Lovastatin/SN38 co-loaded liposomes amplified ICB therapeutic effect via remodeling the immunologically-cold colon tumor and synergized stimulation of cGAS-STING pathway.

Current immune checkpoint blockade (ICB) immunotherapeutics have revolutionized cancer treatment. However, many cancers especially the "immunologically cold" tumors, do not respond to ICB, prompting the search for additional strategies to achieve durable responses. The cGAS-STING pathway, as an essential immune response pathway, has been demonstrated for a potent target to sensitize ICB immunotherapy. However, the low efficiency of conventional STING agonists limits their clinical application. Recent studies have shown that DNA topoisomerase I (TOPI) inhibitor chemodrug SN38 can activate the cGAS-STING pathway and induce an immune response through DNA damage, while the traditional statins medication lovastatin was found to inhibit DNA damage repair, which may in turn upregulate the damaged DNA level. Herein, we have developed a liposomal carrier co-loaded with SN38 and lovastatin (SL@Lip), which can be accumulated in tumors and efficiently released SN38 and lovastatin, addressing the problem of weak solubility of these two drugs. Importantly, lovastatin can increase DNA damage and enhance the activation of cGAS-STING pathway, coordinating with SN38 chemotherapy and exhibiting the enhanced combinational immunotherapy of PD-1 antibody by remodeling the tumor microenvironment in mouse colorectal cancer of both subcutaneous and orthotopic xenograft models. Overall, this study demonstrates that lovastatin-assisted cGAS-STING stimulation mediated by liposomal delivery system significantly strengthened both chemotherapy and immunotherapy of colorectal cancer, providing a clinically translational strategy for combinational ICB therapy in the "immunologically cold" tumors.

Topographic metabolism-function relationships in Alzheimer's disease: A simultaneous PET/MRI study.

Disruptions of neural metabolism and function occur in parallel during Alzheimer's disease (AD). While many studies have shown diverse metabolic-functional relationships in specific brain regions, much less is known about how large-scale network-level functional activity is associated with the topology of metabolism in AD. In this study, we took the advantages of simultaneous PET/MRI and multivariate analyses to investigate the associations between AD-related stereotypical spatial patterns (topographies) of glucose metabolism, measured by fluorodeoxyglucose PET, and functional connectivity, measured by resting-state functional MRI. A total of 101 participants, including 37 patients with AD, 25 patients with mild cognitive impairment (MCI), and 39 cognitively normal controls, underwent PET/MRI scans and cognitive assessments. Three pairs of distinct but optimally correlated metabolic and functional topographies were identified, encompassing large-scale networks including the default-mode, executive and control, salience, attention, and subcortical networks. Importantly, the metabolic-functional associations were not only limited to one-to-one-corresponding regions, but also occur in remote and non-overlapping regions. Furthermore, both glucose metabolism and functional connectivity, as well as their linkages, exhibited various degrees of disruptions in patients with MCI and AD, and were correlated with cognitive decline. In conclusion, our results support distributed and heterogeneous topographic associations between metabolism and function, which are jeopardized by AD. Findings of this study may deepen our understanding of the pathological mechanism of AD through the perspectives of both local energy efficiency and long-term interactions between synaptic disruption and functional disconnection contributing to the clinical symptomatology in AD.

Integrating TSPO PET imaging and transcriptomics to unveil the role of neuroinflammation and amyloid-ß deposition in Alzheimer's disease.

PURPOSE: Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer's disease (AD) through animal and postmortem investigations, direct evidence regarding the impact of genetic factors on microglia response and amyloid-ß (Aß) deposition in AD individuals is lacking. This study aims to elucidate this mechanism by integrating transcriptomics and TSPO, Aß PET imaging in clinical AD cohort. METHODS: We analyzed 85 patients with PET/MR imaging for microglial activation (TSPO, [18F]DPA-714) and Aß ([18F]AV-45) within the prospective Alzheimer's Disease Immunization and Microbiota Initiative Study Cohort (ADIMIC). Immune-related differentially expressed genes (IREDGs), identified based on AlzData, were screened and verified using blood samples from ADIMIC. Correlation and mediation analyses were applied to investigate the relationships between immune-related genes expression, TSPO and Aß PET imaging. RESULTS: TSPO uptake increased significantly both in aMCI (P < 0.05) and AD participants (P < 0.01) and showed a positive correlation with Aß deposition (r = 0.42, P < 0.001). Decreased expression of TGFBR3, FABP3, CXCR4 and CD200 was observed in AD group. CD200 expression was significantly negatively associated with TSPO PET uptake (r =-0.33, P = 0.013). Mediation analysis indicated that CD200 acted as a significant mediator between TSPO uptake and Aß deposition (total effect B = 1.92, P = 0.004) and MMSE score (total effect B =-54.01, P = 0.003). CONCLUSION: By integrating transcriptomics and TSPO PET imaging in the same clinical AD cohort, this study revealed CD200 played an important role in regulating neuroinflammation, Aß deposition and cognitive dysfunction.

Immunological strip sensor for the rapid determination of niacin in dietary supplements and foods.

Herein, four haptens of niacin (Vitamin B3, VB3) were designed, and after a series of experiments, it was concluded that hapten D had the best immune effect. To avoid false positives in the detection of real samples, a monoclonal antibody (mAb) against VB3 was prepared by a matrix effect-enhanced mAb screening method. The concentration of the inhibition rate reaching 50% (IC50) was 603.41 ng mL-1 and the limit of detection (LOD) using an indirect enzyme-linked immunosorbent assay (ic-ELISA) was 54.89 ng mL-1. A lateral flow immunochromatographic assay (LFIA) based on gold nanoparticles was established to detect the concentration of VB3 in compound vitamin B tablets and infant formulas, with a visual LOD of 5 µg mL-1. Using a handheld reader, the quantitative LOD was calculated to be 0.60 µg mL-1. The contents of the compound vitamin B tablets and infant formulas were also verified by liquid chromatography. Therefore, the LFIA developed in this study can be applied to the specific identification and rapid detection of niacin in nutritional dietary supplements, thus meeting the market's demand for efficient niacin detection methods.

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair.

Gefitinib (GEF) is a clinical medication for the treatment of lung cancer targeting the epidermal growth factor receptor (EGFR). However, its efficacy is remarkably limited by low solubility and dissolution rates. In this study, two cocrystals of GEF with co-formers were successfully synthesized using the recrystallization method characterized via Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and 2D Nuclear Overhauser Effect Spectroscopy. The solubility and dissolution rates of cocrystals were found to be two times higher than those of free GEF. In vitro cytotoxicity studies revealed that the cocrystals enhanced the inhibition of cell proliferation and apoptosis in A549 and H1299 cells compared to free GEF. In mouse models, GEF@TSBO demonstrated targeted, safe, and effective antitumor activity with only one-dose administration. Mechanistically, the GEF cocrystals were shown to increase the cellular levels of damaged DNA, while potentially downregulating PARP, thereby impairing the DNA repair machinery and leading to an imbalance between DNA damage and restoration. These findings suggest that the cocrystallization of GEF could serve as a promising adjunct to significantly enhance the physicochemical and biopharmaceutical performance for lung cancer treatment, providing a facial strategy to improve GEF anticancer efficiency with high bioavailability that can be orally administrated with only one dose.

Can antibiotics for enteritis or for urinary tract infection disrupt the urinary microbiota in rats?

Background: To establish antibiotic preregimes and administration routes for studies on urinary microbiota. Methods and materials: Antibiotics for enteritis (Abx-enteritis) and UTIs (Abx-UTI) were administered via gavage and/or urinary catheterisation (UC) for 1 and/or 2 weeks. The effects of these Abx on the urinary microbiota of rats were examined via 16S rRNA sequencing and urine culture, including anaerobic and aerobic culture. Additionally, the safety of the Abx was examined. Results: Abx-enteritis/Abx-UTI (0.5 g/L and 1 g/L) administered via gavage did not alter the microbial community and bacterial diversity in the urine of rats (FDR > 0.05); however, Abx-UTI (1 g/L) administered via UC for 1 and 2 weeks altered the urinary microbial community (FDR < 0.05). Rats administered Abx-UTI (1 g/L) via UC for 1 week demonstrated a distinct urinary microbiota in culture. Abx-enteritis/Abx-UTI administered via gavage disrupted the microbial community and reduced bacterial diversity in the faeces of rats (FDR < 0.05), and Abx-UTI administered via UC for 2 weeks (FDR < 0.05) altered the fecal microbiota. Abx-UTI (1 g/L) administered via UC did not alter safety considerations. In addition, we noticed that UC did not induce infections and injuries to the bladder and kidney tissues. Conclusions: Administration of Abx-UTI via UC for 1 week can be considered a pre-treatment option while investigating the urinary microbiota.

Biomechanical Responses of Different Cap Thicknesses of Corneas After Small Incision Lenticule Extraction: Finite Element Analysis.

Purpose: This study analyzed the biomechanical responses of different corneal cap thicknesses after small incision lenticule extraction (SMILE). Methods: Individual finite element models of myopic eyes were constructed based on the clinical data. Then, four types of corneal cap thicknesses after SMILE were included for each model. The biomechanical effects of material parameters and intraocular pressure on corneas with different cap thicknesses were analyzed. Results: When the cap thickness increased, the vertex displacements of the anterior and posterior corneal surfaces decreased slightly. The corneal stress distributions demonstrated little change. Regarding wave-front aberrations caused by the displacements of the anterior surface, the absolute defocus value decreased slightly, but the magnitude of primary spherical aberration increased slightly. The horizontal coma increased, and the levels of other low-order and high-order aberrations were small and demonstrated little change. The corneal vertex displacement and wave-front aberration were significantly affected by elastic modulus and intraocular pressure, whereas the corneal stress distribution was greatly affected by intraocular pressure. There were obvious individual differences in the biomechanical responses of human eyes. Conclusions: The biomechanical difference of different corneal cap thicknesses after SMILE was small. The effect of corneal cap thickness was significantly less than that resulting from material parameters and intraocular pressure. Translational Relevance: Individual models were constructed based on the clinical data. The elastic modulus was controlled by programming to simulate its heterogeneous distribution in the actual human eye. The simulation was improved to bridge the gap between basic research and clinical care.

Water deficits shape the microbiome of Bermudagrass roots to be Actinobacteria rich.

There is increasing evidence that microbes can help ameliorate plant growth under environmental stress. Still, it is largely unknown what microbes and potential functions are involved in sustaining turfgrass, the major component of urban/suburban landscapes, under drought. We examined microbial responses to water deficits in bulk soil, rhizosphere, and root endosphere of bermudagrass by applying evapotranspiration (ET)-based dynamic irrigation twice per week during the growing season to create six treatments (0%, 40%, 60%, 80%, 100%, and 120% ET) and respective drought-stressed soil conditions. Bacterial and fungal communities were analyzed via marker gene amplicon sequencing and thereafter drought-reshaped potential functions of the bacterial community were projected. Slight yet significant microbial responses to irrigation treatments were observed in all three microhabitats. The root endophytic bacterial community was most responsive to water stress. No-irrigation primarily increased the relative abundance of root endophytic Actinobacteria, especially the genus Streptomyces. Irrigation at ≤40% ET increased the relative abundances of PICRUSt2-predicted functional genes encoding 1-aminocyclopropane-1-carboxylic acid deaminase, superoxide dismutase, and chitinase in root endosphere. Our data suggest that the root endophytic Actinobacteria are likely the key players to improve bermudagrass fitness under drought by modulating phytohormone ethylene production, scavenging reactive oxygen species, or ameliorating nutrient acquisition.

Clinical efficacy of wet dressing combined with chitosan wound dressing in the treatment of deep second-degree burn wounds: A prospective, randomised, single-blind, positive control clinical trial.

To evaluate the efficacy and safety of wet dressing combined with chitosan wound dressing for deep II degree burn wounds, and provide the basis for clinical application. From October 2019 to October 2021, 80 patients with second-degree deep burn treated in the Department of burn and plastic surgery of our hospital were selected as the research objects. Patients were randomly divided into two groups. The control group (40n) was treated with wet compress, and the study group (40n) was treated with wet compress combined with chitosan wound dressing. The wound healing time, wound healing percentage and pain score were used as the effectiveness indexes, and the incidence of adverse events and serious adverse events and the detection rate of bacterial culture of wound exudates were used as the safety indexes. The efficacy and safety of the two groups were compared. The wound healing time of the study group (19.53 ± 2.74 days) was shorter than that of the control group (24.78 ± 4.86 days), the difference was significant (t = 3.571, P = 0.015). The percentage of wound healing at the 14th after treatment in the study group was higher than that in the control group (65.00% versus 37.50%) (X2  = 6.054, P = 0.014). There was no significant difference in pain scores between the two groups at each time point. The scar growth was observed 3 months after wound healing. The scar score of the study group (6.00 ± 0.98) was lower than that of the control group (8.77 ± 1.19) (t = 2.571, P = 0.031). The positive rate of wound secretion culture on the 7th and 14th day was statistically significant (X2  = 4.528, P = 0.033; X2  = 6.646, P = 0.010), and the study group was lower than the control group (29.03% versus 81.82%; 8.11% versus 42.86%). There was no significant difference in treatment cost between the study group and the control group (1258.7 ± 223.6 versus 1248.9 ± 182.3) (t = 1.571, P = 0.071). No adverse events or serious adverse events occurred in both groups. Chitosan wound dressing can significantly shorten the time of wound healing and reduce wound pain and wound infection in patients with deep second-degree burns. And it can effectively improve the situation of scar hyperplasia, which is worthy of clinical application.

A scientometrics study of the nanomedicines assisted in respiratory diseases.

Nanomedicine has been extensively studied for its versatility and broad-spectrum applications of theranostics in the research of respiratory disease. However, to the best of our knowledge, a scientometrics study based on the scientific knowledge assay of the overall situation on nanomedicine applied in the research of respiratory disease has not been reported so far, which would be of major importance to relevant researchers. To explore and exhibit the research status and developing trend of nanomedicines deployed in basic or clinical research in respiratory disease, the research ecosystem and exciting subareas were profiled based on the massive data mining and visualization from the relevant works reported from 2006 to 2021. Data were collected from the Web of Science database. Data statistics software and bibliometric analysis software were employed to visualize the research trend and the relationship between respiratory diseases and nanomedicines in each representative direction. The cluster analysis and burst detections indicated that the improvement of drug delivery and vaccine developments are the up-to-date key directions in nanomedicines for respiratory disease research and treatments. Furthermore, we emphatically studied four branch areas in this field including COVID-19, nanotube, respiratory syncytial virus, and mRNA vaccine those are selected for in-depth mining and bibliometric coupling analysis. Research trends signify the future focuses will center on preventing respiratory diseases with mRNA vaccines using nanoparticle-based approaches. We anticipate our study will enable researchers to have the panorama and deep insights in this area, thus inspiriting further exploitations especially the nanobiomaterial-based systems for theranostic applications in respiratory disease treatment.

The Bladder Microbiome, Metabolome, Cytokines, and Phenotypes in Patients with Systemic Lupus Erythematosus.

Emerging studies reveal unique bacterial communities in the human bladder, with alteration of composition associated to disease states. Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is characterized by frequent impairment of the kidney. Here, we explored the bladder microbiome, metabolome, and cytokine profiles in SLE patients, as well as correlations between microbiome and metabolome, cytokines, and disease profiles. We recruited a group of 50 SLE patients and 50 individually matched asymptomatic controls. We used transurethral catheterization to collect urine samples, 16S rRNA gene sequencing to profile bladder microbiomes, and liquid chromatography-tandem mass spectrometry to perform untargeted metabolomic profiling. Compared to controls, SLE patients possessed unique bladder microbial communities and increased alpha diversity. These differences were accompanied by differences in urinary metabolomes, cytokines, and patients' disease profiles. The SLE-enriched genera, including Bacteroides, were positively correlated with several SLE-enriched metabolites, including olopatadine. The SLE-depleted genera, such as Pseudomonas, were negatively correlated to SLE-depleted cytokines, including interleukin-8. Alteration of the bladder microbiome was associated with disease profile. For example, the genera Megamonas and Phocaeicola were negatively correlated with serum complement component 3, and Streptococcus was positively correlated with IgG. Our present study reveals associations between the bladder microbiome and the urinary metabolome, cytokines, and disease phenotypes. Our results could help identify biomarkers for SLE. IMPORTANCE Contrary to dogma, the human urinary bladder possesses its own unique bacterial community with alteration of composition associated with disease states. Systemic lupus erythematosus (SLE) is a complex autoimmune disease often characterized by kidney impairment. Here, we explored the bladder microbiome, metabolome, and cytokine profiles in SLE patients, as well as correlations between the microbiome and metabolome, cytokines, and disease profiles. Compared to controls, SLE patients possessed a unique bladder microbial community and elevated alpha diversity. These differences were accompanied by differences in bladder metabolomes, cytokines, and patients' disease profiles. SLE-enriched genera were positively correlated with several SLE-enriched metabolites. SLE-depleted genera were negatively correlated to SLE-depleted cytokines. Alteration of the bladder microbiome was associated with disease profile. Thus, our study reveals associations between the bladder microbiome and the bladder metabolome, cytokines, and disease phenotypes. These results could help identify biomarkers for SLE.

Urea fertilization and grass species alter microbial nitrogen cycling capacity and activity in a C4 native grassland.

Soil microbial transformation of nitrogen (N) in nutrient-limited native C4 grasslands can be affected by N fertilization rate and C4 grass species. Here, we report in situ dynamics of the population size (gene copy abundances) and activity (transcript copy abundances) of five functional genes involved in soil N cycling (nifH, bacterial amoA, nirK, nirS, and nosZ) in a field experiment with two C4 grass species (switchgrass (Panicum virgatum) and big bluestem (Andropogon gerardii)) under three N fertilization rates (0, 67, and 202 kg N ha-1). Diazotroph (nifH) abundance and activity were not affected by N fertilization rate nor grass species. However, moderate and high N fertilization promoted population size and activity of ammonia oxidizing bacteria (AOB, quantified via amoA genes and transcripts) and nitrification potential. Moderate N fertilization increased abundances of nitrite-reducing bacterial genes (nirK and nirS) under switchgrass but decreased these genes under big bluestem. The activity of nitrous oxide reducing bacteria (nosZ transcripts) was also promoted by moderate N fertilization. In general, high N fertilization had a negative effect on N-cycling populations compared to moderate N addition. Compared to big bluestem, the soils planted with switchgrass had a greater population size of AOB and nitrite reducers. The significant interaction effects of sampling season, grass species, and N fertilization rate on N-cycling microbial community at genetic-level rather than transcriptional-level suggested the activity of N-cycling microbial communities may be driven by more complex environmental factors in native C4 grass systems, such as climatic and edaphic factors.

Gut Mycobiome in Patients With Chronic Kidney Disease Was Altered and Associated With Immunological Profiles.

Objectives: Mounting evidence suggests that bacterial dysbiosis and immunity disorder are associated with patients with chronic kidney disease (CKD), but the mycobiome is beginning to gain recognition as a fundamental part of our microbiome. We aim to characterize the profile of the mycobiome in the gut of CKD patients and its correlation to serum immunological profiles. Methods and materials: Ninety-two CKD patients and sex-age-body mass index (BMI)-matched healthy controls (HCs) were recruited. Fresh samples were collected using sterile containers. ITS transcribed spacer ribosomal RNA gene sequencing was performed on the samples. An immunoturbidimetric test was used to assess the serum levels of immunological features. Results: The CKD cohort displayed a different microbial community from that in the HC cohort according to principal coordinate analysis (PCoA). (P=0.001). The comparison of the two cohorts showed that the CKD cohort had significantly higher gut microbial richness and diversity (P<0.05). The CKD cohort had lower abundances of Candida, Bjerkandera, Rhodotorula, and Ganoderma compared to the HC cohort, while it had higher Saccharomyces (P<0.05). However, the microbial community alteration was inconsistent with the severity of kidney damage in patients, as only patients in CKD stage 1~3 had differed microbial community concerning for HCs based on PCoA (P<0.05). The serum concentration of the kappa light chain in CKD patients was positively associated with Saccharomyces, whereas the it was negatively associated with Ganoderma (P<0.05). Conclusions: Not only was gut mycobiome dysbiosis observed in CKD patients, but the dysbiosis was also associated with the immunological disorder. These findings suggest that therapeutic strategies targeting gut mycobiome might be effective.

Evolutionary Trend Analysis of Research on 5-ALA Delivery and Theranostic Applications Based on a Scientometrics Study.

5-aminolevulinic acid (5-ALA) has been extensively studied for its sustainability and broad-spectrum applications in medical research and theranostics, as well as other areas. It's a precursor of protoporphyrin IX (PpIX), a sustainable endogenous and naturally-existing photosensitizer. However, to the best of our knowledge, a scientometrics study based on the scientific knowledge assay of the overall situation on 5-ALA research has not been reported so far, which would be of major importance to the relevant researchers. In this study, we collected all the research articles published in the last two decades from the Web of Science Core Collection database and employed bibliometric methods to comprehensively analyze the dataset from different perspectives using CiteSpace. A total of 1595 articles were identified. The analysis results showed that China published the largest number of articles, and SBI Pharmaceuticals Co., Ltd. was the most productive institution that sponsored several of the most productive authors. The cluster analysis and burst detections indicated that the improvement of photodynamic efficacy theranostics is the up-to-date key direction in 5-ALA research. Furthermore, we emphatically studied nanotechnology involvement in 5-ALA delivery and theranostics research. We envision that our results will be beneficial for researchers to have a panorama of and deep insights into this area, thus inspiring further exploitations, especially of the nanomaterial-based systems for 5-ALA delivery and theranostic applications.

Analysis of the Effect of Wound-Edge Microgranular Skin Grafting in the Treatment of Various Small Wounds.

Objective: To explore the clinical effect of wound edge microgranular skin grafting in the treatment of various small wounds. Methods: From September 2018 to September 2021, Yueqing people's Hospital of Wenzhou City, Zhejiang Province collected and recorded the data of 12 patients with chronic wounds and third degree burns. The method of skin grafting with particles at the edge of the wound was used to graft skin on the wound. Scar evaluation scale was used to evaluate the wound. The patients were followed up for 12 months. The preoperative and postoperative data, scar index and patient satisfaction after healing were recorded and statistically analyzed. Results: All patients in this group were followed up for 3-12 months, and the results showed that SCAR Scale score decreased gradually over time, with patient satisfaction ranging from 80% to 96%. The patient gradually healed, scar hyperplasia gradually improved, functional activities gradually returned to normal, clinical effect is satisfactory. Conclusion: Microparticle skin grafting at the edge of wound avoids skin grafting at different skin donor sites. It has the characteristics of simple anesthesia, small trauma and convenient operation. This method can be considered when treating patients with chronic wounds and burns who need skin grafting.

Disrupted coupling between salience network segregation and glucose metabolism is associated with cognitive decline in Alzheimer's disease - A simultaneous resting-state FDG-PET/fMRI study.

The aberrant organization and functioning of three core neurocognitive networks (NCNs), i.e., default-mode network (DMN), central executive network (CEN), and salience network (SN), are among the prominent features in Alzheimer's disease (AD). The dysregulation of both intra- and inter-network functional connectivities (FCs) of the three NCNs contributed to AD-related cognitive and behavioral abnormalities. Brain functional network segregation, integrating intra- and inter-network FCs, is essential for maintaining the energetic efficiency of brain metabolism. The association of brain functional network segregation, together with glucose metabolism, with age-related cognitive decline was recently shown. Yet how these joint functional-metabolic biomarkers relate to cognitive decline along with mild cognitive impairment (MCI) and AD remains to be elucidated. In this study, under the framework of the triple-network model, we performed a hybrid FDG-PET/fMRI study to evaluate the concurrent changes of resting-state brain intrinsic FCs and glucose metabolism of the three NCNs across cognitively normal (CN) (N = 24), MCI (N = 21), and AD (N = 21) groups. Lower network segregation and glucose metabolism were observed in all three NCNs in patients with AD. More interestingly, in the SN, the coupled relationship between network segregation and glucose metabolism existed in the CN group (r = 0.523, p = 0.013) and diminished in patients with MCI (r = 0.431, p = 0.065) and AD (r = 0.079, p = 0.748). Finally, the glucose metabolism of the DMN (r = 0.380, p = 0.017) and the network segregation of the SN (r = 0.363, p = 0.023) were significantly correlated with the general cognitive status of the patients. Our findings suggest that the impaired SN segregation and its uncoupled relationship with glucose metabolism contribute to the cognitive decline in AD.

Antioxidant for treatment of diabetic complications: A meta-analysis and systematic review.

Antioxidants may provide a complementary treatment for patients with chronic diseases. Nevertheless, studies that have measured the effects of antioxidant on diabetes complications have provided conflicting results. This study aimed to elucidate the association between antioxidant and diabetic complications and to develop robust evidence for clinical decisions by systematic reviews and meta-analysis. PubMed, Embase, The Cochrane Library, Web of Science, Scopus databases were searched to collect clinical studies related to the efficacy of antioxidants in the treatment of diabetes complications from inception to May 5, 2021. Statistical meta-analyses were performed using the RevMan 5.4 software. Stata16 software was used to detect publication bias. The data of diabetic nephropathy (DN), diabetic nonalcoholic fatty liver disease (NAFLD), and diabetic periodontitis were collected to analyze the effect of antioxidant on diabetes and the above three complications. The meta-analysis results showed that antioxidant treatment was associated with significantly changes in the fasting plasma glucose (FPG) (standardized mean difference [SMD]: - 0.21 [95% confidence interval [CI]: - 0.33, -0.10], p < 0.001), hemoglobin A1c (HbA1c) (MD: - 0.41 [95% CI: - 0.63, -0.18], p < 0.001), total antioxidant capacity (TAC) (SMD: 0.44 [95% CI: 0.24, 0.63], p < 0.001) and malondialdehyde (MDA) (SMD: - 0.82 [95% CI: - 1.24, -0.41], p < 0.001) than the control group. Antioxidant supplements have the potential to treat three complications of diabetes. In conclusion, the meta-analysis results indicate that antioxidant treatment is effective clinically for diabetes mellitus and its complications.

The Therapeutic Roles of Recombinant Hsp90α on Cornea Epithelial Injury.

Purpose: The purpose of this study was to explore the therapeutic role of heat shock protein 90 (Hsp90) in wound healing of injury cornea epithelium. Methods: The right eye of C57BL/6N male mice were performed the debridement wounds in the center of the cornea using an algerbrush II blade. The injured area was determined by staining the cornea with fluorescein sodium and measured with image-J. Immunoblotting, ELISA and immunochemistry were used for determining protein expression. The quantitation PCR was performed to measure mRNA expression. Results: Hsp90α is upregulated at both the mRNA and protein levels, and is secreted extracellularly into the corneal stroma and tear film during the healing process after corneal injury in mice. This upregulation is associated with activation of HSF1. Administration of recombinant exogenous Hsp90α (eHsp90α) speeds up wound healing of injured corneal epithelium. The eHsp90α binds to low-density lipoprotein (LDL)-related protein-1 (LRP-1) on the corneal epithelial cells and increases phosphorylation of AKT at S473, which is associated with proliferation and migration corneal epithelial cells in vitro or vivo. Inhibition of AKT by its inhibitor LY294002 abolishes eHsp90α-induced migration and proliferation of corneal epithelial cells. Conclusion: Hsp90α is upregulated and secreted after corneal injury and acts to promote the healing process. Recombinant Hsp90α may be a promising therapeutic drug candidate for corneal injury.

Biotin attenuates heat shock factor 4b transcriptional activity by lysine 444 biotinylation.

Genetic mutations in HSF4 cause congenital cataracts. HSF4 exhibits both positive and negative regulation on the transcription of heat shock and non-heat shock proteins during lens development, and its activity is regulated by posttranslational modifications. Biotin is an essential vitamin that regulates gene expression through protein biotinylation. In this paper, we report that HSF4b is negatively regulated by biotinylation. Administration of biotin or ectopic bacterial biotin ligase BirA increases HSF4b biotinylation at its C-terminal amino acids from 196 to 493. This attenuates the HSF4b-controlled expression of αB-crystallin in both lens epithelial cells and tested HEK293T cells. HSF4b interacts with holocarboxylase synthetase (HCS), a ubiquitous enzyme for catalyzing protein biotinylation in mammal. Ectopic HA-HCS expression downregulates HSF4b-controlled αB-crystallin expression. Lysine-mutation analyses indicate that HSF4b/K444 is a potential biotinylation site. Mutation K444R reduces the co-precipitation of HSF4b by streptavidin beads and biotin-induced reduction of αB-crystallin expression. Mutations of other lysine residues such as K207R/K209R, K225R, K288R, K294R and K355R in HSF4's C-terminal region do not affect HSF4's expression level and the interaction with streptavidin, but they exhibit distinct regulation on αB-crystallin expression through different mechanisms. HSF4/K294R leads to upregulation of αB-crystallin expression, while mutations K207R/K209R, K225R, K288R, K255R and K435R attenuate HSF4's regulation on αB-crystallin expression. K207R/K209R blocks HSF4 nuclear translocation, and K345R causes HSF4 destabilization. Taken together, the data reveal that biotin maybe a novel factor in modulating HSF4 activity through biotinylation.