Cytosolic mtDNA-cGAS-STING axis contributes to sepsis-induced acute kidney injury via activating the NLRP3 inflammasome.

BACKGROUND: NLRP3 inflammasome activation is significantly associated with sepsis-induced acute kidney injury (S-AKI). Cytosolic DNA derived from damaged mitochondria has been reported to activate NLRP3 inflammasome via upregulating the cyclic GMP-AMP synthase (cGAS)-the stimulator of interferon genes (STING) axis in nucleus pulposus cell and cardiomyocytes. However, the regulatory effect of mitochondria DNA (mtDNA)-cGAS-STING axis on the NLRP3 inflammasome in S-AKI remains unclear. METHODS: In the current study, we established an in vivo model of S-AKI by intraperitoneally injecting male C57BL/6 J mice with lipopolysaccharide (LPS). Next, selective cGAS inhibitor RU.521, and STING agonist DMXAA were intraperitoneally injected in the mice; then, blood urea nitrogen (BUN), serum creatinine (CRE), urinary kidney injury molecular-1 (KIM-1), pathological changes, and infiltrated neutrophils were detected to assess kidney injury. We also performed western blot and immunofluorescence assays to evaluate STING, cGAS, TBK-1, p-TBK-1, IRF3, p-IRF3, NF-kB, p-NF-kB, NLRP3, cleaved caspase-1, caspase-1, GSDMD-N, and GSDMD expression levels in kidney tissues. IL-18 and IL-1ß in renal tissue were identified by ELISA. In vitro, we treated HK-2 cells with LPS to establish a cell model of S-AKI. Furthermore, ethidium bromide (EtBr) was administered to deplete mitochondria DNA (mtDNA). LPS-induced cytotoxicity was evaluated by LDH release assay. Protein expression of cGAS, STING, and NLRP3 in was quantified by western blot. Cytosolic mtDNA was detected by immunofluorescence and q-PCR. Released IL-1ß and IL-18 in HK-2 supernatants were detected by ELISA. RESULTS: LPS injection induced S-AKI in mice, as evidenced by neutrophil infiltration, tubular vacuolation, and increased levels of serum creatinine (CRE), blood urea nitrogen (BUN), and urinary KIM-1. In addition, LPS activated the cGAS-STING axis and NLRP3 inflammasome in vivo, illustrated by increased phosphorylation levels of TBK-1, IRF3, and NF-kB protein, increased ratio of cleaved caspase-1 to caspase-1 and GSDMD-N to GSDMD, and increased IL-1ß and IL-18 levels. Moreover, the cGAS inhibitor RU.521 effectively attenuated NLRP3 inflammasome and S-AKI; however, these effects were abolished by treatment with the STING agonist DMXAA. Furthermore, cytosolic release of mtDNA and activation of the cGAS-STING-NLRP3 axis were observed in LPS-treated HK-2 cells. Inhibiting mtDNA replication by Ethidium Bromide (EtBr) treatment reduced cytosolic mtDNA accumulation and downregulated the cGAS-STING-NLRP3 axis, ameliorating the cytotoxicity induced by LPS. CONCLUSION: This study demonstrated that the cGAS-STING axis was triggered by cytosolic mtDNA and participated in the development of S-AKI by activating NLRP3 inflammasome. Reducing cytosolic mtDNA accumulation or inhibiting the cGAS-STING axis may be potential therapeutic targets for S-AKI.

Material Basis Elucidation and Quantification of Dandelion through Spectrum-Effect Relationship Study between UHPLC Fingerprint and Antioxidant Activity via Multivariate Statistical Analysis.

The excessive expression of reactive oxygen species is closely connected to many diseases. Considerable studies have demonstrated dandelion as well as its ingredients exhibited antioxidant activity. However, specific material basis reflecting the antioxidant activity has not been comprehensively investigated. In this study, a spectrum-effect relationship study on dandelion between fingerprinting and antioxidant activity was analyzed in detail, while a UHPLC quantification method developed and completely validated for simultaneous determination of active ingredients in dandelion. With the establishment of dandelion fingerprints of different regions, 24 common peaks were characterized. The classic FRAP method and ABTS methods were then used to detect their antioxidant activity. Partial least squares regression analysis, bivariate correlation analysis and grey correlation method were used to accomplish the spectrum-effect relationship. Eventually, the ingredients with antioxidant activity which could be considered as candidate quality markers of dandelion were discovered through spectrum-effect relationship analysis. The six compounds including caftaric acid, chlorogenic acid, caffeic acid, chicoric acid, isochlorogenic acid A, and isochlorogenic acid C were quantitatively determined. The developed UHPLC assay method was accurate, precise, and reliable. The study has elucidated the antioxidant material basis of dandelion and provided a scientific basis for the quality control of dandelion.

ACO2 and ANPEP as novel prognostic markers for gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas.

BACKGROUND: Squamous cell/adenosquamous carcinoma (SC/ASC) is a rarely identified form of gallbladder cancer with poorly understood clinical features. As such, there is an urgent need to identify novel prognostic biomarkers for such gallbladder SC/ASC cases, and for gallbladder adenocarcinomas (ACs). METHODS: The levels of ACO2 and ANPEP proteins were assessed via an EnVision-based immunohistochemical approach using 46 SC/ASC and 80 AC patient samples. RESULTS: There was a marked reduction in levels of ACO2 and ANPEP in gallbladder AC relative to normal adjacent tissue or benign gallbladder lesions. The was a significant correlation between lack of ACO2 and ANPEP and larger tumors, higher tumor-node-metastasis (TNM) staging, invasion, metastasis to regional lymph nodes, and ineligibility for surgical resection in both SC/ASC and AC tumor samples. Kaplan-Meier survival analyses further confirmed a relationship between ACO2 and ANPEP negativity and decreased overall survival in patients with these diseases (p < 0.05 or p < 0.01), and a multivariate regression analysis further established that ACO2 negativity and ANPEP negativity were independently predictive of poor SC/ASC and AC patient outcomes. CONCLUSIONS: ACO2 and ANPEP may have key physiological relevance in cancers of the gallbladder and thus warrant investigation as prognostic biomarkers.

[Clinical experience and efficacy of endoscopic surgery for papillary thyroid microcarcinoma through total areola approach].

OBJECTIVE: To investigate the experience and efficacy of endoscopic thyroidectomy for papillary thyroid microcarcinoma (PTMC) through total areola approach.
 Methods: A total of 117 PTMC patients, who were diagnosed pathologically in Minimally Invasive Surgical Center, Second Xiangya Hospital, Central South University from June 2016 to December 2017, were divided into a endoscopic surgery group (n=72) and an open surgery group (n=45). The number of dissected central lymph nodes, blood loss, amount of drainage, occurrence of postoperative complication and recurrence were collected and compared.
 Results: Compared with the open surgery group, the blood loss was less and the operative time was longer in the endoscopic surgery group (P<0.05). There were no significant differences between the 2 groups in the number of dissected central lymph nodes, amount of drainage and occurrence of postoperative complication (all P>0.05). The mean follow-up time was more than 20 months, and there was no recurrence in the 2 groups. 
 Conclusion: Endoscopic thyroidectomy with central compartment neck dissection through total areola approach is safe and feasible in patients with PTMC. It has many advantages, such as no scar on neck, less blood loss, shorter hospital stay and more acceptable to young patients.

Expression of UGP2 and CFL1 expression levels in benign and malignant pancreatic lesions and their clinicopathological significance.

BACKGROUND: This study investigated UGP2 (uridine diphosphate-glucose pyrophosphorylase-2) and CFL1 (cofilin-1) expression in pancreatic ductal carcinoma (PDC), paracancerous tissue (PT), benign lesions (BL), and normal tissue (NT) and their clinicopathological significance. METHODS: Surgical specimens, which were collected from 106 cases of pancreatic ductal carcinoma, 35 cases of paracancerous tissues, 55 cases of benign lesions and 13 cases of normal pancreatic tissues, were fixed with 4% formaldehyde to prepare conventional paraffin-embedded sections. EnVision immunohistochemical was used to stain for UGP2 and CFL1. Kaplan-Meier survival analysis was performed to assess the correlation of expression pattern with survival. RESULTS: We found that positive UGP2 and CFL1 expression in PDC were significantly higher than those in PT, BL, and NT. In PT and BL with positive UGP2 and CFL1 expression, mild to severe atypical hyperplasia or intraepithelial neoplasia of grades II-III was observed in ductal epithelium. Positive UGP2 and CFL1 expression in cases with high differentiation, no lymph node metastasis, no surrounding invasion, and TNM (tumor-node-metastasis) staging I or/and II were significantly lower than those in cases with poor differentiation, lymph node metastasis, surrounding invasion, and TNM stage III and/or IV. Positive UGP2 expression in male patients was significantly lower than that in female patients. UGP2 and CFL1 expression in PDC were positively correlated. Kaplan-Meier survival analysis showed the degree of differentiation, tumor maximal diameter, TNM stage, lymph node metastasis, and surrounding invasion, and UGP2 and CFL1 expression were closely related to the average survival time of patients with PDC. The survival time of patients with positive UGP2 and CFL1 expression was significantly shorter than that of patients with negative expression. Cox multivariate analysis showed that poor differentiation, tumor maximal diameter ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, and positive UGP2 and CFL1 expression was negatively correlated with the postoperative survival rate and positively correlated with the mortality of patients with PDC. CONCLUSION: Positive expression of UGP2 and CFL1 can serve a valuable prognostic factor in pancreatic cancer.

The clinicopathological significance of forkhead box P1 and forkhead box O3a in pancreatic ductal adenocarcinomas.

Pancreatic ductal adenocarcinoma is a highly malignant tumor with poor prognosis, and the biomarkers for the early diagnosis, targeting therapy, and prognosis are still not clinically available. This study investigated the expression of forkhead box P1 and forkhead box O3a proteins in human pancreatic ductal adenocarcinoma tumor tissues and pancreatic tissues with and without benign lesions using immunohistochemical staining. Results showed that the positive rates of forkhead box P1 and forkhead box O3a protein expression were significantly lower in pancreatic ductal adenocarcinoma tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (p < 0.01). Pancreatic tissues with negative forkhead box P1 and forkhead box O3a protein expression exhibited dysplasia or intraepithelial neoplasia. The positive rates of forkhead box P1 and forkhead box O3a expression were significantly lower in cases with tumor mass >5 cm, lymph node metastasis, invasion to surrounding tissues and organs, and tumor-node-metastasis III + IV stage disease compared to cases with tumor mass ⩽5 cm (p < 0.05), no lymph node metastasis (p < 0.001 and p = 0.001, respectively), no invasion (p = 0.003 and p = 0.004, respectively), and tumor-node-metastasis I or II stage disease (p < 0.05). Kaplan-Meier survival analysis showed that pancreatic ductal adenocarcinoma patients with negative forkhead box P1 and forkhead box O3a expression survived significantly shorter than patients with positive forkhead box P1 and forkhead box O3a expression (p = 0.000). Cox multivariate analysis revealed that negative forkhead box P1 and forkhead box O3a expression was an independent poor prognosis factor in pancreatic ductal adenocarcinoma patients. The area under the curve of a receiver operating characteristic curve was 0.642 for forkhead box P1 (95% confidence interval: 0.553-0.730) and 0.655 for forkhead box O3a (95% confidence interval: 0.6568-0.742). Loss of forkhead box P1 and forkhead box O3a protein expression is associated with carcinogenesis, progression, and poor prognosis in patients with pancreatic ductal adenocarcinomas.

Association of chloride intracellular channel 4 and Indian hedgehog proteins with survival of patients with pancreatic ductal adenocarcinoma.

Pancreatic cancer is the fourth most common cause of cancer-related mortality. Novel molecular biomarkers need to be identified for personalized medicine and to improve survival. The aim of this study was to examine chloride intracellular channel 4 (CLIC4) and Indian Hedgehog (Ihh) expression in benign and malignant lesions of the pancreas and to examine the eventual association between CLIC4 and Ihh expression, with clinicopathological features and prognosis of pancreatic cancer. A retrospective study of specimens collected from January 2000 to December 2011 at the Department of Pathology of the Second and Third Xiangya Hospitals, Central South University was undertaken to explore this question. Immunohistochemistry of CLIC4 and Ihh was performed with EnVision™ in 106 pancreatic ductal adenocarcinoma specimens, 35 paracancer samples (2 cm away from the tumour, when possible or available), 55 benign lesions and 13 normal tissue samples. CLIC4 and Ihh expression in pancreatic ductal adenocarcinoma were significantly higher than in paracancer tissue and benign lesions (CLIC4: P = 0.009 and Ihh: P < 0.0001; CLIC4: P = 0.0004 and Ihh: P = 0.0001 respectively). CLIC4 and Ihh expression was negative in normal pancreatic tissues. The expression of CLIC4 and Ihh was associated significantly with tumour grade, lymph node metastasis, tumour invasion and poor overall survival. Thus CLIC4 and Ihh could serve as biological markers for the progression, metastasis and/or invasiveness of pancreatic ductal adenocarcinoma.

The clinical significance of FRAT1 and ABCG2 expression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with intrinsic resistance to cytotoxic agents. The molecular mechanisms associated with high malignancy and resistance to chemotherapy and radiotherapy have not been fully elucidated. This study investigated the clinicopathological significances of frequently rearranged in advanced T-cell lymphomas-1 (FRAT1) and ATP-binding cassette subfamily G member 2 (ABCG2) expression in PDAC. FRAT1 and ABCG2 protein expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic tissues, and 13 normal pancreatic tissues was measured by immunohistochemistry. FRAT1 and ABCG2 protein was overexpressed in PDAC tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P < 0.01). The percentage of cases with positive FRAT1 and ABCG2 overexpression was significantly higher in PDAC patients with poor differentiation, lymph node metastasis, invasion, and TNM stage III/IV disease than in patients with well-differentiated tumor, no lymph node metastasis and invasion, and TNM stage I/II disease (P < 0.05 or P < 0.01). In pancreatic tissues with benign lesions, tissues with positive FRAT1 and ABCG2 protein expression exhibited dysplasia or intraepithelial neoplasia. Kaplan-Meier survival analysis showed that PDAC patients with positive FRAT1 and ABCG2 expression survived significantly shorter than patients with negative FRAT1 and ABCG2 expression (P < 0.05 or P < 0.001). Cox multivariate analysis revealed that positive FRAT1 and ABCG2 expression was an independent poor prognosis factor in PDAC patients. FRAT1 and ABCG2 overexpression is associated with carcinogenesis, progression, and poor prognosis in patients with PDAC.

Paxillin and carbonic anhydrase IX are prognostic markers in gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas.

AIMS: Squamous cell/adenosquamous carcinomas (SC/ASC) are rare subtypes of gallbladder cancers (GBCs). Clinical characteristics of SC/ASC have not been well documented, and no biological markers of GBC carcinogenesis, progression and prognosis are available. METHODS AND RESULTS: We measured paxillin and CAIX expression in 46 SC/ASCs and 80 adenocarcinomas (ACs) with immunohistochemistry and correlated these data with clinicopathological characteristics. Both paxillin expression and CAIX expression were associated significantly with larger tumours, a higher tumour-node-metastasis (TNM) stage, lymph node metastasis and invasiveness of SC/ASC and AC. Univariate Kaplan-Meier analysis confirmed that paxillin and CAIX expression were associated closely with decreased overall survival in SC/ASC (both P < 0.001) and AC (both P < 0.001). Multivariate Cox regression analysis confirmed that paxillin expression and CAIX expression both independently predicted poor prognosis in SC/ASC and AC patients. We also noted correlations with survival and tumour differentiation, tumour size, TNM stage, lymph node metastasis, tumour invasiveness and sample procurement methods. CONCLUSIONS: Paxillin expression and CAIX expression are both related to clinical/biological behaviour and poor prognosis of GBC.

An Electroconductive and Antibacterial Adhesive Nanocomposite Hydrogel for High-Performance Skin Wound Healing.

Multifunctional hydrogel adhesives inhibiting infections and enabling the electrical stimulation (ES) of tissue reparation are highly desirable for the healing of surgical wounds and other skin injuries. Herein, a therapeutic nanocomposite hydrogel is designed by integrating ß-cyclodextrin-embedded Ag nanoparticles (CDAgNPs) in a polyvinyl alcohol (PVA) matrix enhanced with free ß-cyclodextrin (CD) and an atypical macromolecule made of ß-glucan grafted with hyaluronic acid (HAG). The main objective is to develop a biocompatible dressing combining the electroconductivity and antibacterial activity of CDAgNPs with the cohesiveness and porosity of PVA and the anti-inflammatory, moisturizing, and cell proliferation-promoting properties of HAG. The last component, CD, is added to strengthen the network structure of the hydrogel. PVA/CD/HAG/CDAgNP exhibited excellent adhesion strength, biocompatibility, electroconductivity, and antimicrobial activity against a wide range of bacteria. In addition, the nanocomposite hydrogel has a swelling ratio and water retention capacity suitable to serve as a wound dressing. PVA/CD/HAG/CDAgNP promoted the proliferation of fibroblast in vitro, accelerated the healing of skin wounds in an animal model, and is hemostatic. Upon ES, the PVA/CD/HAG/CDAgNP nanocomposite hydrogel became more efficient both in vitro and in vivo further speeding up the skin healing process thus demonstrating its potential as a next-generation electroconductive wound dressing.

TXNIP knockdown protects rats against bupivacaine-induced spinal neurotoxicity via the inhibition of oxidative stress and apoptosis.

Bupivacaine (BUP) is an anesthetic commonly used in clinical practice that when used for spinal anesthesia, might exert neurotoxic effects. Thioredoxin-interacting protein (TXNIP) is a member of the α-arrestin protein superfamily that binds covalently to thioredoxin (TRX) to inhibit its function, leading to increased oxidative stress and activation of apoptosis. The role of TXNIP in BUP-induced oxidative stress and apoptosis remains to be elucidated. In this context, the present study aimed to explore the effects of TXNIP knockdown on BUP-induced oxidative stress and apoptosis in the spinal cord of rats and in PC12 cells through the transfection of adeno-associated virus-TXNIP short hairpin RNA (AAV-TXNIP shRNA) and siRNA-TXNIP, respectively. In vivo, a rat model of spinal neurotoxicity was established by intrathecally injecting rats with BUP. The BUP + TXNIP shRNA and the BUP + Control shRNA groups of rats were injected with an AAV carrying the TXNIP shRNA and the Control shRNA, respectively, into the subarachnoid space four weeks prior to BUP treatment. The Basso, Beattie & Bresnahan (BBB) locomotor rating score, % MPE of TFL, H&E staining, and Nissl staining analyses were conducted. In vitro, 0.8 mM BUP was determined by CCK-8 assay to establish a cytotoxicity model in PC12 cells. Transfection with siRNA-TXNIP was carried out to suppress TXNIP expression prior to exposing PC12 cells to BUP. The results revealed that BUP effectively induced neurological behavioral dysfunction and neuronal damage and death in the spinal cord of the rats. Similarly, BUP triggered cytotoxicity and apoptosis in PC12 cells. In addition, treated with BUP both in vitro and in vivo exhibited upregulated TXNIP expression and increased oxidative stress and apoptosis. Interestingly, TXNIP knockdown in the spinal cord of rats through transfection of AAV-TXNIP shRNA exerted a protective effect against BUP-induced spinal neurotoxicity by ameliorating behavioral and histological outcomes and promoting the survival of spinal cord neurons. Similarly, transfection with siRNA-TXNIP mitigated BUP-induced cytotoxicity in PC12 cells. In addition, TXNIP knockdown mitigated the upregulation of ROS, MDA, Bax, and cleaved caspase-3 and restored the downregulation of GSH, SOD, CAT, GPX4, and Bcl2 induced upon BUP exposure. These findings suggested that TXNIP knockdown protected against BUP-induced spinal neurotoxicity by suppressing oxidative stress and apoptosis. In summary, TXNIP could be a central signaling hub that positively regulates oxidative stress and apoptosis during neuronal damage, which renders TXNIP a promising target for treatment strategies against BUP-induced spinal neurotoxicity.

Transport of europium colloids in vadose zone lysimeters at the semiarid Hanford site.

The objective of this study was to quantify transport of Eu colloids in the vadose zone at the semiarid Hanford site. Eu-hydroxy-carbonate colloids, Eu(OH)(CO3), were applied to the surface of field lysimeters, and migration of the colloids through the sediments was monitored using wick samplers. The lysimeters were exposed to natural precipitation (145-231 mm/year) or artificial irrigation (124-348 mm/year). Wick outflow was analyzed for Eu concentrations, supplemented by electron microscopy and energy-dispersive X-ray analysis. Small amounts of Eu colloids (<1%) were detected in the deepest wick sampler (2.14 m depth) 2.5 months after application and cumulative precipitation of only 20 mm. We observed rapid transport of Eu colloids under both natural precipitation and artificial irrigation; that is, the leading edge of the Eu colloids moved at a velocity of 3 cm/day within the first 2 months after application. Episodic infiltration (e.g., Chinook snowmelt events) caused peaks of Eu in the wick outflow. While a fraction of Eu moved consistent with long-term recharge estimates at the site, the main mass of Eu remained in the top 30 cm of the sediments. This study illustrates that, under field conditions, near-surface colloid mobilization and transport occurred in Hanford sediments.

[An investigation of fast thermolysis of GAP/AP system by FTIR spectroscopy].

The rapid pyrolysis of GAP/AP system under simulated combustion conditions was investigated by an on-line analysis, i. e. so called T-Jump/FTIR. The results show that the compositions of the main gaseous products for pyrolysis are changed, in comparison with the pyrolyses of single, which indicates that the interactions occur between the components of GAP/AP system. From an obvious effect of pressure on the main gaseous products for GAP/AP pyrolysis it is shown that the interactions between GAP and AP components arise from the gaseous products of AP and both the reactions in gas phase and in gas/condensed phase occur in the GAP/AP mixed system. The interactions between GAP and AP are not affected by test temperature. It is considered that the real time analysis of gaseous products of energetic material pyrolysis under simulated combustion conditions would be carried out by T-Jump/FTIR on-line analysis technique and from microcosmic reaction a technical approach used to explore the rapid pyrolysis of energetic materials and interactions between their components at high temperature and pressure would be developed by the on-line analysis technique from microcosmic reaction.

APEX1 predicts poor prognosis of gallbladder cancer and affects biological properties of CD133+ GBC-SD cells via upregulating Jagged1.

Although APEX1 is associated with the tumorigenesis and progression of some human cancer types, the function of APEX1 in gallbladder cancer (GBC) is unclear. In this study, we found that APEX1 expression is up-regulated in GBC tissues, and APEX1 positive expression is related to aggressive clinicopathological features and poor prognosis of GBC. APEX1 was an independent risk factor of GBC prognosis, and presented some pathological diagnostic significance in GBC. Furthermore, APEX1 was overexpressed in CD133+ GBC-SD cells in comparison with GBC-SD cells. APEX1 knockdown increased the sensitivity of CD133+ GBC-SD cells to 5-Fluorouracil via facilitating cell necrosis and apoptosis. APEX1 knockdown in CD133+ GBC-SD cells dramatically inhibited cell proliferation, migration, and invasion, and promoted cell apoptosis in vitro. APEX1 knockdown in CD133+ GBC-SD cells accelerated tumor growth in the xenograft models. Mechanistically, APEX1 affected these malignant properties via upregulating Jagged1 in CD133+ GBC-SD cells. Thus, APEX1 is a promising prognostic biomarker, and a potential therapeutic target for GBC.

Ferrostatin-1 ameliorates Bupivacaine-Induced spinal neurotoxicity in rats by inhibiting ferroptosis.

Bupivacaine (BUP) has previously been shown to trigger neurotoxicity after spinal anesthesia. Further, ferroptosis has been implicated in the pathological processes associated with various central nervous system diseases. Although the impact of ferroptosis on BUP-induced neurotoxicity in the spinal cord has not been fully understood, this research aims to investigate this relationship in rats. Additionally, this study aims to determine whether ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, can provide protection against BUP-induced spinal neurotoxicity. The experimental model for BUP-induced spinal neurotoxicity involved the administration of 5% bupivacaine through intrathecal injection. Then, the rats were randomized into the Control, BUP, BUP + Fer-1, and Fer-1 groups. BBB scores, %MPE of TFL, and H&E and Nissl stainings showed that intrathecal Fer-1 administration improved functional recovery, histological outcomes, and neural survival in BUP-treated rats. Moreover, Fer-1 has been found to alleviate the BUP-induced alterations related to ferroptosis, such as mitochondrial shrinkage and disruption of cristae, while also reducing the levels of malondialdehyde (MDA), iron, and 4-hydroxynonenal (4HNE). Fer-1 also inhibits the accumulation of reactive oxygen species (ROS) and restores the normal levels of glutathione peroxidase 4 (GPX4), cystine/glutamate transporter (xCT), and glutathione (GSH). Furthermore, double-immunofluorescence staining revealed that GPX4 is primarily localized in the neurons instead of microglia or astroglia in the spinal cord. In summary, we demonstrated that ferroptosis play a pivotal role in mediating BUP-induced spinal neurotoxicity, and Fer-1 ameliorated BUP-induced spinal neurotoxicity by reversing the underlying ferroptosis-related changes in rats.

Association between diabetes status and breast cancer in US adults: findings from the US National Health and Nutrition Examination Survey.

Objectives: The aim of this study was to investigate the association between diabetes status and the risk of breast cancer among adult Americans, exploring the impact of BMI, age, and race on this relationship. Methods: A cross-sectional analysis of 8,249 individuals from the National Health and Nutrition Examination Survey (NHANES) was conducted. Diabetes was categorized as type 2 diabetes and prediabetes, with both conditions diagnosed according to the ADA 2014 guidelines. The association between diabetes status and breast cancer risk was explored using multiple logistic regression analysis. Results: Patients with diabetes had higher odds of breast cancer (OR: 1.51; 95% CI 1.00 to 2.28), Using the two-piecewise linear regression model, it was observed that there is a threshold effect in the risk of breast cancer occurrence at the age of 52 years. Specifically, the risk of breast cancer is relatively low before the age of 52 but increases significantly after this age. Conclusions: This study identified a significant association between diabetes status and breast cancer risk among adult Americans. We also found a threshold effect in breast cancer occurrence at the age of 52. Age was significantly associated with breast cancer risk in both Non-Hispanic White and Non-Hispanic Black individuals. These findings underscore the importance of diabetes management, maintaining a healthy BMI, and age-related risk considerations in reducing breast cancer risk.

Electrostimulation of fibroblast proliferation by an electrospun poly (lactide-co-glycolide)/polydopamine/chitosan membrane in a humid environment.

Exogenous electrical stimulation (ES) facilitates skin wound healing and accelerates cell proliferation. Scaffolds fabricated with electrically-conductive materials combined with ES further promote cellular activity. Here, an electrospun membrane made of poly (lactide-co-glycolide) (PLGA) coated with chitosan (CS) via polydopamine (PDA) serving as a linker was developed and evaluated in vitro for the proliferation and migration of fibroblast cells involved in skin wound repair. PLGA/PDA/CS exhibited multiple optimal characteristics for cell proliferation and dressing materials including good mechanical properties, low cytotoxicity, a super-hydrophilic surface, and an excellent swelling ratio suitable for the absorption of wound exudates. Because of ionic charges, wet PLGA/PDA/CS had an electrical conductivity of 2.85 × 10-3 S/cm, which was comparable to the highest electrical conductivities observed with natural skin. Upon intermittent ES of 100 mV, PLGA/PDA/CS increased fibroblast proliferation 2 and 1.3 times compared to PLGA and PLGA/PDA, respectively. These results demonstrate the potential of PLGA/PDA/CS as a biodegradable polymeric surface for the ES of cells involved in skin wound healing. It also shows that polymers with low electrical conductivity in dry conditions can become suitable for the ES of humid wounds where ionic conductivity is occurring.

FOXP1 and FOXO3a Are Prognostic Markers in Gallbladder Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas.

The pathologic characteristics of squamous cell/adenosquamous carcinomas (SC/ASC) have not been well clarified. As a rare subtype of gallbladder cancer (GBC), no biological markers for diagnosis and prognosis are available. This research evaluated the expression of FOXP1 and FOXO3a in 69 SC/ASC, and 146 adenocarcinoma (AC) samples were analyzed via immunohistochemistry. SC/ASCs were associated with higher rates of lymph node metastasis, invasion, and patients older than 45 years comparing to ACs. FOXP1 and FOXO3a positivity rates were significantly lower in SC/ASC and AC samples from patients with large tumor size, a high TNM stage, lymph node metastasis, invasion, and no history of tumor resection (biopsy only). Positive FOXP1 expression levels were significantly decreased in cases of poorly differentiated AC. The univariate Kaplan-Meier analysis revealed that negative FOXP1 and FOXO3a expression, poor differentiation, large tumor size, high TNM stage, lymph node metastasis, invasion, and an inability to undergo curative resection were all closely associated with decreased overall survival in SC/ASC and AC patients. The multivariate cox regression analysis showed that negative FOXP1 and FOXO3a expression levels were independent predictors of poor prognosis in SC/ASC and AC patients. Our results indicate that negative FOXP1 and FOXO3a expression are closely associated with the pathogenesis, clinicopathologic properties, and prognosis of GBC patients. FOXP1 and FOXO3a may thus be biomarkers of GBC carcinogenesis, progression, and prognosis.

A naphthimide-based ratiometric fluorescent probe for selective and visual detection of phosgene in solution and the gas phase.

As a colorless, highly toxic and widely used chemical reagent, phosgene poses a potentially serious threat to public health and environmental safety. Therefore, there is an urgent need to develop a simple and sensitive method for detecting phosgene. In this work, a ratiometric fluorescent probe (NED) for phosgene was developed by utilizing 4-substituted 1,8-naphthimide unit as the fluorophore and ethylenediamine as the recognition moiety. The probe NED undergoes intramolecular cyclization reaction with phosgene, resulting in a remarkable ratiometric fluorescence response. The probe NED displays high sensitivity (LOD = 4.9 nM), excellent ratiometric fluorescence signal, and high selectivity toward phosgene over other relevant analytes. In addition, paper test strip capable of visually detecting gaseous phosgene has also been fabricated.

3D reconstruction based novel methods are more effective than traditional clinical assessment in breast cancer axillary lymph node metastasis prediction.

The status of axillary lymph node metastases determines the treatment and overall survival of breast cancer (BC) patients. Three-dimensional (3D) assessment methods have advantages for spatial localization and are more responsive to morphological changes in lymph nodes than two-dimensional (2D) assessment methods, and we speculate that methods developed using 3D reconstruction systems have high diagnostic efficacy. This exploratory study included 43 patients with histologically confirmed BC diagnosed at Second Xiangya Hospital of Central South University between July 2017 and August 2020, all of whom underwent preoperative CT scans. Patients were divided into a training cohort to train the model and a validation cohort to validate the model. A 3D axillary lymph node atlas was constructed on a 3D reconstruction system to create various methods of assessing lymph node metastases for a comparison of diagnostic efficacy. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic values of these methods. A total of 43 patients (mean [SD] age, 47 [10] years) met the eligibility criteria and completed 3D reconstruction. An axillary lymph node atlas was established, and a correlation between lymph node sphericity and lymph node metastasis was revealed. By continuously fitting the size and characteristics of axillary lymph nodes on the 3D reconstruction system, formulas and models were established to determine the presence or absence of lymph node metastasis, and the 3D method had better sensitivity for axillary lymph node assessment than the 2D method, with a statistically significant difference in the correct classification rate. The combined diagnostic method was superior to a single diagnostic method, with a 92.3% correct classification rate for the 3D method combined with ultrasound. In addition, in patients who received neoadjuvant chemotherapy (NAC), the correct classification rate of the 3D method (72.7%) was significantly higher than that of ultrasound (45.5%) and CT (54.5%). By establishing an axillary lymph node atlas, the sphericity formula and model developed with the 3D reconstruction system achieve a high correct classification rate when combined with ultrasound or CT and can also be applied to patients receiving NAC.