Targeting Autophagy: A Promising Therapeutic Strategy for Diabetes Mellitus and Diabetic Nephropathy.

Diabetes mellitus (DM) significantly impairs patients' quality of life, primarily because of its complications, which are the leading cause of mortality among individuals with the disease. Autophagy has emerged as a key process closely associated with DM, including its complications such as diabetic nephropathy (DN). DN is a major complication of DM, contributing significantly to chronic kidney disease and renal failure. The intricate connection between autophagy and DM, including DN, highlights the potential for new therapeutic targets. This review examines the interplay between autophagy and these conditions, aiming to uncover novel approaches to treatment and enhance our understanding of their underlying pathophysiology. It also explores the role of autophagy in maintaining renal homeostasis and its involvement in the development and progression of DM and DN. Furthermore, the review discusses natural compounds that may alleviate these conditions by modulating autophagy.

YTHDF1's grip on CRC vasculature: insights into LINC01106 and miR-449b-5p-VEGFA axis.

BACKGROUND: Investigating the unexplored territory of lncRNA m6A modification in colorectal cancer (CRC) vasculature, this study focuses on LINC01106 and YTHDF1. METHODS: Clinical assessments reveal upregulated LINC01106 promoting vascular generation via the miR-449b-5p-VEGFA pathway. RESULTS: YTHDF1, elevated in CRC tissues, emerges as an adverse prognostic factor. Functional experiments showcase YTHDF1's inhibitory effects on CRC cell dynamics. Mechanistically, Me-CLIP identifies m6A-modified LINC01106, validated as a YTHDF1 target through Me-RIP. CONCLUSIONS: This study sheds light on the YTHDF1-mediated m6A modification of LINC01106, presenting it as a key player in suppressing CRC vascular generation.

An integrating strategy for systematic profiling of Chinese patent drug's chemicalome and associated metabolome: Huanghou antidiarrhea dropping pills as a case study.

Huanghou antidiarrhea dropping pills (HADP) is an efficient Chinese patent drug that is clinically used to treat diarrhea. However, its functional materials remain unclear due to the characteristics of traditional Chinese medicine, which is a multi-component and multi-target complex system. In this study, we investigated the intrinsic chemical components and combined with in vivo metabolism to reveal the functional material basis of HADP. Spectral behavior (accurate molecular weight and secondary fragmentation) and chromatographic behavior (retention time) were key criterions that throughout the whole research of components identification, prototypes screening, and tissue distribution. Mass defect filter (MDF), characteristic product ion filter (PIF), and neutral loss filter (NLF) were other three criterions for metabolites searching. Consequently, a total of 102 components in HADP, including alkaloids, lignans, lactones, gingerols, and alkaloid complexes were identified or tentatively characterized. About 39 metabolites that related to 37 prototypes were calculated and matched in bio-samples. Among them, 14 prototypes and 18 metabolites were detected distribution in colon, liver, heart, spleen, lung or kidney. This study provides a systematic investigation into the metabolism of HADP and offers effective analytical strategies for the characterization of compounds and metabolites in Chinese patent drugs.

The alleviating effect of ellagic acid on DSS-induced colitis via regulating gut microbiomes and gene expression of colonic epithelial cells.

The anti-inflammatory effect of ellagic acid (EA) and its possible underlying mechanism in dextran sulfate sodium (DSS)-induced mouse chronic colonic inflammation were studied. It was observed that EA administration significantly alleviated the colonic inflammation phenotypes, including decreasing the disease activity index (DAI), enhancing the body weight loss, and improving the shortened length of the colon and pathological damage of colon tissue. Additionally, EA reshaped the constitution of the gut microbiota by elevating the ratio of Bacteroidetes along with Bacteroides and Muribaculaceae, while decreasing the proportion of Firmicutes. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) revealed that the metabolic function of the gut microbiota was also changed. Furthermore, mouse colon transcriptome analysis showed that the tight junction and peroxisome proliferator-activated receptor (PPAR) signaling pathways were activated and the expressions of related genes were upregulated after EA intervention. These results showed that EA could remodel the gut bacterial composition, change the intestinal epithelial cell gene expressions in mice, and consequently improve the colonic inflammatory symptoms.

Rabies virus glycoprotein 29 (RVG29) promotes CAR-T immunotherapy for glioma.

Chimeric antigen receptor T cell (CAR-T) therapy has limited efficacy for treating glioma because of the infiltrative nature of the blood-brain barrier (BBB) and T cell exhaustion. Conjugation with rabies virus glycoprotein (RVG) 29 enhances the brain-related efficacy of various agents. Here we assess whether RVG enhances the ability of CAR-T cells to cross the BBB and improves their immunotherapy. We generated 70R CAR-T cells (anti-CD70 CAR-T modified with RVG29) and validated their tumor-killing efficacy in vitro and in vivo. We validated their effects on tumor regression in a human glioma mouse orthotopic xenograft model as well as in patient-derived orthotopic xenograft (PDOX) models. The signaling pathways activated in 70R CAR-T cells were revealed by RNA sequencing. The 70R CAR-T cells we generated showed effective antitumor function against CD70+ glioma cells both in vitro and in vivo. 70R CAR-T cells were better able to cross the BBB into the brain than CD70 CAR-T cells under the same treatment conditions. Moreover, 70R CAR-T cells significantly promote the regression of glioma xenografts and improve the physical characteristics of mice without causing overt adverse effects. RVG modification enables CAR-T cells to cross the BBB, and stimulation with glioma cells induces 70R CAR-T cells to expand in a resting state. The modification of RVG29 has a positive impact on CAR-T therapy for brain tumors and may have potential in CAR-T therapy for glioma.

In-vitro and In-vivo Identification, Absorbtion and Metabolism Network Analysis of Filifolium sibiricum Flavonoids Dropping Pill by UHPLC-Q-TOF-MS.

BACKGROUND: Filifolium sibiricum flavonoids dropping pill (FSFp), a unique Chinese Filifolii sibirici herba extract preparation, has the potential as an alternative therapy against S. aureus infection (SA) and antiinfection. However, its chemical composition and in vivo metabolism characteristics remain unknown, which limits its clinical application. METHODS: Here, we aimed to understand the in vitro and in vivo material basis of FSFp. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to identify chemicals in FSFp as well as its phase I and phase II reaction metabolites in plasma, urine and feces. RESULTS: A total of 38 chemicals were characterized in FSFp, including 22 flavonoids, 10 organic acids, 3 chromones, 1 aromatic ketone, 1 coumarin, and 1 ligan. After analysis of the drugged bio-samples, a total of 21 compounds were found in urine, and 16 of them were found in feces, but only one was found in plasma. In addition, 56 FSFp-related metabolites were characterized, of which 56 were in urine, 4 in feces, and 8 in plasma. CONCLUSION: This is the first comprehensive research of FSFp on chemical constituents and metabolic profiles. It was expected that this study would offer reliable support for further investigation of FSFp.

Chemicolome and Metabolome Profiling of Xieriga-4 Decoction, A Traditional Mongolian Medicine, Using the UPLC-QTOF/MS Approach.

Background: Xieriga-4 decoction (XRG-4) is a classic prescription Mongolian medicine that has potent diuretic and anti-inflammatory activities. However, its functional components remain unknown. Purpose: This study aimed to identify the chemical components in XRG-4 and its metabolome in vivo. Methods: An ultra-performance liquid chromatography coupled with a quadrupole time-of-flight tandem mass spectrometry based approach was proposed to systematically profile the chemicolome and metabolome of XRG-4. Result: A total of 106 constituents were identified in XRG-4. Eighty-nine components were identified in biological samples, including 78 in urine (24 prototypes and 54 metabolites), 26 in feces (19 prototypes and 7 metabolites), and 9 in plasma (5 prototypes and 4 metabolites). In other tissues, only a few compounds, including alkaloids and iridoids, were detected. Conclusion: This comprehensive investigation of the chemical and metabolic profiles of XRG-4 provides a scientific foundation for its quality control and administration of clinically-safe medication.

Comparison of biochemical composition of commercial sea cucumbers, Apostichopus japonicus and Parastichopus californicus, under the same culture conditions.

BACKGROUND: Apostichopus japonicus and Parastichopus californicus are two of the most important and profitable commercial sea cucumbers along the North Pacific coast. This study compared the body wall production rate (BWPR), proximate composition, amino acid, fatty acid, trace element and vitamin composition, and nonspecific immune enzyme activities of A. japonicus and P. californicus cultured in an artificial pond. RESULTS: The BWPR, crude fat and ash content in the body walls of A. japonicus and P. californicus showed remarkable differences (P < 0.05). For the 18 amino acids tested, differences in the contents of 15 were significant (P < 0.05) between the two species, except for threonine, methionine and histidine, and their first limiting amino acids were both methionine+cysteine. There were seven saturated and ten unsaturated fatty acids in their body walls, and except for 18:1 and 20:1, the content differences of the other 15 fatty acids were all significant (P < 0.05). Furthermore, between the two sea cucumbers, differences in the content of seven trace elements (Cu, Fe, Mn, Zn, Cr, Ni, Se) and six vitamins (B1, B3, B5, B9, C, E) were significant (P < 0.05). The activities of superoxide dismutase (SOD), catalase (CAT), acid phosphatase (ACP) and alkaline phosphatase (AKP) also showed distinct differences (P < 0.05). CONCLUSION: There are greater differences in the biochemical compositions and contents between A. japonicus and P. californicus, each with its own unique quality advantages. A. japonicus and P. californicus have high nutritional value, which are both the superior sea cucumbers. © 2022 Society of Chemical Industry.

[Differential Expression of Long Non-coding RNA Cancer Susceptibility Candidate 2 and Imprinted Gene H19 in Extrahepatic Cholangiocarcinoma].

Objective To investigate the expression and the potential roles of long non-coding RNA(lncRNA)cancer susceptibility candidate 2(CASC2)and imprinted gene H19 in extrahepatic cholangiocarcinoma(ECC). Methods Four samples from patients with ECC were collected for high-throughput sequencing which was conducted to reveal the transcriptomic profiles of lncRNA CASC2 and H19.Bioinformatics tools were employed to predict the potential roles of the two genes.Another 22 ECC tissue samples and the cholangiocarcinoma cell lines(RBE,QBC939,HuH-28,and HuCCT1)with different degrees of differentiation were selected for validation.The para-carcinoma tissue and normal human intrahepatic biliary epithelial cell(HIBEC)were used as the control groups.The expression levels of lncRNA CASC2 and H19 in carcinoma tissue,para-carcinoma tissue,and cell lines were determined by real-time quantitative polymerase chain reaction(qRT-PCR).The correlation analysis was carried out for the clinical indicators of patients with the expression levels of the target genes. Results The two target genes showed significantly different expression between carcinoma tissue and para-carcinoma tissue(all P<0.05).Specifically,CASC2 had higher expression level in the carcinoma tissue than in the para-carcinoma tissue(t=1.262,P=0.025),whereas the expression of H19 showed an opposite trend(t=1.285,P=0.005).The expression levels of CASC2 in QBC939(t=8.114,P=0.015)and HuH-28(t=9.202,P=0.012)cells were significantly higher than that in the control group.The expression levels of H19 were significantly lower in RBE(t=-10.244,P<0.001),QBC939(t=-10.476,P<0.001),HuH-28(t=-19.798,P<0.001),and HuCCT1(t=-16.193,P=0.004)cells than in the control group.Bioinformatics analysis showed that CASC2 was mainly involved in the metabolic process and H19 in the development of multicellular organisms.Both CASC2 and H19 were related to catalytic activity.The expression level of lncRNA CASC2 was correlated with pathological differentiation(χ 2=6.222,P=0.022)and lymph node metastasis(χ2=5.455,P=0.020),and that of lncRNA H19 with pathological differentiation(χ2=1.174,P=0.029)and tumor size(χ2=-0.507,P=0.037). Conclusions In the case of ECC,lncRNA CASC2 and H19 have transcription disorders.lncRNA CASC2 is generally up-regulated in the carcinoma tissue,while H19 is down-regulated.Both genes have the potential to become new molecular markers for ECC.

Differentially expressed genes in head kidney of Pelteobagrus fulvidraco following Vibrio cholerae challenge.

The yellow catfish (Pelteobagrus fulvidraco) is a freshwater fish with high economic value in eastern China. Nevertheless, pathogens causing bacterial diseases in P. fulvidraco have brought about huge economic loss and high mortality in artificial aquaculture. For disease control, it is critical to further understand the immune system of yellow catfish and immune-related genes with which they respond to pathogenic infections. In this study, high-throughput sequencing methods were used to analyze the transcriptomic spectrum of the head kidney from P. fulvidraco challenged by Vibrio cholera. A total of 45,544 unique transcript fragments (unigenes) were acquired after assembly and annotation, with an average length of 1,373 bp. Additionally, 674 differentially expressed genes (DEGs) were identified after stimulation with V. cholerae, 353 and 321 genes were identified as remarkably up- or downregulated, respectively. To further study the immune-related DEGs, we performed KEGG enrichment and GO enrichment. The results showed gene regulation of response to stimulus, immune response, immune system progress, response to external stimuli and cellular response to stimuli. Analysis of KEGG enrichment is important to identify chief immune related pathways. Real-time quantitative reverse transcription-PCR (qRT-PCR) results indicated 10 immune response genes that were found to be upregulated compared to a control group after 6 h of V. cholerae challenging. In summary, the results of our study are helpful to determine the defense mechanisms and immune system responses of yellow catfish in reaction to bacterial challenges.

A case report of rhabdomyolysis and osteofascial compartment syndrome in a patient with hypothyroidism and diabetes.

BACKGROUND: Hypothyroidism is frequent and has various forms of muscle involvement. We report the diagnosis and treatment of a case of rhabdomyolysis, bilateral osteofascial compartment syndrome (OCS) of the lower extremities, and peroneal nerve injury causing bilateral foot drop in a diabetic patient with hypothyroidism. CASE PRESENTATION: A 66-year-old man with diabetes for 22 years was admitted because of drowsiness, tiredness, facial swelling, and limb twitching for 2 months, and red and swollen lower limb skin for 3 days. Serum creatinine kinase (CK), CK-MB, myoglobin (Mb), blood glucose, and HbA1c were elevated. TSH, thyroid peroxidase antibodies, and antithyroglobulin antibodies were elevated. FT3 and FT4 were low. Urine was dark brown. He was diagnosed with hypothyroidism, rhabdomyolysis, and OCS. CK, CK-MB, and Mb returned to normal after treatment with thyroid hormone, insulin, albumin infusion, ceftriaxone, ulinastatin, and hemofiltration, and the redness and swelling of the lower limbs were relieved, but the patient developed dropping feet. The patient recovered well but had to undergo rehabilitation. CONCLUSION: Hypothyroidism may induce rhabdomyolysis, OCS, and other complications. This case reminds us of the importance of screening for hypothyroidism and strengthens the clinicians' understanding of the disease.

Preparation and characterization of carboxymethylcellulose based citric acid cross-linked magnetic aerogel as an efficient dye adsorbent.

A low-cost, collectable, and efficient material is essential for adsorbing water pollution, such as dyes and heavy metal ions pollution. In this work, we proposed a novel strategy for the preparation of an efficient and collectable magnetic aerogel as adsorbent for dye. The magnetic aerogels were prepared from sodium carboxymethylcellulose (CMC) hydrogel using citric acid (CA) as the crosslinker, followed by vacuum freeze-drying technique to obtain aerogels. The effects of magnetic Fe3O4 nanoparticle contents on the adsorption properties of the aerogels were investigated. The results show that the as-prepared magnetic composite aerogels exhibit porous structure and display good adsorption and collectable performance for methylene blue (MB) in water with the removal rate of 97.5% in 6 h. The maximum compress strength and absorption capacity of the magnetic aerogel with 1 wt% Fe3O4 nanoparticle loading for MB is 0.13 MPa and 83.6 mg/g, respectively. Aerogels with Fe3O4 nanoparticles exhibited magnetism which enables the aerogels to easily collect. This excellent structure stability and collectability guarantees long-term integrity and floatability of the magnetic aerogels in water.

Identification of Survival-Associated Hub Genes in Pancreatic Adenocarcinoma Based on WGCNA.

Pancreatic adenocarcinoma is one of the leading causes of cancer-related death worldwide. Since little clinical symptoms were shown in the early period of pancreatic adenocarcinoma, most patients were found to carry metastases when diagnosis. The lack of effective diagnosis biomarkers and therapeutic targets makes pancreatic adenocarcinoma difficult to screen and cure. The fundamental problem is we know very little about the regulatory mechanisms during carcinogenesis. Here, we employed weighted gene co-expression network analysis (WGCNA) to build gene interaction network using expression profile of pancreatic adenocarcinoma from The Cancer Genome Atlas (TCGA). STRING was used for the construction and visualization of biological networks. A total of 22 modules were detected in the network, among which yellow and pink modules showed the most significant associations with pancreatic adenocarcinoma. Dozens of new genes including PKMYT1, WDHD1, ASF1B, and RAD18 were identified. Further survival analysis yielded their valuable effects on the diagnosis and treatment of pancreatic adenocarcinoma. Our study pioneered network-based algorithm in the application of tumor etiology and discovered several promising regulators for pancreatic adenocarcinoma detection and therapy.

KIAA1199 promotes migration and invasion by Wnt/ß-catenin pathway and MMPs mediated EMT progression and serves as a poor prognosis marker in gastric cancer.

BACKGROUND: KIAA1199 was upregulated in diverse cancers, but the association of KIAA1199 with gastric cancer (GC), the biological role of KIAA1199 in GC cells and the related molecular mechanisms remain to be elucidated. METHODS: KIAA1199 expression was analysed by reverse transcription-polymerase chain reaction assay (RT-PCR) and immunohistochemistry (IHC) in GC patient tissue. The small hairpin RNA (shRNA) was applied for the knockdown of endogenous KIAA1199 in NCI-N87 and AGS cells. MTT, colony formation, scratch wounding migration, transwell chamber migration and invasion assays were employed respectively to investigate the role of KIAA1199 in GC cells. The potential signaling pathway of KIAA1199 induced migration and invasion was detected. RESULTS: KIAA1199 was upregulated in GC tissue and was an essential independent marker for poor prognosis. Knockdown KIAA1199 suppressed the proliferation, migration and invasion in GC cells. KIAA1199 stimulated the Wnt/ß-catenin signaling pathway and the enzymatic activity of matrix metalloproteinase (MMP) family members and thus accelerated the epithelial-to-mesenchymal transition (EMT) progression in GC cells. CONCLUSION: These findings demonstrated that KIAA1199 was upregulated in GC tissue and associated with worse clinical outcomes in GC, and KIAA1199 acted as an oncogene by promoting migration and invasion through the enhancement of Wnt/ß-catenin signaling pathway and MMPs mediated EMT progression in GC cells.

Expression characteristics of proteins of IGF-1R, p-Akt, and survivin in papillary thyroid carcinoma patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is related to increased risk of papillary thyroid carcinoma (PTC). Insulin-like growth factor-1 receptor (IGF-1R) is increased in patients with T2DM. The increased IGF-1R may be responsible for the development of PTC. In this study, we investigated the expression of phosphorylation of Akt (p-Akt)/survivin pathway activated by IGF-1R in PTC subjects with and without diabetes.Clinicopathological data of 20 PTC patients with T2DM were retrospectively analyzed and compared with those of 21 PTC subjects without diabetes. Meanwhile, IGF-1R, p-Akt, and survivin expressions of PTC tissues were detected by immunohistochemical staining.The immunohistochemical results found that the expression level of IGF-1R was significantly higher in diabetic PTC patients than that in nondiabetic PTC patients (P < 0.05). However, no significant differences of p-Akt and survivin expression were found between PTC patients with T2DM and PTC patients without T2DM. In addition, among 20 PTC patients with T2DM, subgroup analysis showed that the ratio of tumor size >10 mm was significantly higher in IGF-1R moderate to strong expression group than that in IGF-1R negative to weak expression group (P < 0.05).IGF-1R expression level was higher in PTC patients with T2DM, and the increased IGF-1R expression was associated with lager tumor size. IGF-1R may play an important role in carcinogenesis and tumor growth in PTC patients with T2DM.

[Influence Factors on Serum Thyroid Hormone Level in Healthy People].

OBJECTIVE: To explore the influences of age, gender and season on serum thyroid stimulating hormone level and thyroid hormone level in healthy people. METHODS: There were 2 564 healthy volunteers enrolled in this study, whom were divided into different groups according to gender, age and the season. The levels of serum TSH, T3, T4, FT3, FT4 were measured and the data were statistically analyzed. RESULTS: The level of serum TSH in both young and middle-age groups of female was higher than that in the same age groups of male. The serum levels of T3, FT3, FT4 in both young and middle-age groups of female were lower than those in the same age groups of male (P < 0.05). In female, the serum level of TSH was increasing with age. However, the serum levels of FT3, FT4 had the opposite tendency. The level of serum FT3 in young group was higher than that in elderly group of, but T4 were lower. Lower levels of TSH, T3, FT4 were found in summer instead of winter (P < 0.05) and there was no significant difference of FT3 between that two seasons. The levels of serum TSH, T3, T4 and FT4 were correlated with seasons (r = 0.079, 0.092,-0.137, 0.140). CONCLUSION: The levels of serum TSH and thyroid hormones are influenced by age, gender and seasons, which needs to be considered for the diagnosis of thyroid diseases and evaluation of thyroid function.

Down-regulation of WAVE2, WASP family verprolin-homologous protein 2, in gastric cancer indicates lymph node metastasis and cell migration.

BACKGROUND: WAVE2 plays a crucial role in actin polymerisation and cell migration. We aimed to investigate the expression and cellular functions of WAVE2 in human gastric cancer (GC). MATERIALS AND METHODS: The level of WAVE2 was determined using quantitative PCR (Q-PCR) in a cohort of human gastric tissues. Expression of WAVE2, ARP2, NWASP, ROCK1 and ROCK2 was examined using RT-PCR in paired tissues. WAVE2 and ARP2 protein co-expression was examined. Anti-WAVE2 transgene ribozymes were constructed and transiently transfected into human GC cells. RESULTS: Down-regulation of WAVE2 expression in GC was significantly correlated with lymph node metastasis. WAVE2 was positively correlated with E-cadherin and negatively with TWIST. Immunohistochemically, WAVE2 and ARP2 were not co-expressed in serial mirror sections. In vitro, WAVE2 knockdown was shown to increase cell motility, whilst ROCK inhibitor treatment reduced this effect in HGC27 cells. CONCLUSION: WAVE2 is down-regulated in GC and loses its metastatic role in GC. Knockdown of WAVE2 could increase metastatic potential by promoting the growth, invasiveness, motility, adhesiveness and suppressing EMT (epithelial-mesenchymal transition) of GC cells.