation of 1,2-dichloroethane (EDC). The formation of Nb-O-Ce bonds was observed to enhance the surface acidic sites, thereby improving HCl selectivity and reducing the production of chlorinated byproducts. Meanwhile, it inhibits the formation of Ru-O-Ce and promotes the generation of highly dispersed RuO2 particles on the surface, enhancing the redox properties and mobility of the surface oxygen, thus increasing CO2 selectivity. In situ diffuse reflectance infrared Fourier transform spectroscopy results revealed that chlorine species preferentially attach to Nb species rather than to oxygen vacancies on the Ru/Nb/CeO2 catalyst. This allows more alkane groups to oxidize to formate on the oxygen vacancies, reducing byproduct concentration. Additionally, the oxidation of alkane groups to carboxylic acids is initiated on the Nb species, completing a comprehensive oxidation process under the synergistic effect of RuO2.

lncRNA NORAD alleviates dysfunction of renal proximal tubular epithelial cells during the sepsis-associated acute kidney injury by modulating the miR-155-5p-PDK1 axis.

The sepsis-associated acute kidney injury (Sa-AKI) is closely related to high mortality rates worldwide. Injury to the renal proximal tubular epithelial cells (RPTECs), caused by pathological conditions, is a major cause of acute kidney injury (AKI). The lncRNA NORAD has been reported to be positively associated with kidney cancers. However, the biological roles and underlying mechanisms of NORAD in RPTECs during AKI are still unclear. In this study, we found that NORAD was significantly downregulated in RPTECs from AKI tissues. Overexpression of NORAD alleviated RPTECs injury induced by lipopolysaccharide (LPS). Additionally, glucose metabolism was significantly impaired during AKI, and LPS treatment inhibited glucose metabolism in RPTECs. We demonstrated that NORAD rescued the LPS-induced inhibition of glucose metabolism in RPTECs. Furthermore, miRNA-155-5p was significantly upregulated in RPTECs from AKI. Through bioinformatics analysis, RNA pull-down, RNA IP, and luciferase assays, we showed that NORAD directly associated with miR-155-5p to downregulate its expression. Moreover, overexpression of miR-155-5p inhibited glucose metabolism by directly targeting the 3'UTR of the glucose metabolism enzyme, pyruvate dehydrogenase kinase 1 (PDK1). Finally, rescue experiments validated that NORAD's protective effect on RPTECs injury was mediated through modulation of the miR-155-5p-PDK1-glucose metabolism pathway. In summary, these results reveal that lncRNA NORAD can alleviate RPTECs dysfunction by targeting the miR-155-5p-PDK1 axis, suggesting that NORAD has the potential to contribute to the development of therapeutic approaches against Sa-AKI.

Module-Level Polaritonic Thermophotovoltaic Emitters via Hierarchical Sequential Learning.

Thermophotovoltaic (TPV) generators provide continuous and high-efficiency power output by utilizing local thermal emitters to convert energy from various sources to thermal radiation matching the bandgaps of photovoltaic cells. Lack of effective guidelines for thermal emission control at high temperatures, poor thermal stability, and limited fabrication scalability are the three key challenges for the practical deployment of TPV devices. Here we develop a hierarchical sequential-learning optimization framework and experimentally realize a 6″ module-scale polaritonic thermal emitter with bandwidth-controlled thermal emission as well as excellent thermal stability at 1473 K. The 300 nm bandwidth thermal emission is realized by a complex photon polariton based on the superposition of Tamm plasmon polariton and surface plasmon polariton. We experimentally achieve a spectral efficiency of 65.6% (wavelength range of 0.4-8 µm) with statistical deviation less than 4% over the 6″ emitter, demonstrating industrial-level reliability for module-scale TPV applications.

[Electrophysiological technique for treatment of chronic prostatiti: Curative effect observation].

OBJECTIVE: To observe the clinical effect of electrophysiological technique in treating chronic prostatitis. METHODS: Choose 40 patients of chronic prostatitis/chronic pelvic pain syndrome (chronicprostatis/chronicpelvicpainsyndrome, CP/CPPS) in People's Hospital in Zhijin and People's hospital in Guizhou Province from January 2022 to April 2023, The patients were randomly divided into control group (n=20) and treatment group (n=20). The treatment group received low-frequency neuromuscular electrical stimulation combined with drug therapy, while the control group received drug therapy alone. The improvement of prostatitis symptom score (NIH-CPSI) and International Prostatitis Symptom score (IPSS) before and after treatment was compared and analyzed. RESULTS: A total of 37 patients were followed up (1 patient in the treatment group withdrew due to hypersensitivity to the electrode; 2 patients in the control group were lost to follow-up. )There was no significant difference in baseline data between the two groups (P > 0.05). The NIH-CPSI score and IPSS score before and after treatment were compared between the two groups, and the difference was statistically significant (P< 0.05). The IPSS score of the two groups after treatment was compared, the average reduction of the treatment group was 15.84±0.92 points, and that of the control group was 7.17±0.40 points, and the difference was statistically significant (t=4.792, P< 0.05). The NIH-CPSI score of the two groups after treatment was compared, and the average reduction was 17.47±0.92 points in the treatment group and 10.56±0.49 points in the control group. The difference between the two groups was statistically significant (t=6.654, P< 0.05). CONCLUSION: The effect of electrophysiological combined drug therapy is obviously better than that of simple drug therapy. Electrophysiological therapy for chronic prostatitis has definite clinical effect and is worth promoting and applying.

Integration of ATAC-Seq and RNA-Seq reveals FOSL2 drives human liver progenitor-like cell aging by regulating inflammatory factors.

BACKGROUND: Human primary hepatocytes (PHCs) are considered to be the best cell source for cell-based therapies for the treatment of end-stage liver disease and acute liver failure. To obtain sufficient and high-quality functional human hepatocytes, we have established a strategy to dedifferentiate human PHCs into expandable hepatocyte-derived liver progenitor-like cells (HepLPCs) through in vitro chemical reprogramming. However, the reduced proliferative capacity of HepLPCs after long-term culture still limits their utility. Therefore, in this study, we attempted to explore the potential mechanism related to the proliferative ability of HepLPCs in vitro culture. RESULTS: In this study, analysis of assay for transposase accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed for PHCs, proliferative HepLPCs (pro-HepLPCs) and late-passage HepLPCs (lp-HepLPCs). Genome-wide transcriptional and chromatin accessibility changes during the conversion and long-term culture of HepLPCs were studied. We found that lp-HepLPCs exhibited an aged phenotype characterized by the activation of inflammatory factors. Epigenetic changes were found to be consistent with our gene expression findings, with promoter and distal regions of many inflammatory-related genes showing increased accessibility in the lp-HepLPCs. FOSL2, a member of the AP-1 family, was found to be highly enriched in the distal regions with increased accessibility in lp-HepLPCs. Its depletion attenuated the expression of aging- and senescence-associated secretory phenotype (SASP)-related genes and resulted in a partial improvement of the aging phenotype in lp-HepLPCs. CONCLUSIONS: FOSL2 may drive the aging of HepLPCs by regulating inflammatory factors and its depletion may attenuate this phenotypic shift. This study provides a novel and promising approach for the long-term in vitro culture of HepLPCs.

Development of a Single-Molecule Nanobalance Ratiometric Electrochemical DNA Biosensor Using a Triblock Poly-Adenine Probe.

The development of electrochemical DNA biosensors has been limited by their reliability and reproducibility due to many interfering factors such as electrode properties, DNA surface densities, and complex biological samples. In this work, we developed a nanobalance polyA hairpin probe (polyA-HP), which was effectively assembled onto the gold electrode surface through the affinity between the central polyA fragment and the Au surface. One flanking probe of the polyA-HP captured the target sequence together with a MB-labeled signal probe, and the other flanking probe captured a reference probe simultaneously. The MB signal related to the amount of target was normalized by the reference Fc signal; thus, the signal-to-noise (S/N) was as high as 2000, and the reproducibility was remarkably improved to 2.77%, even facing deliberately changed experiment conditions. By designing a hairpin structure at the terminal of the polyA-HP, the selectivity and specificity were dramatically improved for the analysis of mismatched sequences. The analysis performance of biological samples was dramatically improved after normalization, which is critical for its practicability. Our novel biosensor is a universal single-molecule platform for ratiometric biosensors with excellent performance in real samples, indicating great potential for next-generation high-precision electrochemical sensors.

Pulsed microwave photonic vector network analyzer based on direct sampling.

Pulsed VNAs enabling large dynamic measurement at a low pulse duty cycle are necessary for the characterization of active devices due to the overheating damage risk under continuous wave stimulation. In this paper, we proposed a pulsed microwave photonic vector network analyzer (p-MPVNA) based on direct sampling. With the broad system bandwidth of the p-MPVNA and undersampling technique, pulsed signals are received thru asynchronous wideband detection, and pulsed S-parameters are calculated thru vector superposition. In asynchronous wideband detection, the continuous spectrum of the pulsed signal is discretized into multiple frequency components. A low repetition rate optical pulse train undersamples the pulsed signal, and the discretized frequency components are aliased. The frequency components in the main lobe including most energy of the pulse signal are vector superimposed to calculate the pulsed S-parameter. The proposed p-MPVNA has a dynamic range decreases rate of 10log(duty cycle) when pulse duty cycle is below 10% , which is much slower than that of 20log(duty cycle) for classical narrowband detection. An experimental p-MPVNA is established for validation. A 6 to 18 GHz microwave amplifier is measured with continuous and pulsed power supply and the measured gain curves are consistent with the results from a commercial VNA. The system dynamic range decrease with pulse duty cycle is verified by the pulsed S-parameter measurement of a 10 GHz low pass filter under continuous and pulsed stimulation.

Development and validation of a risk prediction model for the recurrence of foot ulcer in type 2 diabetes in China: A longitudinal cohort study based on a systematic review and meta-analysis.

AIMS: To develop and validate a risk prediction model for Chinese patients with type 2 diabetes with the recurrence of diabetic foot ulcers (DFUs) based on a systematic review and meta-analysis. METHODS: A prospective analysis was performed with 1333 participants and followed up for 60 months. Three models were analysed using a derived cohort. The risk factors were screened using meta-analysis and logistic regression, and the missing variables were interpolated by multiple imputation. The internal validation was performed using the bootstrap procedure, and the validation cohort was applied to the external validation. The performance of the model was evaluated in the area under the discrimination Receiver Operating Characteristic Curve (ROC). Calibration and discrimination methods were used for the validation cohort. The variables were selected according to their clinical and statistical importance to construct the nomograms. RESULTS: Three models were developed and validated. Model 1 included seven social and clinical indicators like sex, diabetes mellitus duration, previous DFU, location of ulcer, smoking, history of amputation, and foot deformity. Model 2 included four more indicators besides those in Model 1, which were statin agents used, antiplatelet agents used, systolic blood pressure, and body mass index. Model 3 added further laboratory indicators to Model 2, such as LDL-C, HbA1C, fibrinogen, and blood urea nitrogen. In the derivation cohort, 20.1% (206/1027) participants with DFU recurred as compared to the validation cohort, which was 38.2% (117/306). The areas under the curve in the derivation cohort for Models 1-3 were 0.781 (0.744-0.817), 0.843 (0.813-0.873), and 0.899 (0.876-0.922), respectively. The Youden indexes for Models 1-3 were 0.430, 0.559, and 0.653, respectively. Model 3 showed the highest sensitivity and specificity. All models performed well for both discrimination and calibration. CONCLUSIONS: Models 1-2 were non-invasive, which indicate their role in general screening for patients at a high risk of recurrence of DFU. However, Model 3 offers a more specific screening due to its best performance in predicting the risk of DFU recurrence amongst the three models.

Heterocyclic Boron Acid Catalyzed Dehydrative Amidation of Aliphatic/Aromatic Carboxylic Acids with Amines.

A commercially available and versatile dehydrative amidation catalyst, featuring a thianthrene boron acid structure, has been developed. The catalyst shows high catalytic activity to both aliphatic and less reactive aromatic carboxylic acid substrates, including several bioactive or clinical molecules with a carboxylic acid group.

Perinatal outcomes of singletons following double vitrification-warming procedures: a retrospective study using propensity score analysis.

BACKGROUND: Although repeated cryopreservation is an occasional occurrence, the effect on perinatal outcomes is unclear. Therefore, the aim of this study was to evaluate the perinatal outcomes of singletons after embryo re-cryopreservation. METHODS: In this retrospective study, a total of 647 singleton live births after blastocyst freeze-thaw embryo transfer cycles were investigated. They were divided into two groups: vitrified-warmed blastocysts (once-vitrified group) and vitrified-warmed blastocysts derived from thawed cleaved embryos (re-vitrified group). Propensity score matching (PSM) was used to control for potential confounding factors. RESULTS: A total of 592 infants were included in the once-vitrified group, and 55 infants were included in the re-vitrified group. After PSM, 108 cases were generated for comparison. The median gestational age was 38 weeks for both groups, and the birthweights were comparable (3390.6 ± 601.5 g vs. 3412.8 ± 672.6 g, P > 0.05). The incidence of preterm birth (PTB) (20.4% vs. 16.7%), low birthweight (LBW) (3.7% vs. 7.4%), macrosomia (11.1% vs. 16.7%) and large for gestational age (LGA) (29.6% vs. 22.2%) were not significantly different between the two groups. Logistic regression analysis indicated that double vitrification-warming procedures did not affect the occurrence of PTB (OR, 2.58 [95% CI, 0.77, 8.63]), LBW (OR, 0.83 [95% CI, 0.08, 8.29]), macrosomia (OR, 0.60 [95% CI, 0.13, 2.69]), or LGA (OR, 1.51 [95% CI, 0.53, 4.27]) (P > 0.05, for all). CONCLUSION: Our findings demonstrate that double vitrification-warming procedures do not increase the risk of adverse neonatal outcomes compared with those of once-vitrified embryos.

Exploring the potential anti-Alzheimer disease mechanisms of Alpiniae Oxyphyliae Fructus by network pharmacology study and molecular docking.

Alpiniae Oxyphyliae Fructus (AOF) (yizhi) is a frequently medicated Chinese herb for Alzheimer disease (AD) treatment. The present study investigated the components and potential mechanisms of AOF through network pharmacology analysis and molecular docking. The results showed that AOF contains at least 20 active ingredients and involves 184 target genes. A total of 301 AD-related genes were obtained from the DisGeNET, GeneCards, GEO, OMIM, and Alzheimer Disease: Genes databases. A total of 41 key targets were identified from the topology analysis of the AOF-AD target network. These key targets are involved in 105 signal pathways, such as the PI3K-Akt, HIF-1, and MAPK pathways, and can regulate gene transcription, cell death, cell proliferation, drug response, and protein phosphorylation. AOF's active ingredients, Chrysin, Isocyperol, Izalpinin, Linolenic acid, CHEMBL489541, Oxyphyllenone A, Oxyphyllenone B, and Oxyphyllol C, show high affinity to targets, including PPARG, ESR1, and AKT1. These findings provide a new basis for AOF application and anti-AD study.

Mechanisms of Actinidia chinensis Planch in treating colon cancer based on the integration of network pharmacology, molecular docking, and experimental verification.

BACKGROUND: As an anticancer Chinese herbal medicine, the effective components and mechanism of Actinidia chinensis Planch (ACP, Tengligen) in the treatment of colon cancer are still unclear. In the present study, the integration of network pharmacology, molecular docking, and cell experiments was employed to study the effective mechanism of ACP against colon cancer. METHODS: The Venn diagram and STRING database were used to construct the protein-protein interaction network (PPI) of ACP-colon cancer, and further topological analysis was used to obtain the key target genes of ACP in colon cancer. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to visualize the related functions and pathways. Molecular docking between key targets and compounds was determined using software such as AutoDockTools. Finally, the effect of ACP on CT26 cells was observed in vitro. RESULTS: The study identified 40 ACP-colon key targets, including CASP3, CDK2, GSK3B, and PIK3R1. GO and KEGG enrichment analyses found that these genes were involved in 211 biological processes and 92 pathways, among which pathways in cancer, PI3K-Akt, p53, and cell cycle might be the main pathways of ACP against colon cancer. Molecular docking verified that the key components of ACP could stably bind to the corresponding targets. The experimental results showed that ACP could inhibit proliferation, induce apoptosis, and downregulate the phosphorylation of PIK3R1, Akt, and GSK3B in CT26 cells. CONCLUSION: ACP is an anti-colon cancer herb with multiple components, and involvement of multiple target genes and signaling pathways. ACP can significantly inhibit proliferation and induce apoptosis of colon cancer cells, which may be closely related to the regulation of PI3K/AKT/GSK3B signal transduction.

The Values and Perspectives of Organoids in the Field of Metabolic Syndrome.

Metabolic syndrome (MetS) has become a global health problem, and the prevalence of obesity at all stages of life makes MetS research increasingly important and urgent. However, as a comprehensive and complex disease, MetS has lacked more appropriate research models. The advent of organoids provides an opportunity to address this issue. However, it should be noted that organoids are still in their infancy. The main drawbacks are a lack of maturity, complexity, and the inability to standardize large-scale production. Could organoids therefore be a better choice for studying MetS than other models? How can these limitations be overcome? Here, we summarize the available data to present current progress on pancreatic and hepatobiliary organoids and to answer these open questions. Organoids are of human origin and contain a variety of human cell types necessary to mimic the disease characteristics of MetS in their development. Taken together with the discovery of hepatobiliary progenitors in situ, the dedifferentiation of beta cells in diabetes, and studies on hepatic macrophages, we suggest that promoting endogenous regeneration has the potential to prevent the development of end-stage liver and pancreatic lesions caused by MetS and outline the direction of future research in this field.

SDF-1 inhibits the dedifferentiation of islet ß cells in hyperglycaemia by up-regulating FoxO1 via binding to CXCR4.

Islet ß cell dedifferentiation is one of the most important mechanisms in the occurrence and development of diabetes. We studied the possible effects of chemokine stromal cell-derived factor-1 (SDF-1) in the dedifferentiation of islet ß cells. It was noted that the number of dedifferentiated islet ß cells and the expression of SDF-1 in pancreatic tissues significantly increased with diabetes. In islet ß cell experiments, inhibition of SDF-1 expression resulted in an increase in the number of dedifferentiated cells, while overexpression of SDF-1 resulted in a decrease. This seemed to be contradicted by the effect of diabetes on the expression of SDF-1 in pancreatic tissue, but it was concluded that this may be related to the loss of SDF-1 activity. SDF-1 binds to CXCR4 to form a complex, which activates and phosphorylates AKT, subsequently increases the expression of forkhead box O1 (FOXO1), and inhibits the dedifferentiation of islet ß cells. This suggests that SDF-1 may be a novel target in the treatment of diabetes.

TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.

BACKGROUND: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. METHODS: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle-specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression. RESULTS: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. CONCLUSIONS: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.