Abscisic acid-mediated autoregulation of the MYB41-BRAHMA module enhances drought tolerance in Arabidopsis.

Drought stress poses a substantial challenge to plant growth and agricultural productivity worldwide. Upon water depletion, plants activate an abscisic acid (ABA) signaling pathway, leading to stomatal closure to reduce water loss. The MYB family of transcription factors plays diverse roles in growth, development, stress responses and biosynthesis, yet their involvement in stomatal regulation remains unclear. Here, we demonstrate that ABA significantly upregulates the expression of MYB41, MYB74, and MYB102, with MYB41 serving as a key regulator that induces the expression of both MYB74 and MYB102. Through luciferase assays, chromatin immunoprecipitation (ChIP) assays and electrophoretic mobility shift assays (EMSA), we reveal that MYB41 engages in positive feedback regulation by binding to its own promoter, thus amplifying its transcription in Arabidopsis (Arabidopsis thaliana). Furthermore, our investigation showed that MYB41 recruits BRAHMA (BRM), the core ATPase subunit of the SWI/SNF complex, to the MYB41 promoter, facilitating the binding of HISTONE DEACETYLASE 6 (HDA6). This recruitment triggers epigenetic modifications, resulting in reduced MYB41 expression characterized by elevated H3K27me3 levels and concurrent decreases in H3ac, H3K27ac, and H3K14ac levels in wild-type plants compared to brm knockout mutant plants. Our genetic and molecular analyses show that ABA mediates autoregulation of the MYB41-BRM module, which intricately modulates stomatal movement in A. thaliana. This discovery sheds light on a drought response mechanism with the potential to greatly enhance agricultural productivity.

Long-term exercise preserves pancreatic islet structure and ß-cell mass through attenuation of islet inflammation and fibrosis.

Islet fibrosis is associated with the disruption of islet structure and contributes to ß-cell dysfunction, playing an essential role in the pathogenesis of type 2 diabetes. Physical exercise has been shown to attenuate fibrosis in various organs; however, the effect of exercise on islet fibrosis has not been defined. Male Sprague-Dawley rats were divided into four groups: normal diet sedentary [N-Sed], normal diet + exercise [N-Ex], high-fat diet sedentary [H-Sed], and high-fat diet + exercise [H-Ex]. After 60 weeks of exercise, 4452 islets from Masson-stained slides were analyzed. Exercise led to a 68% and 45% reduction in islet fibrosis in the normal and high-fat diet groups and was correlated with a lower serum blood glucose. Fibrotic islets were characterized by irregular shapes and substantial loss of ß-cell mass, which were significantly reduced in the exercise groups. Remarkably, the islets from exercised rats at week 60 were morphologically comparable to those of sedentary rats at 26 weeks. In addition, the protein and RNA levels of collagen and fibronectin, and the protein levels of hydroxyproline in the islets were also attenuated by exercise. This was accompanied by a significant reduction in inflammatory markers in the circulation Interleukin-1 beta (IL-1ß)] and pancreas [IL-1ß, Tumor Necrosis Factor-alpha, Transforming Growth Factor-ß, and Phosphorylated Nuclear Factor Kappa-B p65 subunit], lower macrophage infiltration, and stellate cell activation in the islets of exercised rats. In conclusion, we have demonstrated that long-term exercise preserves pancreatic islet structure and ß-cell mass through anti-inflammatory and anti-fibrotic actions, suggesting additional rationales for the success of exercise training in the prevention and treatment of type 2 diabetes that should be further explored.

Microglial SCAP deficiency protects against diabetes-associated cognitive impairment through inhibiting NLRP3 inflammasome-mediated neuroinflammation.

Hyperglycemia-induced pathological microglial responses and subsequent neuronal damage are notable characteristics of diabetes-associated cognitive impairment (DACI). Cholesterol accumulation in the brain is a prevalent consequence of diabetes mellitus (DM), exacerbating pathological microglial responses. Regarding disordered glucose and lipid metabolism, the Sterol Regulatory Element-Binding Protein (SREBP) cleavage-activating protein (SCAP), a cholesterol sensor, exhibits increased expression and abnormal translocation from the endoplasmic reticulum to the Golgi, amplifying the inflammatory response. Therefore, we hypothesized that overexpression of microglia-SCAP and cholesterol accumulation in DM mice could induce pathological microglial responses associated with DACI. Our type 2 DM mice model presented an abnormal increase in microglial SCAP expression. The functional loss of microglia-specific SCAP in DM mice improved cognitive impairment, neuronal synaptic plasticity deficits, and abnormal microglial responses. Mechanistically, the accumulated SCAP directly bound to and enhanced the activation of the microglial-specific inflammatory amplifier, NLRP3 inflammasome, in Golgi, thereby increasing pathological microglial responses and promoting neuronal damage. These findings indicate an important regulatory axis of microglial responses from SCAP to the NLRP3 inflammasome pathway in microglia. These underscore the crosstalk between cholesterol disorders and pathological microglial responses, offering a promising avenue for pharmaceutical interventions in DACI.

Molecular Characterization of Class 1 Integrons and Carbapenem-Resistant Genes in Enterobacter cloacae Complex Isolates.

Enterobacter cloacae complex (ECC) widely exists in the hospital environment and is one of the important conditional pathogens of hospital-acquired infection. To investigate the distribution of integrons and carbapenem-resistant genes in clinical ECC, 70 isolates of ECC from non-sputum specimens were collected. Class 1 and class 2 integron integrase gene intI1 and intI2, as well as common carbapenem-resistant genes, blaKPC, blaVIM, blaIMP, blaNDM, blaGES, and blaOXA-23, were screened. Gene cassette arrays and common promoters of class 1 integron together with subtypes of carbapenem-resistant genes were determined by sequencing. Resistant rates to commonly used antimicrobial agents between class 1 integron-positive and integron-negative ECC isolates were analyzed. The whole-genome of blaNDM-7 harboring Enterobacter hormaechei was sequenced and the sequence around blaNDM-7 was analyzed. Twenty isolates were positive for intI1. Nineteen different antimicrobial-resistant gene cassettes and 11 different gene cassette arrays, including aadA22-lnuF, were detected in this study. Common promoters of class 1 integron PcH1, PcW, PcW-P2, and PcH2 were detected in 12, 4, 3, and 1 isolates, respectively. The rates of antimicrobial resistance of intI1-positive isolates were higher than those of intI1-negative isolates to clinical commonly used antimicrobial agents. Carbapenem-resistant genes blaKPC-2, blaNDM-1, blaNDM-2, and blaNDM-7 were detected in 2, 1, 1, and 1 isolates, respectively. blaNDM-7 was located between bleMBL and IS5. To the best of our knowledge, this study reported for the first time of blaNDM-7 in ECC isolate in China.

Identification of C1q/TNF-related protein 4 as a novel appetite-regulating peptide that reduces food intake in Siberian sturgeon (Acipenser baerii).

Emerging findings point to a role for C1q/TNF-related protein 4 (CTRP4) in feeding in mammals. However, it remains unknown whether CTRP4 regulates feeding in fish. This study aimed to determine the feeding regulation function of CTRP4 in Siberian sturgeon (Acipenser baerii). In this study, the Siberian sturgeon ctrp4 (Abctrp4) gene was cloned, and Abctrp4 mRNA was shown to be highly expressed in the hypothalamus. In the hypothalamus, Abctrp4 mRNA decreased during fasting and reversed after refeeding. Subsequently, we obtained the AbCTRP4 recombinant protein by prokaryotic expression and optimized the expression and purification conditions. Siberian sturgeon (81.28 ± 14.75 g) were injected intraperitoneally using 30, 100, and 300 ng/g Body weight (BW) AbCTRP4 to investigate its effect on feeding. The results showed that 30, 100, and 300 ng/g BW of the AbCTRP4 significantly reduced the cumulative food intake of Siberian sturgeon at 1, 3, and 6 h. Finally, to investigate the potential mechanism of CTRP4 feeding inhibition, 300 ng/g BW AbCTRP4 was injected intraperitoneally. The findings demonstrated that AbCTRP4 treatment for 1 h significantly promoted the mRNA levels of anorexigenic peptides (pomc, cart, and leptin) while suppressing the mRNA abundances of orexigenic peptides (npy and agrp).In addition, the jak2/stat3 pathway in the hypothalamus was significantly activated after 1 h of AbCTRP4 treatment. In conclusion., this study confirms the anorexigenic effect of CTRP4 in Siberian sturgeon.

Adverse associations between maternal deoxynivalenol exposure and birth outcomes: a prospective cohort study in China.

BACKGROUND: Deoxynivalenol (DON), one of the most prevalent mycotoxins, has been found to cause fetal growth retardation in animals. However, limited evidence exists regarding its effects on pregnant women. METHODS: Maternal urinary concentration of total DON (tDON) and free DON (fDON) in the second trimester was measured using liquid chromatography with tandem mass spectrometry. Provisional daily intake (PDI) of DON was calculated based on tDON concentration. Linear and logistic regression models were used to evaluate the association between DON exposure levels and birth weight, birth length, and the risk of small for gestational age (SGA). RESULTS: Among 1538 subjects, the median concentrations of tDON and fDON were 12.1 ng/mL and 5.1 ng/mL, respectively. The PDI values revealed that the median DON intake was 0.7 µg/kg bw, and 35.9% of the total population exceeded the provisional maximum tolerable daily intake (PMTDI) of 1 µg/kg bw. Compared with the lowest tertile, birth weight decreased by 81.11 g (95% CI: -127.00, -35.23) for tDON (P-trend < 0.001) and 63.02 g (95% CI: -108.72, -17.32) for fDON (P-trend = 0.004) in the highest tertile. Each unit increase in Ln-tDON and Ln-fDON was also inversely associated with birth weight. Furthermore, compared to those who did not exceed PMTDI, pregnant women whose PDI exceeded PMTDI had lower birth weight (ß = -79.79 g; 95% CI: -119.09, -40.49) and birth length (ß = -0.21 cm; 95% CI: -0.34, -0.07), and a higher risk of SGA (OR = 1.48; 95% CI: 1.02, 2.15) in their offspring. Similar associations with birth weight, birth length, and SGA were found when comparing the highest tertile of PDI to the lowest tertile (all P-trend < 0.05). CONCLUSIONS: Maternal DON exposure is related to decreased birth weight. Our findings implicate that DON exposure during pregnancy may cause fetal growth faltering, and measures should be taken to reduce DON exposure in pregnant women.

Molecular characterization of class 1 integrons in carbapenem-resistant Enterobacterales isolates.

OBJECTIVE: Carbapenem-resistant Enterobacterales (CRE) infections result in higher treatment costs and mortality rates. Integrons play important roles in emergence and spread of antibiotic resistant genes. To get a better understand on the effects of integron on CRE resistance, distribution of common carbapenemase genes and class 1 integron in clinical CRE isolates were investigated. METHOD: Carbapenemase genes, including blaKPC, blaVIM, blaIMP, blaNDM, blaGES, blaVEB and blaOXA-23, were screened in 161 CRE isolates and subtypes of these genes were confirmed through sequence analysis. Class 1 integron was screened and common promoter and gene cassette arrays were determined by sequencing. The resistant rates to clinical commonly used antibiotics between integron positive and integron negative CRE isolates were compared. RESULTS: Of 161 CRE isolates, the most prevalent carbapenemase gene was blaKPC-2, which was detected in 139 isolates, including 99 Klebsiella pneumoniae. Class 1 integron was detected in 78 isolates. Twenty different gene cassettes, including two carbapenemase genes blaVEB-1 and blaIMP-4, and nine different gene cassette arrays, including blaVEB-1-aadB-arr-2-cmlA5-blaOXA-10-aadA1, aadB-catB8-blaOXA-10-aadA1-dfrA1-aacA4 and blaIMP-4-qacG-aacA4-catB3, were detected. Five types of common promoters were identified. Relative weak promoter PcH1 was the dominant type. Resistant rates of CRE isolates containing class 1 integrons to ceftazidime, amikacin, trimethoprim/sulfamethoxazole and gentamicin were higher than those without class 1 integrons (P < 0.05). CONCLUSION: Class 1 integrons play important roles in the emergence and spread of CRE resistance. To the best of our knowledge, this is the first report of aadB-catB8-blaOXA-10-aadA1-dfrA1-aacA4 and blaIMP-4-qacG-aacA4-catB3 in the same Providencia rettgeri isolate and blaVEB-1-aadB-arr-2-cmlA5-blaOXA-10-aadA1 in P. rettgeri.

Association of Breastfeeding Practices During the First 3 Months with Infant Sleep Trajectories: A Prospective Cohort Study.

BACKGROUND: Breastfeeding has numerous effects on maternal and child health. The effect of breastfeeding on infant sleep remains inconclusive. OBJECTIVES: We aimed to examine whether full breastfeeding (FBF) during the first 3 mo is associated with longitudinal infant sleep trajectories in their first 2 y of life. METHODS: The study was embedded in the Tongji Maternal and Child Health Cohort study. Information on infant feeding practices was collected at 3 mo of age, and maternal/child pairs were assigned to the FBF or the non-FBF group (including partially breastfeeding and exclusive formula feeding) on the basis of feeding practices during the first 3 mo of life. Sleep data of infants were obtained at 3, 6, 12, and 24 mo. Total, night, and day sleep trajectories across 3 to 24 mo were estimated with group-based models. Each sleep trajectory was differentiated on the basis of sleep duration at 3 mo (long/moderate/short) and the interval from 6 to 24 mo (moderate/short). Multinomial logistic regression was used to investigate the association of breastfeeding practices with infant sleep trajectories. RESULTS: Among the 4056 infants studied, 2558 (63.1%) received FBF for 3 mo. When compared with FBF infants, non-FBF infants had shorter sleep duration at 3, 6, and 12 mo (P < 0.01). Non-FBF infants were more likely to experience Moderate-Short (OR: 1.31; 95% CI: 1.06, 1.61) and Short-Short (OR: 1.56; 95% CI: 1.12, 2.16) total sleep trajectories and more likely to experience Moderate-Short (OR: 1.84; 95% CI: 1.22, 2.77), and Short-Moderate (OR: 1.40; 95% CI: 1.06, 1.85) night sleep trajectories than FBF infants. CONCLUSIONS: Full breastfeeding for ≥3 mo were positively associated with longer infant sleep duration. Infants fully breastfed were more likely to experience better sleep trajectories characterized by longer duration in their first 2 y of life. Full breastfeeding may benefit infants through healthy sleep.

A Novel Bifidobacterium/Klebsiella Ratio in Characterization Analysis of the Gut and Bile Microbiota of CCA Patients.

Cholangiocarcinoma (CCA) is a serious health problem worldwide. The gut and bile microbiota have not been clearly characterized in patients with CCA, and better noninvasive diagnostic approaches for CCA need to be established. The aim of this study was to investigate the characteristics of the gut and bile microbiota in CCA patients. Forty-two CCA patients and 16 healthy normal controls (HNCs) were enrolled. DNA was extracted from fecal and bile samples and subjected to 16S rRNA gene analysis. We found that there were significant differences in the species diversity, structure, and composition of the microbial communities between the CCA group and the HNC grouAt the phylum level, compared with that in the HNC group, the relative abundance of Firmicutes and Actinobacteriota was significantly decreased in the CCA group, whereas Proteobacteria and Bacteroidota were significantly enriched. The Firmicutes/Bacteroidota (F/B) ratio significantly decreased in the CCA group compared to the HNC grouThe relative abundance of Klebsiella in the CCA group was significantly higher than that in the HNC group, while the relative abundance of Bifidobacterium was significantly decreased. The Bifidobacterium/Klebsiella (B/K) ratio was established as a novel biomarker and was found to be significantly decreased in the CCA group compared with the HNC grouOur findings provide evidence supporting the use of Klebsiella and Bifidobacterium as noninvasive intestinal microbiomarkers for improving the diagnosis of CCA.

DNA methylation-mediated low expression of ZNF582 promotes the proliferation, migration, and invasion of clear cell renal cell carcinoma.

OBJECTIVE: The methylation of DNA promoter region mediates the low expression of many tumor suppressor genes and plays an essential part in cancer progression. We investigated methylation and expression of ZNF582 in clear cell renal cell carcinoma (ccRCC), and to study the function of ZNF582 in ccRCC cells. METHODS: Methylation data and mRNA expression data of TCGA-KIRC were obtained from TCGA database to screen methylation-driven genes. Survival analysis and gene set enrichment analysis (GSEA) were done for the target gene. The methylation degree and mRNA level of ZNF582 in ccRCC cell line were detected by methylation-specific PCR (MSP) and qRT-PCR, respectively. Effects of overexpression of ZNF582 on ccRCC cells were assessed via CCK-8, flow cytometry, wound healing, Transwell, and cell adhesion assays. RESULTS: Eighteen methylation-driven genes were identified via bioinformatics methods. Among them, ZNF582 was noticeably hypermethylated and lowly expressed in tumor tissue, and ZNF582 methylation and expression levels were pronouncedly associated with prognosis and clinical stage. MSP also displayed that the ZNF582 DNA promoter region was hypermethylated in ccRCC cells, and the mRNA expression of ZNF582 was dramatically elevated after demethylation. In vitro cell experiments disclosed that overexpression of ZNF582 markedly hindered cell proliferation, invasion, migration, and fostered cell apoptosis and adhesion of ccRCC. CONCLUSION: ZNF582 was hypermethylated in ccRCC, which mediated its low level. Overexpression of ZNF582 inhibited tumor cell proliferation, migration and invasion. This study generates novel ideas for ccRCC diagnosis and treatment.

The mediating role of HbA1c in the association between elevated low-density lipoprotein cholesterol levels and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus.

BACKGROUND: Increased levels of low-density lipoprotein cholesterol (LDL-C) have been identified as one potential risk factor for diabetic peripheral neuropathy (DPN) in patients. The current study seeks to clarify the link between LDL-C, hyperglycemia, and DPN in patients with type 2 diabetes mellitus (T2DM). METHODS: Here, a total of 120 T2DM individuals were recruited. These volunteers with T2DM were divided into 2 groups, based on the presence or absence of peripheral neuropathy. Additionally, their baseline characteristics were compared. Association among LDL-C and glycosylated hemoglobin (HbA1c) levels and DPN, particularly with respect to specific nerve conduction velocity were analyzed. To identify factors influencing DPN, regression was performed. Furthermore, mediation analysis was employed to evaluate the indirect, direct and total effects of LDL-C on specific nerve conduction velocity, with HbA1c serving as a mediator. RESULTS: Compared to 55 patients without DPN, 65 patients with DPN demonstrated elevated levels of LDL-C and HbA1c. Both LDL-C and HbA1c have been found to be associated with reduced the motor fiber conduction velocities of Ulnar (or the Common peroneal) nerve in diabetic patients. HbA1c is one of the known risk factors for DPN in individuals with T2DM. Further mediation analysis revealed that the effect of LDL-C on the Ulnar (or the Common peroneal) nerve motor fiber conduction velocities are fully mediated by HbA1c in patients with T2DM. CONCLUSIONS: The impact of elevated LDL-C levels upon the Ulnar (or the Common peroneal) nerve motor fiber conduction velocities in patients with T2DM was found to be entirely mediated by increased HbA1c levels.

Circ_0068631 sponges miR-139-5p to promote the growth and metastasis of cutaneous squamous cell carcinoma by upregulating HOXB7.

BACKGROUND: Circular RNAs (circRNAs) are often dysregulated in cancers and closely related to cancer progression, including cutaneous squamous cell carcinoma (CSCC). However, the role and mechanism of circ_0068631 in CSCC progression have not been reported. METHODS: The expression of circ_0068631, microRNA-139-5p (miR-139-5p), and homeobox B7 (HOXB7) was measured by real-time quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, and colony formation assay were used to measure cell proliferation. Cell apoptosis was assessed by flow cytometry. Cell migration was detected by transwell assay. The interaction between miR-139-5p and circ_0068631 or HOXB7 was confirmed by dual-luciferase reporter assay. A xenograft tumor model was established to confirm the function of circ_0068631 in vivo. RESULTS: Circ_0068631 was upregulated in CSCC tissues and cells, and its silencing could inhibit CSCC cell proliferation and metastasis while promoting apoptosis in vitro, as well as restrain CSCC tumor growth in vivo. Circ_0068631 acted as a sponge of miR-139-5p, and miR-139-5p inhibition reversed the repressive effect of circ_0068631 knockdown on CSCC cell progression. Furthermore, HOXB7 was a target of miR-139-5p, and miR-139-5p inhibited the malignant behaviors by downregulating HOXB7 expression in CSCC cells. Further, circ_0068631 sponged miR-139-5p to regulate HOXB7 expression. CONCLUSION: Circ_0068631 functioned as a novel oncogene in CSCC progression by regulating miR-139-5p/HOXB7 axis, suggesting that circ_0068631 may be a potential target for CSCC treatment. HIGHLIGHTS: Circ_0068631 was overexpressed in CSCC tissues and cells. Circ_0068631 downregulation suppressed CSCC progression via miR-139-5p. Circ_0068631 regulated HOXB7 via sponging miR-139-5p.

The emerging role of circRNAs on skeletal muscle development in economical animals.

CircRNAs are a novel type of closed circular molecules formed through a covalent bond lacking a 5'cap and 3' end tail, which mainly arise from mRNA precursor. They are widely distributed in plants and animals and are characterized by stable structure, high conservativeness in cells or tissues, and showed the expression specificity at different stages of development in different tissues. CircRNAs have been gradually attracted wide attention with the development of RNA sequencing, which become a new research hotspot in the field of RNA. CircRNAs play an important role in gene expression regulation. Presently, the related circRNAs research in the regulation of animal muscle development is still at the initial stage. In this review, the formation, properties, biological functions of circRNAs were summarized. The recent research progresses of circRNAs in skeletal muscle growth and development from economic animals including livestock, poultry and fishes were introduced. Finally, we proposed a prospective for further studies of circRNAs in muscle development, and we hope our research could provide new ideas, some theoretical supports and helps for new molecular genetic markers exploitation and animal genetic breeding in future.

Fine Mapping and Candidate Gene Prediction of Tuber Shape Controlling Ro Locus Based on Integrating Genetic and Transcriptomic Analyses in Potato.

Tuber shape is one of the most important quality traits in potato appearance. Since poor or irregular shape results in higher costs for processing and influences the consumers' willingness to purchase, breeding for shape uniformity and shallow eye depth is highly important. Previous studies showed that the major round tuber shape controlling locus, the Ro locus, is located on chromosome 10. However, fine mapping and cloning of tuber shape genes have not been reported. In this study, the analyses of tissue sectioning and transcriptome sequencing showed that the developmental differences between round and elongated tuber shapes begin as early as the hook stage of the stolon. To fine map tuber shape genes, a high-density genetic linkage map of the Ro region on chromosome 10 based on a diploid segregating population was constructed. The total length of the genetic linkage map was 25.8 cM and the average marker interval was 1.98 cM. Combined with phenotypic data collected from 2014 to 2017, one major quantitative trait locus (QTL) for tuber shape was identified, which explained 61.7-72.9% of the tuber shape variation. Through the results of genotyping and phenotypic investigation of recombinant individuals, Ro was fine mapped in a 193.43 kb interval, which contained 18 genes. Five candidate genes were preliminarily predicted based on tissue sections and transcriptome sequencing. This study provides an important basis for cloning Ro gene(s).

Integrating Intact Mass Analysis and Middle-Down Mass Spectrometry Approaches to Effectively Characterize Trastuzumab and Adalimumab Structural Heterogeneity.

Comprehensive characterization of therapeutic monoclonal antibody (mAb) structures is critical for drug development but remains challenging due to the inherent structural heterogeneity. In this study, an integrated strategy has been developed to characterize trastuzumab structural heterogeneity, which has prominent advantages in fast sample preparation with minimal artifacts, and complementary information obtained from intact mass and middle-down analyses. Our methods were all developed on an electron transfer dissociation (ETD)-enabled Q-TOF instrument. As a result, more than 13 structurally different proteoforms were easily identified and quantified through native and denatured intact mass analysis, which may result from the collective differences in glycosylation and C-terminal lysine clipping. Based on collision-induced dissociation and ETD-combined middle-down analysis, sequence coverage values of 28, 45, and 41% for trastuzumab Fc/2, Lc, and Fd subunits, respectively, were reached in a single LC run. The main glycan structure and relative abundance level were determined, and the glycosylation site was confirmed to be on the Fc fragment Asn 61. We finally integrated the native MS and middle-down results to have a more realistic detection of molecular weight, sequence variants, and glycosylation variants of trastuzumab. Applying the integrated strategy, we successfully completed the comprehensive characterization of adalimumab and found unexpected C-terminal lysine-modified variants (dataset identifier PXD021287). Overall, our integration strategy can be easily implemented for in-depth mAb structural heterogeneity characterization during pharmaceutical development and quality control.

Role of gut microbiome in the outcome of cancer immunotherapy.

Nearly 3 × 1013 types of bacteria colonize the human intestine. These colonized bacteria help in maintaining intestinal homeostasis by establishing a complex relationship with the intestinal epithelium and lymphoid tissue. Alteration in the composition of the intestinal microbiota is associated with susceptibility to various pathological conditions, such as autoimmune disorders, diabetes, inflammation and cancer. Of late, several researchers have focused on examining the effects of gut microbiota on the outcome of various cancer treatment protocols. Side effects and complications of traditional chemotherapy and allogeneic hematopoietic cell transplantation are associated with intestinal dysbiosis. Gut microbiota affects the efficacy of immune checkpoint inhibitor-based immunotherapy. The gut is inhabited by diverse resident bacteria, of which, few enhance, while others inhibit the host response to immunotherapy. This review focuses on the correlation between intestinal microbiota and the outcome of tumor immunotherapy. Additionally, the molecular mechanisms underlying the effects of gut microbiota on the efficacy of cancer immunotherapy have been reviewed. Further studies are needed for the identification of distinct gut microbiota and their efficacy in tumor immunotherapy as certain types of intestinal bacteria could function as novel adjuvant drugs to enhance the effectiveness of antitumor therapy in humans.

Resveratrol attenuates TNBC lung metastasis by down-regulating PD-1 expression on pulmonary T cells and converting macrophages to M1 phenotype in a murine tumor model.

Triple-negative breast cancer (TNBC) is an invasive breast cancer with the characteristics of easy to develop distant metastasis. Immune escape is one of the main reasons for TNBC growth and metastasis. Enhancement of T cell-mediated anti-tumor activity may benefit to inhibit tumor metastasis and improve the efficacy of cancer therapy. As a natural bioactive substance, resveratrol shows potential capability to prevent or suppress the development of a variety of cancers through direct or indirect effects, including immunoregulatory effect. However, whether resveratrol might affect lung metastasis of TNBC, and whether the effect of resveratrol might be associated with resveratrol-regulated immune responses in tumor microenvironment is still unknown. In this study, by using an experimental metastatic mouse 4 T1 tumor model, we identified that resveratrol may suppress TNBC lung metastasis by elevating local anti-tumor immunity. Indeed, an increase in the cytotoxic activity of CD8+T cells as well as the levels of type 1 cytokine IFN-γ and IL-2 in the lungs of resveratrol-treated tumor bearing mice were observed. The enhanced CD8+T cell activity and Th1 immune responses by resveratrol administration might be related to the down-regulated PD-1 expression on pulmonary CD8+T cells and CD4+T cells. Resveratrol may also convert macrophages to M1 phenotype in the lungs of tumor bearing mice. However, it seems likely resveratrol has no effect on pulmonary myeloid-derived suppressor cell activation. Our results provide an evidence that resveratrol might be a promising candidate agent for adjuvant therapy in the process of TNBC metastasis.

Inverted U-shaped correlation between serum low-density lipoprotein cholesterol levels and cognitive functions of patients with type 2 diabetes mellitus.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) metabolic disorder is common in individuals with diabetes. The role of LDL-C in mild cognitive impairment (MCI) remains to be explored. We aim to investigate the associations between LDL-C at different levels and details of cognition decline in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM (n = 497) were recruited. Clinical parameters and neuropsychological tests were compared between patients with MCI and controls. Goodness of fit was assessed to determine the linear or U-shaped relationship between LDL-C and cognitive function. The cut-off point of LDL-C was calculated. Correlation and regression were carried out to explore the relationship between cognitive dysfunction and LDL-C levels above and below the cut-off point. RESULTS: Although no significant difference in LDL-C levels was detected in 235 patients with MCI, compared with 262 patients without MCI, inverted-U-shaped association was determined between LDL-C and Montreal Cognitive Assessment (MoCA). The cut-off point of LDL-C is 2.686 mmol/l. LDL-C (>2.686 mmol/l) is positively related to Trail Making Test B (TMTB) indicating executive function. LDL-C (<2.686 mmol/l) is positively associated with Clock Drawing Test (CDT) reflecting visual space function in patients with T2DM. CONCLUSION: Inverted U-shaped correlation was found between serum LDL-C and cognitive function in patients with T2DM. Despite that the mechanisms of different LDL-C levels involved in special cognitive dysfunctions remain incompletely clarified, excessive LDL-C damages executive function, while the deficient LDL-C impairs visual space function. TRIAL REGISTRATION: ChiCTR-OCC-15006060 .

Photosensitizer-Modified MnO2 Nanoparticles to Enhance Photodynamic Treatment of Abscesses and Boost Immune Protection for Treated Mice.

The emergence of drug-resistant bacteria and easy recurrence has been challenging in the clinical treatment of skin abscesses resulting from bacterial infections (e.g., by Staphylococcus aureus (S. aureus)). Herein, an antibacterial nanoagent capable of modulating the abscess microenvironment is designed to enhance photodynamic treatment of skin abscesses, and subsequently activate the immune system to effectively prevent abscess recurrence. In the system, manganese dioxide nanoparticles (MnO2 NPs) with high catalytic reactivity toward H2 O2 are modified with photosensitizer chlorine e6 (Ce6) and coated with polyethylene glycol (PEG). The obtained Ce6@MnO2 -PEG NPs, by triggering the decomposition of lesion endogenous H2 O2 , are able to effectively relieve the hypoxic abscess microenvironment during S. aureus infection. The light-triggered photodynamic bacterial killing effect could thus be remarkably enhanced, resulting in effective in vivo therapy of S. aureus-induced skin abscesses. Interestingly, a notable pathogen-specific immunological memory effect against future infection by the same species of bacteria is elicited after such treatment, owing to the release of bacterial antigens post photodynamic therapy (PDT) together with the adjuvant-like function of manganese ions to activate the host immune system. This work thus presents a new type of photodynamic nanoagent particularly promising for highly effective light-triggered abscess treatment and prevention of abscess recurrence.

Synthesis of Hollow Biomineralized CaCO3-Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity.

The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO3-PDA) composite hollow nanoparticles as a multifunctional theranostic nanoplatform. Because of the high sensitivity of such nanoparticles to pH, with rapid degradation under a slightly acidic environment, the photoactivity of the loaded photosensitizer, i.e., chlorin e6 (Ce6), which is quenched by PDA, is therefore increased within the tumor under reduced pH, showing recovered fluorescence and enhanced singlet oxygen generation. In addition, due to the strong affinity between metal ions and PDA, our nanoparticles can bind with various types of metal ions, conferring them with multimodal imaging capability. By utilizing pH-responsive multifunctional nanocarriers, effective in vivo antitumor photodynamic therapy (PDT) can be realized under the precise guidance of multimodal imaging. Interestingly, at normal physiological pH, our nanoparticles are quenched and show much lower phototoxicity to normal tissues, thus effectively reducing skin damage during PDT. Therefore, our work presents a unique type of biomineralized theranostic nanoparticles with inherent biocompatibility, multimodal imaging functionality, high antitumor PDT efficacy, and reduced skin phototoxicity.