LRRC8A as a central mediator promotes colon cancer metastasis by regulating PIP5K1B/PIP2 pathway.

Colorectal cancer (CRC) has been the third most common malignancy and the second cause of cancer-related mortality. As the core of volume-sensitive chloride currents, leucine-rich repeat-containing 8A (LRRC8A) contributes to tumor progression but is not consistent, especially for whom the roles in colon carcinoma metastasis were not fully elucidated. Herein, LRRC8A proteins were found highly expressed in hematogenous metastasis from human colorectal cancer samples. The oxaliplatin-resistant HCT116 cells highly expressed LRRC8A, which was related to impaired proliferation and enhanced migration. The over-expressed LRRC8A slowed proliferation and increased migration ex vivo and in vivo. The elevated LRRC8A upregulated the focal adhesion, MAPK, AMPK, and chemokine signaling pathways via phosphorylation and dephosphorylation. Inhibition of LRRC8A impeded the TNF-α signaling cascade and TNF-α-induced migration. LRRC8A binding to PIP5K1B regulated the PIP2 formation, providing a platform for LRRC8A to mediate cell signaling transduction. Importantly, LRRC8A self-regulated its transcription via NF-κB1 and NF-κB2 pathways and the upregulation of NIK/NF-κB2/LRRC8A transcriptional axis was unfavorable for colon cancer patients. Collectively, our findings reveal that LRRC8A is a central mediator in mediating multiple signaling pathways to promote metastasis and targeting LRRC8A proteins could become a potential clinical biomarker-driven treatment strategy for colon cancer patients.

Exercise ameliorates lipid droplet metabolism disorder by the PLIN2-LIPA axis-mediated lipophagy in mouse model of non-alcoholic fatty liver disease.

Excessive hepatic lipid droplets (LDs) accumulation-induced lipid metabolism disorder contributes to the development of non-alcoholic fatty liver disease (NAFLD). Exercise is a promising therapeutic strategy for NAFLD. However, the mechanism by which exercise ameliorates NAFLD through regulating the catabolism of hepatic LDs remains unclear. In the present study, we investigated the effect of perilipin2 (PLIN2)-lysosomal acid lipase (LIPA) axis mediating exercise-triggered lipophagy in a high-fat diet (HFD)-induced NAFLD mouse model. Our results showed that exercise could reduce HFD-induced hepatic LDs accumulation and change the expression of lipolysis-related enzymes. Moreover, exercise upregulated the expression of microtubule associated protein 1 light chain 3 (LC3) and autophagy-related proteins, and downregulated sequestosome 1 (P62) expression and promoted autophagosomes formation. Interestingly, exercise downregulated PLIN2 expression, upregulated LIPA expression, and increased the activity of hepatic LIPA and serum levels of LIPA in the NAFLD mouse model. Further mechanistic studies demonstrated that adenosine monophosphate-activated protein kinase (AMPK) activator-5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) treatment significantly increased mRNA levels and protein expression of LIPA and LC3II and decreased levels of PLIN2 and P62 in palmitic acid (PA)-treated HepG2 cells. PLIN2 silencing and LIPA overexpression notably increased the mRNA level and protein expression of LC3II and decreased the mRNA level and protein expression of p62, respectively. In summary, our findings reveal novel insights into the effect of exercise on improving lipid droplet metabolism disorder in NAFLD. Enhancing the PLIN2-LIPA axis-mediated lipophagy may be one of the key mechanisms involved in NAFLD alleviation by exercise.

LRRC8A promotes the initial development of oxaliplatin resistance in colon cancer cells.

Leucine-rich repeat-containing 8 A (LRRC8A) is an essential component of the volume-regulated anion channel (VRAC), which plays a vital role in cell proliferation, migration, apoptosis, and drug resistance. In this study, we investigated the effects of LRRC8A on oxaliplatin resistance in colon cancer cells. The cell viability was measured after oxaliplatin treatment with cell counting kit-8 (CCK8) assay. RNA sequencing was used to analyze the differentially expressed genes (DEGs) between HCT116 and oxaliplatin-resistant HCT116 cell line (R-Oxa) cells. CCK8 assay and apoptosis assay indicated that R-Oxa cells significantly promoted drug resistance to oxaliplatin compared with native HCT116 cells. R-Oxa cells, deprived of oxaliplatin treatment for over six months (R-Oxadep), maintained a similar resistant property as R-Oxa cells. The LRRC8A mRNA and protein expression were markedly increased in both R-Oxa and R-Oxadep cells. Regulation of LRRC8A expression affected the resistance to oxaliplatin in native HCT116 cells, but not R-Oxa cells. Furthermore, The transcriptional regulation of genes in the platinum drug resistance pathway may contribute to the maintenance of oxaliplatin resistance in colon cancer cells. In conclusion, we propose that LRRC8A promotes the acquisition rather than the maintenance of oxaliplatin resistance in colon cancer cells.

LRRC8A is responsible for exosome biogenesis and volume regulation in colon cancer cells.

Exosomes are vital mediators for intercellular communications in the tumor microenvironment to accelerate colon cancer progression. Leucine-rich repeat-containing 8A (LRRC8A), the core component of the volume-regulated anion channel, is closely associated with acquiring heterogeneity for tumor cells. However, the role of LRRC8A in the exosomes remains largely unknown. Here, we reported that LRRC8A was one of the compositions in the exosomes released from colon cancer HCT116 cells. Down-regulation of LRRC8A proteins inhibited ex vivo cell growth and induced apoptosis. Consistently, chloride channel blockers DCPIB and NPPB inhibited cell growth and induced cell apoptosis in a time or concentration-dependent manner. Interestingly, the total amounts and proportions of different diameter exosomes released in 6 h were not altered by the treatment of DCPIB and NPPB in HCT116 cells. In contrast with the inhibition of LRRC8A, overexpression of LRRC8A proteins in HCT116 cells released significantly more distinct populations of exosomes. Importantly, the switches of ratios for exosomes in a hypotonic challenge were eliminated by DCPIB treatment. Collectively, our results uncovered that LRRC8A proteins were responsible for the exosome generation and sorted into exosomes for monitoring the volume regulation.

Predictive Factors of Postoperative Peritumoral Brain Edema after Meningioma Resection.

BACKGROUND: Postoperative peritumoral brain edema (PTBE) is the progressively exacerbating cerebral edema following meningiomas resection. OBJECTIVE: The study aims to identify the predictive factors of postoperative PTBE. MATERIALS AND METHODS: A retrospective study was conducted on the 117 cases of patients who underwent meningioma. The histopathological features of the tumors were re-assessed according to WHO 2016 classification. Clinical and pathohistological features were analyzed. RESULTS: Thirteen patients (11.1%) were diagnosed having postoperative PTBE. Preoperative seizure (odds ratio [OR] = 6.125, P = 0.039) and histological prominent nucleoli (OR = 3.943, P = 0.039) were the independent risk factors for postoperative PTBE. Meningiomas with a parietal localization were more likely to develop postoperative PTBE (OR = 3.576, P = 0.054). Brain invasion and large tumor volume did not increase complication rate. Preoperative edema index was significantly higher in brain invasive meningiomas (3.0 ± 2.2 versus 1.8 ± 1.7, P = 0.001). Patients having moderate preoperative PTBE were prone to the complication (21.4% versus 7.9%, P = 0.100). CONCLUSIONS: Preoperative seizure were the predictive factors for postoperative PTBE. Careful venous protection during the operation may be helpful, especially for tumors locating in the parietal lobe. Prominent nucleoli observed in postoperative pathology should warrant surgeons' attention. Comprehensive perioperative management is essential for these patients.

Impact of Surgeon Experience on Postoperative Rehemorrhage in Spontaneous Basal Ganglia Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (SICH) is of high mortality and morbidity. SICH in the basal ganglia is usually attributed to chronic hypertension. Postoperative rehemorrhage is a severe complication, and it is relative to surgical techniques. METHODS: A retrospective survey was conducted on 123 patients with basal ganglia SICH who received surgery from January 2015 to January 2019. Postoperative rehemorrhage within 24 hours was recorded. Preoperative clinical parameters, surgeon experience (<10 and >20 years), operation time, surgical approach, and hemostasis technique were recorded and analyzed. RESULTS: The total postoperative rehemorrhage rate was 12.2% (15/123). The univariable analysis showed general surgeons had a higher postoperative rehemorrhage rate than experienced surgeons (30.4% vs. 8.6%, respectively; P = 0.068). The operation time (minutes) in experienced surgeons was significantly longer (164.9 ± 53.5 vs. 137.7 ± 30.8, P = 0.016), but they had a higher chance to locate the responsible vessel (74.2% vs. 40.0%, P = 0.001), respectively. Logistic analysis indicated that experienced surgeons significantly reduced the risk of rehemorrhage (odds ratio [OR], 0.242; P = 0.021). Transsylvian approach was a protective factor for postoperative rehemorrhage (OR, 0.291; P = 0.045). CONCLUSIONS: Surgeons' experience plays the most important role in postoperative rehemorrhage. Surgeons with rich experience were willing to spend more time to achieve definitive hemostasis in operation. The use of a transsylvian approach can significantly reduce the rehemorrhage rate. Packing hemostasis with gelatin sponge may increase complications.

Excessive Hemostasis on the Scalp Increases Superficial Surgical Site Infection Rate in Cranioplasty.

BACKGROUND: Cranioplasty is a routine procedure, but it carries a significantly higher complication rate over standard clean cranial surgery. Surgical site infection is the most common but severe complication. Risk factors for surgical site infection are still debated. METHODS: A retrospective survey of 155 patients (≥16 years old) who exclusively underwent customized titanium cranioplasty from April 2014 to January 2017 was performed. Preoperative clinical parameters, surgeon's hemostasis technique, temporalis dissection, operative time, intraoperative blood loss, postoperative catheter duration and drainage, postoperative hemorrhage and extradural fluid collection (EDFC), and prophylactic antibiotics were recorded and compared between patients with superficial surgical site infection (sSSI) and patients with non-sSSI. RESULTS: Overall sSSI rate was 10.3%. Binary logistic analysis showed excessive hemostasis on scalp (odds ratio = 10.302, P = 0.000), presence of postoperative EDFC (odds ratio = 12.740, P = 0.003), and postoperative drainage >277 mL (odds ratio = 10.302, P = 0.000) were independent risk factors for sSSI. Patients who received excessive hemostasis had a longer operative time (P = 0.000). A flaccid cranial defect was a protective factor for postoperative EDFC (odds ratio = 0.130, P = 0.044), whereas presence of ventriculoperitoneal shunt could induce EDFC formation (odds ratio = 9.598, P = 0.020). Postoperative subgaleal drainage was correlated to the size of cranial defect (standardized ß = 0.347, P = 0.000). Timing of cranioplasty and use of prophylactic antibiotics were not related to sSSI. CONCLUSIONS: Surgeons should lower the hemostasis standard for cranioplasty, as this would promote wound healing and reduce operative time, which subsequently decreases SSI rate.

Long-term moderate exercise enhances specific proteins that constitute neurotrophin signaling pathway: A TMT-based quantitative proteomic analysis of rat plasma.

Physical exercise has been reported to increase neurotrophin in brain tissues as hippocampus as well as increased neurotrophic level peripherally in blood plasma and might have an effect on/or affect molecular processes of energy metabolism (and homeostasis). In this study, using quantitative proteomic analysis, we obtained a plasma protein profile from the rat with long-term moderate exercise. A total of 752 proteins were identified in the plasma. Among them, 54 proteins were significant up-regulated and 47 proteins were down-regulated in the plasma of exercise group compared with the control group. Bioinformatic analyses showed that these altered proteins are widely involved in multiple biological processes, molecular functions and cellular components, which connect with 11 signaling pathways. Interestingly, 5 up-regulated proteins Rap1b, PTPN11, ARHGDIA, Cdc42 and YWHAE, confirmed by Western blots, are involved in the neurotrophin signaling pathway which shows the lowest P value among the identified pathways. Further analyses showed that the 5 neurotrophin-signaling-pathway-related proteins participate in two important protein-protein interaction networks associated to cell survival and apoptosis, axonal development, synapse formation and plasticity. This study provides an exercise-induced plasma protein profile, suggesting that long-term exercise enhances the proteins involved in neurotrophin signaling pathway which may contribute to health benefit. SIGNIFICANCE: Physical activity contributes to myriad benefits on body health across the lifespan. The changes in plasma proteins after chronic moderate exercise may be used as biomarkers for health and may also play important roles in increase of cardiovascular fitness, enhancement of immune competence, prevention of obesity, decrease of risk for neurological disorders, cancer, stroke, diabetes and other metabolic disorders. Using a TMT-based proteomic method, this study identified 101 altered proteins in the plasma of rats after long-term moderate treadmill running, which may provide novel biomarkers for further investigation of the underlying mechanism of physical exercise. We confirmed that exercise enhances 5 proteins of the neurotrophin signaling pathway that may contribute to health benefits.

[Management of postoperative complications of basicranial tumor resection under nasal endoscopy].

OBJECTIVE: To explore medical and nursing management of postoperative complications of basicranial tumor resection through nasal endoscopy. METHOD: Retrospective analysis was carried out in 178 patients with skull base tumors who underwent nasal endoscopic resection of basicranial tumors under general anesthesia, and controlled hypotension was conducted during the surgery. Different surgical approaches were applied in terms of anatomical regions which the tumor involved. RESULT: Postoperative complications occurred in 87 of 178 patients, including cerebrospinal fluid rhinorrhea, intracranial infections, diabetes insipidus, etc. Eighty-five cases with complications recovered through proper medical and nursing care, except for 2 cases of death. CONCLUSION: Because there is a higher risk for nasal endoscopic basicranial procedure, doctors and nurses are required to master multidisciplinary skills and experiences. Careful and rigorous nursing care of postoperative complications is quite important for successful management of basicranial operative patients.

[Aeroallergen spectrum of patients with child allergic rhinitis in Changsha area of China].

OBJECTIVE: To investigate aeroallergen spectrum and allergy positive rates of patients with child allergic rhinitis and analyze its related factors. METHOD: Skin prick test was carried out in 562 cases with child allergic rhinitis using 13 inhaled allergens, and detailed history was collected in all cases. RESULT: Four hundred and fifty-seven (81.3%) of 562 cases showed positive reaction to at least one allergen out of 13 allergens. The most common allergens found in patients was Dermatophagoides farinae and Dermatophagoides pteronyssinus, and positive reaction was 93.1% in child allergic rhinitis, followed by tropical mite, Periplaneta americana, Blattella germanica and dog hair. The pollen allergen, most common in American and European, was pretty rare in this study. The prevalence of child allergic rhinitis was significantly higher in urban than in rural (P<0.01). There was no adverse effect appeared in children with allergic rhinitis underwent skin prick test. CONCLUSION: The major allergen of allergic rhinitis is mite for child allergic rhinitis, and relates to housing enviroment. Most of patients with child allergic rhinitis can be treated by the mite specific immunotherapy. The skin prick test is a safe technique for diagnosis of children with allergic rhinitis.

[Aeroallergen spectrum of 387 patients with allergic rhinitis in Changsha area].

OBJECTIVE: To investigate aeroallergen spectrum of patients with allergic rhinitis in Changsha area and analyze its related factors. METHOD: Skin prick test was carried out in 463 cases with allergic rhinitis using 13 inhaled allergens, and detailed history was collected in all cases. RESULT: Three hundred and eighty-seven cases (83.6%) showed positive reaction to at least one allergen of 13 allergens. The most common allergens found in patients were Dermatophagoides farinae and Dermatophagoides pteronyssinus, followed by tropical mite, Periplaneta americana, Blattella germanica and dog hair. The rate of positive reaction to only one specie allergen were 51.9%, and most of them were positive reaction to mites (49.6%). The degree of positive reaction was significantly related to family history, asthma, age and housing environment. CONCLUSION: The major allergen of allergic rhinitis is mite, and the degree of positive reaction relates to genetics, asthma, age and housing environment.