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Although video-assisted breast surgery is gaining popularity, endoscopic reconstruction after mastectomy is still facing lots of problems, bring about that endoscopic method has not yet become a standard procedure for breast cancer reconstruction. Here, we introduce a novel surgical technique of video-assisted transaxillary nipple-sparing mastectomy and immediate implant-based breast reconstruction and describe the detailed surgical procedure using this technique. Detailed steps of surgical procedure, the patient characteristics and the mean operative time of this new technique were described in this article. All patients were asked to score their satisfaction with their reconstructed breasts preoperatively, 1 month, 3 months, 6 months and 12 months postoperatively using the BREAST-Q. At first, we used our “conventional method” and performed on 10 patients from April 2017 to June 2020; the operative time was 324.80 ± 66.39 minutes. After improving several procedures of the technique, the “optimized method” was performed on 14 cases from July 2020 to November 2020; the operative time decreased to 193.71 ± 28.75 minutes with shortest was 133 minutes; the optimized method was novel and easy to learn and be generalized. Most of the patients were satisfied with the reconstruction results. There was no significant difference between preoperative scores and scores at 3 months, 6 months and 12 months (p = 0.364). Since there is no wound on the breast dome, no obvious postoperative complications were observed except for one patient presented with infection. This new technique has allowed surgeons to achieve excellent and reproducible outcomes in a single-stage procedure and represents an excellent technique for patients who wish to have a scarless and aesthetically pleasing appearance after mastectomy for breast cancer. This article also highlights the mean operative time (193.71 ± 28.75 minutes) that has been made possible with this new technique. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Background In recently years, breast endoscopic reconstruction surgery is becoming increasingly popular. And we have explored a series of endoscopic breast reconstruction procedures and applied it to our day surgery under the epidemic control of the novel coronavirus. Methods The present study was a retrospective analysis. Patients who underwent unilateral breast endoscopic reconstruction surgery in the West China Hospital from April 2017 to February 2021 were included in the study. Patients were divided into the following three groups: ward exploration period (WEP), ward maturation period (WMP), and day surgery period (DSP), respectively. We compared the results of postoperative complications, hospitalization costs, operation time, and BREAST-Q (a patient-reported outcome instrument measuring health-related quality-of-life and patient satisfaction in breast surgery) scale scores among the three groups of patients. Results A total of 66 patients were included (WEP n=30, WMP n=14, DSP n=22). Four people refused to complete the BREAST-Q scale, and five patients missed complication record sheets. Patients in the DSP and WMP groups had slightly higher postoperative satisfaction with their breasts than WEP, but there was no statistically significant difference (3 months postoperatively: WEP vs. WMP =0.515, WEP vs. DSP =0.418, WMP vs. DSP =0.982). On the postoperative BREAST-Q scale scores of psychosocial, sexual life and chest well-being, patients with DSP scored slightly higher than those with WEP versus WMP, but there was no statistically significant difference. The incidence of postoperative complications was generally higher in the WEP group than in the WMP and DSP groups, but there was no statistically significant incidence of either major or minor complications (P=1.000). With the use of prostheses and mesh, patients in the DSP group had lower hospitalization costs than other two groups. In terms of operative time, patients in the WMP and DSP groups had shorter operative times compared with the WEP group, and the results were statistically significant (WEP vs. WMP =0.000, WEP vs. DSP =0.000, WMP vs. DSP =0.243). Conclusions We believe that performing our newly developed endoscopic breast reconstructive surgery at a day surgery center is safe and reliable.

The safety protection of elderly pedestrians has always been the focus of passive safety research in car collision accidents. Lower limb protection efficiency for pedestrians is lower than occupant...

Background & Objective: Nowadays, the interaction between natural products and microRNAs provides a promising field for exploring the chemopreventive agents for various cancers. As a member of microRNAs, the expression of let-7f-5p is universally downregulated in Colorectal Cancer (CRC). The present study aimed to uncover the function of let-7f-5p in the proliferation of human colon cancer cell line Caco2 and explored chemopreventive agents from natural resources that can prevent the development of CRC. Methods: Herein, Caco2 cells were transfected with let-7f-5p mimic and inhibitor to manipulate let-7f-5p levels, and the expression of let-7f-5p was performed by RT-qPCR. Next, we determined how let-7f-5p regulates Caco2 cell proliferation by using MTT, wound-healing, cell cycle, and colony formation assays. Besides, to further understand the effect of let-7f-5p, we evaluated the protein level of AMER3 and SLC9A9 by using western blotting assays. Results: The results showed a suppressive function of let-7f-5p on Caco2 cell proliferation and then put forward a triterpenoid (Rotundic Acid, RA) which significant antagonized the effect of cell proliferation, restitution after wounding, and colony formation caused by let-7f-5p. Moreover, the western blot results further indicated that the inhibitory effect of RA might be due to its suppressive role in let-7f-5p-targeted AMER3 and SLC9A9 regulation. Conclusion: Our validation study results confirmed that let-7f-5p was a potent tumor suppressor gene of Caco2 cell proliferation, and RA showed as a regulator of the effect of let-7f-5p on cell proliferation and then could be a potential chemopreventive agent for CRC treatment.

Background The intestine is the well-acknowledged important organ where the nutritional molecules are absorbed. Meanwhile, intestinal ailments, including intestinal mucosal atrophy, barrier dysfunction (leaky gut), inflammation bowel disease (ulcerative colitis and Crohn's disease), irritable bowel syndrome (IBS), dysbacteriosis, and cancers (sporadic and colitis-associated intestinal cancers), have always been the top-ranking diseases that we are confronting. However, although there are several reports on the intestinal modulatory effects for the food macromolecular components (polysaccharides and prebiotics), the effects of low-molecular-weight phytochemicals from foods, especially those from functional foods, on intestinal ailments have not been methodically understood. Scope and approach Various functional foods and their low-molecular-weight phytochemicals that help protect intestinal homeostasis have been demonstrated. The preliminary in vitro results are not included due to the uncertainty of their in vivo efficacy. This review compiles only in vivo bioactive reports and findings with solid pieces of evidence (both human and animal-based ones) to demonstrate the practical use of the food and its low-molecular-weight phytochemicals as complementary therapies or dietary supplements for intestinal health and their underlying mechanism of action. Key findings and conclusions Functional foods (both the whole food and extracts) and their low-molecular-weight phytochemicals can benefit intestinal health of both small and large intestines at different stages of intestinal ailments through promoting intestinal epithelial renewal and barrier function, restoring intestinal flora, inhibiting intestinal inflammation and tumor growth, and exerting intestinal-cancer preventive effects. Therefore, depending on the circumstances of the intestinal ailment, intake of certain functional foods or their low-molecular-weight phytochemicals can relieve the symptom of intestinal ailments and contribute to the maintenance of intestinal homeostasis at different levels.

Lower limb injuries occupy a high percentage of the traffic accident injuries among road users. However, the injury outcomes in accident statistics is somehow different from the results in cadaver tests. The purpose of this study is to determine the influence of active muscle function on the kinetics result of lower limb injuries during emergency braking in car frontal collision. Based on a human body numerical model regrading a Chinese 50th percentile male lower extremity with active muscles, frontal collisions under different overlaps were established. Then, by comparing the peak forces and moments of the femur and tibia, the dynamic responses of lower limbs under different load conditions were determined. Furthermore, the distribution of stress indicators was analyzed to determine the influence of active muscle and collision overlaps on the injury outcomes at a micro level. Results show that active muscle has a significant effect on the lower limbs, which are particularly affected by the increase of bending moments. The moment caused by the active muscles in the right tibia is 3.7 times greater than that of the femur. Moreover, the effect of active muscle is more significant in small overlap frontal impact. In the 25% overlap collision, the moment caused by the active muscles of the tibia increase by 1.2 times that of the 40% offset collision. In conclusion, this study can provide an explanation on the differences of lower limb injuries between the cadaveric tests and traffic accidents statistics.

Sucralose is one of the most widely used artificial sweeteners, free of nutrients and calories. Its approval and uses correlate with many of the worldwide epidemiological changes in inflammatory bowel disease (IBD). Multiple animal studies by us and others showed that sucralose exacerbated ileitis in SAMP1/YitFc mice and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. In this study, we further investigated the effect of sucralose on dextran sulfate sodium (DSS)-induced colitis in mice and the associated mechanisms. Male C57BL/6 mice received 1.5 mg ml-1 sucralose in drinking water for 6 weeks. Then, 2.5% DSS was added to drinking water for 7 days to induce ulcerative colitis (UC). The results showed that, compared with the DSS group, administration of sucralose exacerbated the severity of colitis as indicated by the further decrease in body weight, increase in disease activity index (DAI) and the expression of pro-inflammatory cytokines, as well as the activation of the TLR5-MyD88-NF-κB signaling pathway, and the disturbances of intestinal barrier function, along with changes in the intestinal microbiota. Our findings indicate that sucralose may increase the susceptibility to DSS-induced colitis through causing dysbiosis of intestinal microbiota and damage to the intestinal barrier.

The purpose of this study is to determine the effect of active muscle on lower limb injury in frontal vehicles collision, and to provide corresponding biomechanical parameters for the protective de...

Summary Background Patients on dialysis were susceptible to coronavirus disease 2019 (COVID-19) and were prone to severe clinical characteristics after infection; acute kidney injury was related to mortality in COVID-19 cases. Limited is known about the characteristics of COVID-19 patients with end-stage renal disease not requiring renal replacement therapy (RRT). Aim Evaluate clinical characteristics, course and outcomes of COVID-19 patients with chronic kidney disease (CKD) who did not require RRT and those on dialysis. Design A two-center retrospective study. Methods A total of 836 adult patients with COVID-19 (24 CKD not on dialysis; 15 dialysis-dependent CKD) were included. The study includes no patients with renal transplantation. Risk factors were explored. Results CKD not requiring RRT is an independent risk factor for in-hospital death [adjusted odds ratio (aOR) 7.35 (95% CI 2.41–22.44)] and poor prognosis [aOR 3.01 (95% CI 1.23–7.33)]. Compared with COVID-19 cases without CKD, those with CKD not requiring RRT showed similar percentage of initial moderate cases (75.00% vs. 73.65%) but higher incidence of in-hospital neutrophilia (50.00% vs. 27.30%) or death (50.00% vs. 9.03%). The odds ratio of dialysis associated to mortality in CKD patients was 2.00 (95% CI 0.52–7.63), suggesting COVID-19 patients with dialysis-dependent CKD were at greater risk of in-hospital death. For COVID-19 patients with CKD not requiring RRT, statins reduced the risk of neutrophilia [OR 0.10 (95% CI 0.01–0.69)] while diuretics increased the risk of neutrophilia [OR 15.4 (95% CI 1.47–160.97)], although both showed no association to mortality. Conclusion COVID-19 patients with CKD presented high incidence of neutrophilia, poor prognosis and in-hospital death, with dialysis patients being more vulnerable.

ObjectiveThis study investigated the influence of Coronavirus Disease 2019 (COVID-19) on lung function in early convalescence phase.MethodsA retrospective study of COVID-19 patients at the Fifth Affiliated Hospital of Sun Yat-sen University were conducted, with serial assessments including lung volumes (TLC), spirometry (FVC, FEV1), lung diffusing capacity for carbon monoxide (DLCO),respiratory muscle strength, 6-min walking distance (6MWD) and high resolution CT being collected at 30 days after discharged.ResultsFifty-seven patients completed the serial assessments. There were 40 non-severe cases and 17 severe cases. Thirty-one patients (54.3%) had abnormal CT findings. Abnormalities were detected in the pulmonary function tests in 43 (75.4%) of the patients. Six (10.5%), 5(8.7%), 25(43.8%) 7(12.3%), and 30 (52.6%) patients had FVC, FEV1, FEV1/FVC ratio, TLC, and DLCO values less than 80% of predicted values, respectively. 28 (49.1%) and 13 (22.8%) patients had PImax and PEmax values less than 80% of the corresponding predicted values. Compared with non-severe cases, severe patients showed higher incidence of DLCO impairment (75.6%vs42.5%,p = 0.019), higher lung total severity score (TSS) and R20, and significantly lower percentage of predicted TLC and 6MWD. No significant correlation between TSS and pulmonary function parameters was found during follow-up visit.ConclusionImpaired diffusing-capacity, lower respiratory muscle strength, and lung imaging abnormalities were detected in more than half of the COVID-19 patients in early convalescence phase. Compared with non-severe cases, severe patients had a higher incidence of DLCO impairment and encountered more TLC decrease and 6MWD decline.

Supplemental Digital Content is available in the text., Objective: Endothelial Cav-1 (caveolin-1) expression plays a relevant role during atherogenesis by controlling NO production, vascular inflammation, LDL (low-density lipoprotein) transcytosis, and extracellular matrix remodeling. Additional studies have identified cholesterol-rich membrane domains as important regulators of autophagy by recruiting ATGs (autophagy-related proteins) to the plasma membrane. Here, we investigate how the expression of Cav-1 in the aortic endothelium influences autophagy and whether enhanced autophagy contributes to the atheroprotective phenotype observed in Cav-1–deficient mice. Approach and Results: To analyze the impact of Cav-1 deficiency on regulation of autophagy in the aortic endothelium during the progression of atherosclerosis, we fed Ldlr−/− and Cav-1−/−Ldlr−/− mice a Western diet and assessed autophagy in the vasculature. We observe that the absence of Cav-1 promotes autophagy activation in athero-prone areas of the aortic endothelium by enhancing autophagic flux. Mechanistically, we found that Cav-1 interacts with the ATG5-ATG12 complex and influences the cellular localization of autophagosome components in lipid rafts, which controls the autophagosome formation and autophagic flux. Pharmacological inhibition of autophagy attenuates the atheroprotection observed in Cav-1−/− mice by increasing endothelial inflammation and macrophage recruitment, identifying a novel molecular mechanism by which Cav-1 deficiency protects against the progression of atherosclerosis. Conclusions: These results identify Cav-1 as a relevant regulator of autophagy in the aortic endothelium and demonstrate that pharmacological suppression of autophagic flux in Cav-1–deficient mice attenuates the atheroprotection observed in Cav-1−/− mice. Additionally, these findings suggest that activation of endothelial autophagy by blocking Cav-1 might provide a potential therapeutic strategy for cardiovascular diseases including atherosclerosis.

Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed increased proteolysis, endocytosis, phagocytosis, and lysosomal clearance of extracellular matrix and apoptotic cells. SMCs acquired a limited repertoire of macrophage markers and functions via biogenesis of degradative organelles through an mTOR/β-catenin/MITF-dependent pathway, but were distinguishable from conventional macrophages by an absence of hematopoietic lineage markers and certain immune effectors even in the context of hyperlipidemia. Similar mTOR activation and induction of a degradative SMC phenotype in a model of mild TAAD due to Fbn1 mutation greatly worsened disease with near-uniform lethality. The finding of increased lysosomal markers in medial SMCs from clinical TAAD specimens with hyperplasia and matrix degradation further supports the concept that proliferation of degradative SMCs within the media causes aortic disease, thus identifying mTOR-dependent phenotypic modulation as a therapeutic target for combating TAAD.

This study aimed to observe the immunomodulatory effects of oligopeptides derived from jackfruit (Artocarpus heterophyllus Lam.) (JOPs). 200 female BALB/c mice in five groups were respectively given deionized water (control), whey protein (0.20 g per kg body weight (BW)) and JOPs at doses of 0.20, 0.40, and 0.80 g per kg BW by intragastric administration on a daily basis. 7 tests were conducted to determine the immunomodulatory effects of JOPs on immune organ indexes, cellular and humoral immune responses, macrophage phagocytosis, and natural killer (NK) cell activity. Spleen T lymphocyte sub-populations and serum cytokine and immunoglobulin levels were tested to study how JOPs improved the immune system. We found that JOPs could significantly enhance innate and adaptive immune responses in mice by the improvement of cell-mediated and humoral immunity, macrophage phagocytosis capacity and NK cell activity. The immunomodulatory effects may be based on increased T and Th cell percentages, serum interleukin (IL)-1α, IL-10, tumor necrosis factor (TNF)-α, production of immunoglobulin (Ig) M, IgG, and IgA, and depressed interferon (IFN)-γ secretion. These results suggest that dietary JOPs could be valuable as potential immunomodulators.

Residues, potential sources and ecotoxicological effects of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were analyzed in typical urban river networks of Shanghai. In total, 47 surface sediments were collected in each of the sampling seasons (summer and winter). Laboratory analysis by GC-ECD showed that OCPs and PCBs concentrations were in medium levels compared to other national and international areas. As for OCP compounds, HCHs and DDTs were two dominant pollutants, with ∑HCHs concentrations ranging from 1.74 to 28.78 ng/g and ∑DDTs concentrations ranging from 0.88 to 25.45 ng/g. For individual HCHs, β-HCH was the most dominant HCH compound, with a mean value of 5.06 ng/g, followed by α-HCH (3.50 ng/g) in winter. A similar case of HCHs was also found in the summer season. Concentrations of ∑18PCBs varied from 6.67 to 37.10 ng/g in winter and from 10.63 to 45.55 ng/g in summer. Individual PCB 28, 101, 118 and 123 were dominant among all congeners, with averages of 3.16, 1.55, 2.47 and 2.37 ng/g in winter, 3.11, 2.34, 4.92 and 4.41 ng/g in summer, respectively. ∑20OCPs (the sum of twenty OCPs) concentrations in cultivated land areas were more abundant than that in artificial surface areas, indicating an abundance of pesticides and fertilizers in cultivated lands. Analysis of possible sources indicated that both industrial and agricultural residues contributed to higher HCHs and DDTs concentrations, which mainly originated from weathered pesticides with aerobic transformation processes. For PCB compounds, a significant seasonal variation, atmospheric precipitation, and surface runoff were the major factors for fluctuated PCBs concentrations. Ecotoxicological assessment based on established sediment quality guidelines (SQGs) showed that DDT compounds have a potential threat to the aquatic environment of our study area.

Background: Atherosclerosis is driven by synergistic interactions between pathological, biomechanical, inflammatory, and lipid metabolic factors. Our previous studies demonstrated that absence of caveolin-1 (Cav1)/caveolae in hyperlipidemic mice strongly inhibits atherosclerosis, which was attributed to activation of endothelial nitric oxide (NO) synthase (eNOS) and increased production of NO and reduced inflammation and low-density lipoprotein trafficking. However, the contribution of eNOS activation and NO production in the athero-protection of Cav1 and the exact mechanisms by which Cav1/caveolae control the pathogenesis of diet-induced atherosclerosis are still not clear. Methods: Triple-knockout mouse lacking expression of eNOS , Cav1 , and Ldlr were generated to explore the role of NO production in Cav1-dependent athero-protective function. The effects of Cav1 on lipid trafficking, extracellular matrix remodeling, and vascular inflammation were studied both in vitro and in vivo with a mouse model of diet-induced atherosclerosis. The expression of Cav1 and distribution of caveolae regulated by flow were analyzed by immunofluorescence staining and transmission electron microscopy. Results: We found that absence of Cav1 significantly suppressed atherogenesis in Ldlr −/− eNOS −/− mice, demonstrating that athero-suppression is independent of increased NO production. Instead, we find that the absence of Cav1/caveolae inhibited low-density lipoprotein transport across the endothelium and proatherogenic fibronectin deposition and disturbed flow-mediated endothelial cell inflammation. Consistent with the idea that Cav1/caveolae may play a role in early flow-dependent inflammatory priming, distinct patterns of Cav1 expression and caveolae distribution were observed in athero-prone and athero-resistant areas of the aortic arch even in wild-type mice. Conclusions: These findings support a role for Cav1/caveolae as a central regulator of atherosclerosis that links biomechanical, metabolic, and inflammatory pathways independently of endothelial eNOS activation and NO production.

Objectives Older adults who undergo kidney transplantation (KT) are living longer with a functioning graft and are at risk for age-related adverse events including fractures. Understanding recipient, transplant, and donor factors and the outcomes associated with fractures may help identify older KT recipients at increased risk. We determined incidence of hip, vertebral, and extremity fractures; assessed factors associated with incident fractures; and estimated associations between fractures and subsequent death-censored graft loss (DCGL) and mortality. Design This was a prospective cohort study of patients who underwent their first KT between January 1, 1999, and December 31, 2014. Setting We linked data from the Scientific Registry of Transplant Recipients to Medicare claims through the US Renal Data System. Participants The analytic population included 47 815 KT recipients aged 55 years or older. Measurements We assessed the cumulative incidence of and factors associated with post-KT fractures (hip, vertebral, or extremity) using competing risks models. We estimated risk of DCGL and mortality after fracture using adjusted Cox proportional hazards models. Results The 5-year incidence of post-KT hip, vertebral, and extremity fracture for those aged 65 to 69 years was 2.2%, 1.0%, and 1.7%, respectively. Increasing age was associated with higher hip (adjusted hazard ratio [aHR] = 1.37 per 5-y increase; 95% confidence interval [CI] = 1.30-1.45) and vertebral (aHR = 1.31; 95% CI = 1.20-1.42) but not extremity (aHR = .97; 95% CI = .91-1.04) fracture risk. DCGL risk was higher after hip (aHR = 1.34; 95% CI = 1.12-1.60) and extremity (aHR = 1.30; 95% CI = 1.08-1.57) fracture. Mortality risk was higher after hip (aHR = 2.31; 95% CI = 2.11-2.52), vertebral (aHR = 2.80; 95% CI = 2.44-3.21), and extremity (aHR = 1.85; 95% CI = 1.64-2.10) fracture. Conclusion Our findings suggest that older KT recipients are at higher risk for hip and vertebral fracture but not extremity fracture; and those with hip, vertebral, or extremity fracture are more likely to experience subsequent graft loss or mortality. These findings underscore that different fracture types may have different underlying etiologies and risks, and they should be approached accordingly. J Am Geriatr Soc 67:1680-1688, 2019.

Several lines of evidence suggest an inhibitory role of dietary nucleotides (NTs) against oxidative stress and inflammation, which promote senescence in age-associated cardiovascular diseases. We sought to test whether the dietary NTs could retard the hydrogen peroxide (H2O2)-induced senescence of human umbilical vein endothelial cells (HUVECs) and to elucidate the efficiency of different NTs as well as the potential mechanism. Senescence was induced in HUVECs by 4 h exposure to 200 µM H2O2 and was confirmed using senescence-associated-β-galactosidase staining (SA-β-gal), cell viability, and Western blot analyses of p16INK4A and p21Waf1/Cip1 after 24 h administration of growth medium. We find that NTs retards oxidative stress-induced HUVECs senescence, as shown by a lower percentage of SA-β-gal-positive cells, lower expression of p16INK4A, and p21Waf1/Cip1 as well as higher cell viability. GMP100 was the most excellent in delaying HUVECs senescence, which was followed by the NTs mixture, NMN, CMP50, and UMP50/100, while AMP retards HUVECs senescence by specifically reducing p15INK4b expression. NTs all have significant anti-inflammatory effects, AMP and CMP were more prominent in restoring mitochondrial function, GMP and CMP were more competent at eliminating ROS and MDA, while AMP and UMP were more efficient at enhancing antioxidant enzyme activity. The role of the NTs mixture in retarding HUVECs senescence is full-scaled. These results stated that the mechanisms of NTs retarding HUVECs senescence could be related to its antioxidant and anti-inflammation properties promoting cell proliferation and protecting mitochondrial function activities.

Nitric oxide (NO), a free radical, plays a critical role in a wide range of physiological and pathological processes. Due to its pleiotropic function, it has been widely investigated in various types of cancers and is strongly associated with cancer development. Mounting pieces of evidence show that NO regulates various cancer-related events, which mainly depends on phosphorylating the key proteins in several signaling pathways. However, phosphorylation of proteins modulated by NO signaling pathway may lead to different effects in different types of cancer, which is complex and remains unclear. Therefore, in this review, we focus on the effect of protein phosphorylation modulated by NO signaling pathway in different types of cancers including breast cancer, lung cancer, prostate cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, and neuroblastoma. Phosphorylation of key proteins, including p38 MAPK, ERK, PI3K, STAT3, and p53, modified by NO in various signaling pathways affects different cancer-related processes including cell apoptosis, proliferation, angiogenesis, metastasis, and several cancer therapies. Our review links the NO signaling pathway to protein phosphorylation in cancer development and provides new insight into potential targets and cancer therapy.

Peptic ulcer has a serious impact on people’s health around the world, and traditional medicines can cause adverse reactions. This study investigated the protective effects of tilapia collagen oligopeptides (TCOPs) on gastroduodenal injury. Seventy-two specific pathogen-free (SPF) male Sprague Dawley (SD) rats were randomly divided into six groups according to body weight: normal control group, ethanol group, whey protein group (500 mg/kg BW), and three TCOPs dose groups (250, 500, 1000 mg/kg BW). After intragastric administration for 30 days, the acute gastroduodenal injury was induced by anhydrous ethanol (5 mL/kg, intragastrically) in all groups except the normal control group. Biomarkers in gastric and duodenal tissue and serum were measured. Furthermore, western blot was used to detect the expression of apoptosis-related proteins. The results showed that the administration with TCOPs significantly reduced gastric and duodenal ulcer index, increased gastric juice pH, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, along with the reduction of malondialdehyde (MDA) contents. TCOPs decreased tumor Necrosis Factor-α (TNF-α), interleukin-1β (IL-1β), and myeloperoxidase (MPO) levels, while interleukin– 10 (IL-10) levels were increased. Furthermore, pepsinogens 1 (PG1), pepsinogens 2 (PG2), gastrin (GAS), and the pepsinogen ratio (PGR) were decreased, the prostaglandin E2 (PGE2) and NO contents were increased after TCOPs intervention. Moreover, TCOPs up-regulated the expression of Bcl-2 and inhibited the expression of Bax and Caspase-3. In conclusion, TCOPs have protective effects on ethanol-induced gastroduodenal injury through gastrointestinal mucosal microcirculation promotion, antioxidation, anti-inflammation, and anti-apoptosis mechanisms.

This study investigated the antioxidant effects of whey protein peptide on learning and memory in aging C57BL/6N mice. A total of 72 SPF male C57BL/6N mice were used. Twelve mice were randomly selected as the control group, and the other mice were intraperitoneally injected with D-galactose (100 mg/kg body weight for 6 weeks), during which, the mice in the control group were intraperitoneally injected with the same amount of normal saline. After 6 weeks, the blood was taken from the epicanthus and the serum MDA level was measured, according to which, the mice were randomly divided into the model control group, the whey protein group (1.5 g/kg body weight), and three Whey protein peptide (WHP) intervention groups (0.3 g/kg body weight, 1.5 g/kg body weight, 3.0 g/kg body weight). The water solution of the test sample was administered by oral gavage every day. The intervention period was 30 days, during which, the model control group, the whey protein group, and the whey protein peptide group continued receiving intraperitoneal injections of D-galactose, while the control group continued receiving intraperitoneal injections of normal saline. After the intervention, behavioral experiments were conducted in the following order: open field test, water maze test, and new object recognition test. After the behavioral experiment, the morphology of hippocampal formation was observed by HE staining and TUNEL labeling. Oxidative stress-related indexes in the serum, liver, and brain were detected. Expression levels of the cholinergic system-related enzymes and proinflammatory cytokines in brain tissue were detected. Western blot was used to detect the expression of synaptic plasticity-related proteins in the mouse brain. The results showed that WHP could significantly improve the accumulation of MDA and PC, increase the activities of SOD and GSH-Px, resist oxidative stress injury, and enhance the potential of endogenous antioxidant defense mechanisms. WHP can significantly improve the decline of aging-related spatial exploration, body movement, and spatial and non-spatial learning/memory ability. Its specific mechanism may be related to reducing the degeneration of hippocampal nerve cells, reducing the apoptosis of nerve cells, improving the activity of AChE, reducing the expression of inflammatory factors (TNF-α and IL-1β) in brain tissue, reducing oxidative stress injury, and improving the expression of p-CaMKⅡ and BDNF synaptic plasticity protein. These results indicate that WHP can improve aging-related oxidative stress, as well as learning and memory impairment.

The pigment cell-specific protein PMEL forms a functional amyloid matrix in melanosomes onto which the pigment melanin is deposited. The amyloid core consists of a short proteolytic fragment, which we have termed the core-amyloid fragment (CAF) and perhaps additional parts of the protein, such as the PKD domain. A highly O-glycosylated repeat (RPT) domain also derived from PMEL proteolysis associates with the amyloid and is necessary to establish the sheet-like morphology of the assemblies. Excluded from the aggregate is the regulatory N-terminus, which nevertheless must be linked in cis to the CAF in order to drive amyloid formation. The domain is then likely cleaved away immediately before, during, or immediately after the incorporation of a new CAF subunit into the nascent amyloid. We had previously identified a 21 amino acid long region, which mediates the regulatory activity of the N-terminus towards the CAF. However, many mutations in the respective segment caused misfolding and/or blocked PMEL export from the endoplasmic reticulum, leaving their phenotype hard to interpret. Here, we employ a saturating mutagenesis approach targeting the motif at single amino acid resolution. Our results confirm the critical nature of the PMEL N-terminal region and identify several residues essential for PMEL amyloidogenesis.

Functional near-infrared spectroscopy (fNIRS)is a brain-imaging technology used to reveal brain activity by measuring blood oxygenation. Using fNIRS we measured activity in the left prefrontal lobe of 8–14 month-old infants as they crawled or were pushed in a stroller and as they were given a passive attention task or an active executive function (EF) task. For each task, we measured peak total hemoglobin concentration and peak Oxy relative to baseline. Results revealed differences in peak Oxy levels for crawling vs. strolling and between the EF and passive cognitive tasks, with total hemoglobin greater for the EF task than the passive attention task. These results support the theoretical view that both active locomotion and EF engage the prefrontal cortex (PFC) during early development.

Radiation therapy is widely used in the treatment of tumor diseases, but it can also cause serious damage to the body, so it is necessary to find effective nutritional supplements. The main purpose of this study is to evaluate the protective effect of whey hydrolysate peptides (WHPs) against 60Coγ radiation damage in mice and explore the mechanism. BALB/c mice were given WHPs by oral gavage administration for 14 days. Then, some mice underwent a 30-day survival test after 8 Gy radiation, and other mice received 3.5 Gy radiation to analyze the changes in body weight, hematology and bone marrow DNA after three and 14 days. In addition, through further analysis of the level of oxidative stress and intestinal barrier function, the possible mechanism of the radioprotective effect of WHPs was explored. The study found WHPs can prolong survival time, restore body weight, and increase the number of peripheral blood white blood cells and bone marrow DNA content in irradiated mice. In addition, WHPs can significantly improve the antioxidant capacity, inhibit pro-inflammatory cytokines and protect the intestinal barrier. These results indicate that WHPs have a certain radioprotective effect in mice, and the main mechanism is related to reducing oxidative damage.

COVID-19 patients present high incidence of kidney abnormalities, which are associated with poor prognosis and mortality. The identification of SARS-CoV-2 in the kidney of COVID-19 patients suggests renal tropism of SARS-CoV-2. However, whether there is a specific target of SARS-CoV-2 in the kidney remains unclear. Herein, by using in silico simulation, co-immunoprecipitation, fluorescence resonance energy transfer, fluorescein isothiocyanate labelling, and rational design of antagonist peptides, we demonstrate that kidney injury molecule-1 (KIM1), a molecule dramatically upregulated upon kidney injury, binds with the receptor-binding domain of SARS-CoV-2 and facilitates its attachment to cell membrane, with the immunoglobulin variable Ig-like (Ig V) domain of KIM1 playing a key role in this recognition. The interaction between SARS-CoV-2 receptor-binding domain and KIM1 is potently blockaded by a rationally designed KIM1-derived polypeptide AP2. In addition, our results also suggest interactions between KIM1 Ig V domain and the receptor-binding domains of SARS-CoV and MERS-CoV, pathogens of two severe infectious respiratory diseases. Together, these findings suggest KIM1 as a novel receptor for SARS-CoV-2 and other coronaviruses. We propose that KIM1 may thus mediate and exacerbate the renal infection of SARS-CoV-2 in a ‘vicious cycle’, and KIM1 could be further explored as a therapeutic target.

Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10). Here we report that mice with a brain EC-specific deletion of Pdcd10 (Pdcd10BECKO) survive up to 6-12 months and develop bona fide CCM lesions in all regions of brain, allowing us to visualize the vascular dynamics of CCM lesions using transcranial two-photon microscopy. This approach reveals that CCMs initiate from protrusion at the level of capillary and post-capillary venules with gradual dissociation of pericytes. Microvascular beds in lesions are hyper-permeable, and these disorganized structures present endomucin-positive ECs and α-smooth muscle actin-positive pericytes. Caveolae in the endothelium of Pdcd10BECKO lesions are drastically increased, enhancing Tie2 signaling in Ccm3-deficient ECs. Moreover, genetic deletion of caveolin-1 or pharmacological blockade of Tie2 signaling effectively normalizes microvascular structure and barrier function with attenuated EC-pericyte disassociation and CCM lesion formation in Pdcd10BECKO mice. Our study establishes a chronic CCM model and uncovers a mechanism by which CCM3 mutation-induced caveolae-Tie2 signaling contributes to CCM pathogenesis., Animal models that fully recapitulate human CCM pathogenesis are not currently available. Here, the authors establish a novel CCM model and reveal that caveolae-Tie2 signaling is involved in CCMs formation at the level of venules, which is accompanied by gradual dissociation of pericytes.

TUG tethering proteins bind and sequester GLUT4 glucose transporters intracellularly, and insulin stimulates TUG cleavage to translocate GLUT4 to the cell surface and increase glucose uptake. This effect of insulin is independent of phosphatidylinositol 3-kinase, and its physiological relevance remains uncertain. Here we show that this TUG cleavage pathway regulates both insulin-stimulated glucose uptake in muscle and organism-level energy expenditure. Using mice with muscle-specific Tug (Aspscr1)-knockout and muscle-specific constitutive TUG cleavage, we show that, after GLUT4 release, the TUG C-terminal cleavage product enters the nucleus, binds peroxisome proliferator-activated receptor (PPAR)γ and its coactivator PGC-1α and regulates gene expression to promote lipid oxidation and thermogenesis. This pathway acts in muscle and adipose cells to upregulate sarcolipin and uncoupling protein 1 (UCP1), respectively. The PPARγ2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The ATE1 arginyltransferase, which mediates a specific protein degradation pathway and controls thermogenesis, regulates the stability of the TUG product. We conclude that insulin-stimulated TUG cleavage coordinates whole-body energy expenditure with glucose uptake, that this mechanism might contribute to the thermic effect of food and that its attenuation could promote obesity. Insulin stimulates TUG cleavage to translocate GLUT4 and enhance glucose uptake. Here Bogan and colleagues show that the TUG cleavage product regulates thermogenic gene transcription, thereby coupling glucose uptake to organismal energy expenditure.

Inflammation plays a major role in the pathogenesis of several vascular pathologies, including abdominal aortic aneurysm (AAA). Evaluating the role of inflammation in AAA pathobiology and potentially outcome in vivo requires non-invasive tools for high-resolution imaging. We investigated the feasibility of X-ray computed tomography (CT) imaging of phagocytic activity using nanoparticle contrast agents to predict AAA outcome. Methods: Uptake of several nanoparticle CT contrast agents was evaluated in a macrophage cell line. The most promising agent, Exitron nano 12000, was further characterized in vitro and used for subsequent in vivo testing. AAA was induced in Apoe -/- mice through angiotensin II (Ang II) infusion for up to 4 weeks. Nanoparticle biodistribution and uptake in AAA were evaluated by CT imaging in Ang II-infused Apoe -/- mice. After imaging, the aortic tissue was harvested and used from morphometry, transmission electron microscopy and gene expression analysis. A group of Ang II-infused Apoe -/- mice underwent nanoparticle-enhanced CT imaging within the first week of Ang II infusion, and their survival and aortic external diameter were evaluated at 4 weeks to address the value of vessel wall CT enhancement in predicting AAA outcome. Results: Exitron nano 12000 showed specific uptake in macrophages in vitro. Nanoparticle accumulation was observed by CT imaging in tissues rich in mononuclear phagocytes. Aortic wall enhancement was detectable on delayed CT images following nanoparticle administration and correlated with vessel wall CD68 expression. Transmission electron microscopy ascertained the presence of nanoparticles in AAA adventitial macrophages. Nanoparticle-induced CT enhancement on images obtained within one week of AAA induction was predictive of AAA outcome at 4 weeks. Conclusions: By establishing the feasibility of CT-based molecular imaging of phagocytic activity in AAA, this study links the inflammatory signal on early time point images to AAA evolution. This readily available technology overcomes an important barrier to cross-sectional, longitudinal and outcome studies, not only in AAA, but also in other cardiovascular pathologies and facilitates the evaluation of modulatory interventions, and ultimately upon clinical translation, patient management.

COVID-19 patients present high incidence of kidney abnormalities, which are associated with poor prognosis and high mortality. Identification of SARS-CoV-2 in kidney of COVID-19 patients suggests renal tropism and direct infection. Presently, it is generally recognized that SARS-CoV-2 initiates invasion through binding of receptor-binding domain (RBD) of spike protein to host cell-membrane receptor ACE2, however, whether there is additional target of SARS-CoV-2 in kidney remains unclear. Kidney injury molecule-1 (KIM1) is a transmembrane protein that drastically up-regulated after renal injury. Here, binding between SARS-CoV2-RBD and the extracellular Ig V domain of KIM1 was identified by molecular simulations and co-immunoprecipitation, which was comparable in affinity to that of ACE2 to SARS-CoV-2. Moreover, KIM1 facilitated cell entry of SARS-CoV2-RBD, which was potently blockaded by a rationally designed KIM1-derived polypeptide. Together, the findings suggest KIM1 may mediate and exacerbate SARS-CoV-2 infection in a ‘vicious cycle’, and KIM1 could be further explored as a therapeutic target.

This study aimed to investigate the immunomodulatory effects of walnut (Juglans regia L.) oligopeptides (WOPs). Female BALB/c mice were randomly assigned to control, whey protein control and three WOPs groups, given deionized water, 220 mg/kg BW whey protein, 110, 220 and 440 mg/kg BW WOPs daily through drinking water for 30 days, respectively. The immonomodulatory activity determination of WOPs involved innate and adaptive immunity, spleen T lymphocyte subpopulations, serum cytokine and immunoglobulin levels. Our results showed that WOPs could significantly improve humoral and cell-mediated immune responses, macrophage phagocytosis and natural killer cell activity. Moreover, increased T and Th cells percentages, cytokines secretion of interleukin (IL)-2, IL-10, IL-12 and granulocyte–macrophage colony stimulating factor, and production of immunoglobulin (Ig)A, IgG, IgM and intestinally secreted IgA also contributed to these improvements. All these above indicated that WOPs could be a promising immunomodulatory dietary supplement at dosages ranging from 110 to 440 mg/kg BW.