Comprehensive Analysis of the Associations of LOXL1-4 with Prognosis and Immune Infiltration in Breast Cancer.

Objective: Invasive breast cancer (BRCA) poses a major challenge to women's health due to its high incidence and poor prognosis. Dysregulated Lysine oxidase-like (LOXL) family genes are implicated in tumor progression across malignancies. Understanding the role of Lysine oxidase-like (LOXL) family genes in BRCA is crucial for advancing treatment strategies. Methods: TIMER, Oncomine, TNMplot, TCGA, GTEx and GEPIA datasets were used to investigate LOXL1-4 expression in breast cancer. The UALCAN and HPA datasets were utilized to detect the protein levels of LOXL1-4 in BRCA. Kaplan-Meier Plotter was used to analyze the prognostic values of LOXL1-4 in BRCA patients. Gene ontology (GO) and KEGG pathway enrichment analyses, conducted through DAVID 6.8 and R, revealed potential biological functions. TIMER was used to explore the link between LOXL1-4 expression and tumor immune infiltration. The cBioPortal dataset was used to analyze LOXL1-4 alterations and CNV-survival links in breast cancer. GSCA was used to assess LOXL1-4's correlations with immune infiltration. LOXL1-4's links to the eight immune checkpoint genes were analyzed using R's pheatmap. Results: Our study revealed that aberrant expression of LOXL1/2/4 in BRCA significantly affects relapse-free survival (RFS), overall survival (OS), and distant metastasis-free survival (DMFS), particularly highlighting the prognostic importance of LOXL4. LOXL1-4 displayed substantial relationships with the tumor immune microenvironment and immune cell infiltration. Furthermore, copy number variations (CNVs) of LOXL1-4 are significantly associated with immune infiltration in BRCA, particularly LOXL2 CNV, which significantly impacts OS and progression-free survival (PFS). Conclusion: The correlation between LOXL1-4 expression, prognosis, and immune infiltration in BRCA underscores their potential as biomarkers for prognosis and targets for immunotherapy.

Correlation analysis of hypertension, traditional Chinese medicine constitution, and LPL gene polymorphism in the elderly in communities in Shanghai.

BACKGROUND: Research on the genetic mechanisms of hypertension has been a hot topic in the cardiovascular field. OBJECTIVE: To study the correlation between senile hypertension and traditional Chinese medicine (TCM) constitution and lipoprotein lipase (LPL) gene polymorphism and to provide the theoretical basis for TCM prevention and treatment of hypertension. METHODS: The elderly population in communities in Shanghai (hypertensive: 264 cases; non-hypertensive: 159 cases) was taken as the research object. Essential data and information on TCM constitution were collected. The LPL gene mutation was detected using the second-generation sequencing method. Statistical analysis was performed to clarify the relationship between hypertension and senile hypertension. The correlation of TCM constitution with risk factors and LPL gene polymorphisms was studied. RESULTS: The primary TCM constitutions in the hypertension group were phlegm-dampness constitution (51.52%), yin-deficiency constitution (17.42%), balanced constitution (15.53%), and yin-deficiency (9.43%). Logistic regression analysis showed that the phlegm-dampness constitution (P< 0.05, OR = 2.587) and yin-deficiency constitution (P< 0.01, OR = 2.693) were the risk constitutions of hypertension in the elderly. A total of 37 LPL gene mutation loci (SNP: 22; new discovery: 15) were detected in the LPL gene, and the mutation rates of rs254, rs255, rs3208305, rs316, rs11570891, rs328, rs11570893, and rs13702 were relatively high, which were 26.24%, 26.24%, 16.08%, 14.66%, 13.24%, 12.06%, and 10.64%. In the phlegm-dampness group, the proportion of rs254 CC type, rs255 TT type, and rs13702 TT type in the hypertensive group (77.21%, 77.21%, and 93.38%) was higher than that in the non-hypertensive group (56.41%, 56.41%, and 82.05%), The difference was statistically significant (P< 0.05). CONCLUSION: The phlegm-dampness constitution and yin-deficiency constitution are the risk factors of hypertension in the elderly; in the phlegm-dampness population, rs254 CC type, rs255 TT type, and rs13702 TT type are the risk factors for elderly hypertension.

Effect of endo-1,4-beta-xylanase supplementation to low-energy diets on performance, blood constituents, nutrient digestibility, and gene expressions related growth of broiler chickens.

The presence of soluble and insoluble non-starch polysaccharides (NSP) was reported to reduce nutrient utilisation, and adversely impact the broilers' growth performance; accordingly, NSP-degrading enzymes are essential supplements to cereal-based diets. Therefore, the current trial was conducted to characterise the impacts of supplemental xylanase (Xyl) to diets with low-ME levels on performance, carcass traits, blood parameters, nutrient digestibility and some genes expressions in broiler chickens. A total of 600 1-day-old Ross 308 male broiler chicks were randomly assigned to 6 treatments with 10 replications of 10 birds each per group in a completely randomised design. The 6 treatments were as follow: (1) basal diets with balanced ME content served as control (positive control, PC), (2) low-energy diet (negative control 1 [NC1]; ME content reduced by 70 kcal/kg compared with PC), (3) low-energy diet (negative control 2 [NC2]; ME content reduced by 140 kcal/kg compared with PC), (4) NC1 + 100 g/ton xylanase (NC1 + 100Xyl), (5) NC2 + 100 g/ton xylanase (NC2 + 100Xyl), and (6) NC1 + 50 g/ton xylanase (NC1 + 50Xyl). At the end of the experiment (35 days of age), the reduction of energy in the NC diets yielded lower live body weight (BW) and total body weight gain (BWG) (p ˂ 0.001); however, it significantly increased feed intake (p ˂ 0.05), leading to worst feed conversion ratio (FCR) and European production efficiency factor (EPEF) (p ˂ 0.01) than PC. There was non-significant variation in final BW, BWG, FCR, or EPEF between the PC group and the NC groups supplemented with Xyl. Carcass yield, gizzard, liver and, muscle relative weights were not influenced by dietary treatments; while broilers fed diet with low-energy diets with or without Xyl addition had lower abdominal fat (p ˂ 0.01) than PC. Furthermore, broilers fed on low-ME diets supplemented with Xyl showed a reduction in plasma total cholesterol (p ˂ 0.05) and low density lipoprotein (p ˂ 0.01) levels. Greater antibody titre against Newcastle disease (p ˂ 0.05) was recorded in the NC1 + 100Xyl and NC2 + 100Xyl groups. The addition of Xyl to low-energy diets significantly improved (p ˂ 0.05) fibre digestibility compared to the PC group. Moreover, enzyme supplementation increased muscle total lipids content and decreased muscle thiobarbituric acid retroactive substance content. In addition, enzyme supplementation increased gene expression related to growth and gene expression related to fatty acid synthesis. It was concluded that a low-ME diet might diminish broiler performance, whereas Xyl supplementation to low-ME diets beneficially affected growth performance, abdominal fat percentage, nutrient digestibility and immunity for broilers, and gene expressions related to growth and fatty acid synthesis in broiler chickens fed low-energy diets.

Maresin1 prevents sepsis-induced acute liver injury by suppressing NF-κB/Stat3/MAPK pathways, mitigating inflammation.

Aims: The treatment of sepsis remains challenging and the liver is a non-neglectful target of sepsis-induced injury. Uncontrolled inflammatory responses exert a central role in the pathophysiological process of sepsis-induced acute liver injury (SI-ALI). Maresin1 (MaR1) is a derivative of omega-3 docosahexaenoic acid (DHA), which has been shown to have anti-inflammatory effects and is effective in a variety of sepsis-related diseases. This study aimed to determine the effect of MaR1 on cecal ligation and puncture (CLP)-caused SI-ALI and explore its possible mechanisms. Main methods: Mice were subjected to CLP, and then intravenously injected via tail vein with low-dose MaR1 (0.5 ng, 200 µL) or high-dose MaR1 (1 ng, 200 µL) or sterile normal saline (NS) (200 µL) 1 h later. Then, the survival rate, body weight change, liver function, bacterial load, neutrophil infiltration, and inflammatory cytokines were detected. Results: MaR1 significantly increased the 7-day survival rate and reduced the bacterial load in peritoneal lavage fluid and blood in a dose-dependent manner in mice with SI-ALI. Treatment with MaR1 could also restore the function of the liver in septic mice. Besides, MaR1 exerted anti-inflammatory effects by decreasing the expression of pro-inflammatory molecules (TNF-α, IL-6 and IL-1ß), bacterial load, and neutrophil infiltration and increasing the expression of anti-inflammatory molecules (IL-10). Significance: Our experimental results showed that MaR1 alleviated liver injury induced by sepsis. This work highlighted a potential clinic use of MaR1 in treating acute inflammation of SI-ALI, but also provided new insight into the underlying molecular mechanism.

Enhanced serum levels of tumor necrosis factor-α, interleukin-1ß, and -6 in sarcopenia: alleviation through exercise and nutrition intervention.

BACKGROUND: Limited research has been conducted on the post-intervention inflammatory status in sarcopenic patients, despite previous studies revealing elevated pro-inflammatory markers. This study aimed to investigate the potential elevation of specific pro-inflammatory cytokines in sarcopenic patients and evaluate the effects of exercise and nutritional support interventions on these cytokine levels. METHODS: In this post-hoc analysis of a randomized controlled trial (RCT), 57 individuals with sarcopenia from the RCT and 57 non-sarcopenic participants from the same geriatric community cohort that did not participate in the RCT were enrolled. Grip strength and body composition measurements were recorded. Tumor necrotizing factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-15 levels were assessed at baseline for both groups and after a 12-week intervention consisting of resistive exercise and supplementation with branched-chain amino acids, calcium, and vitamin D3 in the patients with sarcopenia. RESULTS: The sarcopenic group demonstrated significantly lower body weight, body mass index, grip strength, and skeletal muscle mass index. Moreover, sarcopenic patients exhibited higher levels of TNF-α (p=0.007), IL-1ß (p<0.001), and IL-6 (p<0.001), while no significant difference was observed in IL-15 (p=0.345) between participants with and those without sarcopenia. Following the intervention, the sarcopenic group experienced significant improvements in grip strength and skeletal muscle mass index with a notable reduction in TNF-α (p=0.003), IL-1ß (p=0.012) and IL-6 (p=0.001) levels. CONCLUSIONS: Sarcopenic patients exhibit elevated levels of TNF-α, IL-1ß, and IL-6, which declined after nutrition support and exercise interventions. However, further research is necessary to evaluate the long-term impact of these interventions on cytokine levels.

Cell-based screen identifies porphyrins as FGFR3 activity inhibitors with therapeutic potential for achondroplasia and cancer.

Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including the most common form of human dwarfism, achondroplasia (ACH). Targeting FGFR3 activity holds great promise as a therapeutic approach for treatment of these diseases. Here, we established a receptor/adaptor translocation assay system that can specifically monitor FGFR3 activation, and we applied it to identify FGFR3 modulators from complex natural mixtures. An FGFR3-suppressing plant extract of Amaranthus viridis was identified from the screen, and 2 bioactive porphyrins, pheophorbide a (Pa) and pyropheophorbide a, were sequentially isolated from the extract and functionally characterized. Further analysis showed that Pa reduced excessive FGFR3 signaling by decreasing its half-life in FGFR3-overactivated multiple myeloma cells and chondrocytes. In an ex vivo culture system, Pa alleviated defective long bone growth in humanized ACH mice (FGFR3ACH mice). Overall, our study presents an approach to discovery and validation of plant extracts or drug candidates that target FGFR3 activation. The compounds identified by this approach may have applications as therapeutics for FGFR3-associated cancers and skeletal dysplasias.

Compare the effectiveness of extracorporeal shockwave and hyperbaric oxygen therapy on enhancing wound healing in a streptozotocin-induced diabetic rodent model.

Studies have revealed that both extracorporeal shock-wave therapy (ESWT) and hyperbaric oxygen therapy (HBOT) can accelerate wound healing. This study aimed to compare the effectiveness of ESWT and HBOT in enhancing diabetic wound healing. A dorsal skin defect in a streptozotocin-induced diabetes rodent model was used. Postoperative wound healing was assessed once every 3 days. Histologic examination was performed with hematoxylin and eosin staining. Proliferation marker protein Ki-67 (Ki-67), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and 8-hydroxy-2-deoxyguanosine (8-OHdG) were evaluated with immunohistochemical (IHC) staining. The wound area was significantly reduced in the ESWT and HBOT groups compared to that in the diabetic controls. However, the wound healing time was significantly increased in the HBOT group compared to the ESWT group. Histological findings showed a statistical increase in neovascularization and suppression of the inflammatory response by both HBOT and ESWT compared to the controls. IHC staining revealed a significant increase in Ki-67, VEGF, and eNOS but suppressed 8-OHdG expression in the ESWT group compared to the HBOT group. ESWT facilitated diabetic wound healing more effectively than HBOT by suppressing the inflammatory response and enhancing cellular proliferation and neovascularization and tissue regeneration.

World Health Organization survey on the level of integration of traditional Chinese medicine in Chinese health system rehabilitation services.

Background: To meet the growing global demand for rehabilitation services, the World Health Organization (WHO) launched Rehabilitation 2030. This study was commissioned by the WHO to investigate the integration degree of traditional Chinese medicine (TCM) in Chinese health system rehabilitation services and the demand for TCM rehabilitation in China. Methods: Twenty TCM rehabilitation experts and relevant government administrators were invited to complete the questionnaire between September 2019 and January 2022. The development of traditional, complementary, and integrative medicine (TCI) rehabilitation in China was assessed primarily based on six different health system components. Results: 26 policies, regulations, and national strategic plans related to TCI rehabilitation were issued by relevant government departments since 2002; notably, 14 policies related to TCI rehabilitation development were intensively introduced from 2016 to 2021. These policies cover the three main areas of financing, infrastructure development, and service delivery. The National Administration of Traditional Chinese Medicine's investment in TCM clinical capacity infrastructure and scientific research in 2019-2021 increased by 66% compared to 2010-2012, and the average number of TCM hospitals with rehabilitation departments in 2020 increased by 6.5% compared to 2018. The proportion of community health service centers providing TCM services in primary medical and health institutions has increased by 30.8% over the past 10 years. Conclusion: Long-term continuous policies, substantial financial investment, and expansion of the scope of TCI rehabilitation services in primary care institutions have effectively contributed to the rapid development of TCI rehabilitation. However, human resources and financing mechanisms for TCI rehabilitation need further improvement.

Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation.

The CD39-CD73-adenosinergic pathway converts adenosine triphosphate (ATP) to adenosine for inhibiting anti-tumor immune responses. Therefore, targeting CD73 to reinvigorate anti-tumor immunity is considered the novel cancer immunotherapy to eradicate tumor cells. To fully understand the critical role of CD39/CD73 in colon adenocarcinoma (COAD), this study aims to comprehensive investigate the prognostic significance of CD39 and CD73 in stage I-IV COAD. Our data demonstrated that CD73 staining strongly marked malignant epithelial cells and CD39 was highly expressed in stromal cells. Attractively, tumor CD73 expression was significantly associated with tumor stage and the risk of distant metastasis, which suggested CD73 was as an independent factor for colon adenocarcinoma patients in univariate COX analysis [HR = 1.465, 95%CI = 1.084-1.978, p = 0.013]; however, high stromal CD39 in COAD patients was more likely to have favorable survival outcome [HR = 1.458, p = 1.103-1.927, p = 0.008]. Notably, high CD73 expression in COAD patients showed poor response to adjuvant chemotherapy and high risk of distant metastasis. High CD73 expression was inversely associated with less infiltration of CD45+ and CD8+ immune cells. However, administration with anti-CD73 antibodies significantly increased the response to oxaliplatin (OXP). Blockade of CD73 signaling synergistically enhanced OXP-induced ATP release, which is a marker of immunogenic cell death (ICD), promotes dendritic cell maturation and immune cell infiltration. Moreover, the risk of colorectal cancer lung metastasis was also decreased. Taken together, the present study revealed tumor CD73 expression inhibited the recruitment of immune cells and correlated with a poor prognosis in COAD patients, especially patients received adjuvant chemotherapy. Targeting CD73 to markedly increased the therapeutic response to chemotherapy and inhibited lung metastasis. Therefore, tumor CD73 may be an independent prognostic factor as well as the potential of therapeutic target for immunotherapy to benefit colon adenocarcinoma patients.

Efficacy of Aromatherapy at Relieving the Work-Related Stress of Nursing Staff from Various Hospital Departments during COVID-19.

This study aimed to evaluate the efficacy of aromatherapy in relieving the stress of nursing staff working in different departments during COVID-19. A total of 26 nursing staff from Taiwan were recruited for this study. Bergamot essential oil was diffused for over a four-week period in four different hospital departments. We assessed heart rate variability indicators, Nurse Stress Checklist, and Copenhagen Burnout Inventory before and after the intervention. The results of the analysis showed that during a high workload period, aromatherapy had no significant effect on regulating physical stress. Subjective measurements showed a significant impact on work concern and personal fatigue. Moreover, there were large differences among the four departments; the aromatherapy treatment had a weak effect on those with a heavy workload, whereas those with a lighter workload showed a stronger effect. Finally, this study provides practical results about aromatherapy stress reduction applied during the pandemic on first-line medical staff.

Genome-Wide Identification, Expression Analysis, and Potential Roles under Abiotic Stress of the YUCCA Gene Family in Mungbean (Vigna radiata L.).

YUCCA, belonging to the class B flavin-dependent monooxygenases, catalyzes the rate-limiting step for endogenous auxin synthesis and is implicated in plant-growth regulation and stress response. Systematic analysis of the YUCCA gene family and its stress response benefits the dissection of regulation mechanisms and breeding applications. In this study, 12 YUCCA genes were identified from the mungbean (Vigna radiata L.) genome and were named based on their similarity to AtYUCCAs. Phylogenetic analysis revealed that the 12 VrYUCCAs could be divided into 4 subfamilies. The evidence from enzymatic assays in vitro and transgenetic Arabidopsis in vivo indicated that all the isolated VrYUCCAs had biological activity in response to IAA synthesis. Expression pattern analysis showed that functional redundancy and divergence existed in the VrYUCCA gene family. Four VrYUCCAs were expressed in most tissues, and five VrYUCCAs were specifically highly expressed in the floral organs. The response toward five stresses, namely, auxin (indole-3-acetic acid, IAA), salinity, drought, high temperatures, and cold, was also investigated here. Five VrYUCCAs responded to IAA in the root, while only VrYUCCA8a was induced in the leaf. VrYUCCA2a, VrYUCCA6a, VrYUCCA8a, VrYUCCA8b, and VrYUCCA10 seemed to dominate under abiotic stresses, due to their sensitivity to the other four treatments. However, the response modes of the VrYUCCAs varied, indicating that they may regulate different stresses in distinct ways to finely adjust IAA content. The comprehensive analysis of the VrYUCCAs in this study lays a solid foundation for further investigation of VrYUCCA genes' mechanisms and applications in breeding.

2,6-Disubstituted Piperidine Alkaloids with Neuroprotective Activity from Hippobroma longiflora.

Three new alkaloids, hipporidine A (1: ), hipporidine B (2: ), and (-)-lobeline N-oxide (3: ), were discovered from the whole plant of Hippobroma longiflora together with five known compounds (4: -8: ). Their 2,6-disubstituted piperidine structures were established based on the HRESIMS, NMR (COSY, HMBC, HSQC, NOESY), and UV spectroscopic data. Hipporidines A (1: ) and B (2: ) possess a rare 1,3-oxazinane moiety. Compound 3: is the N-oxide derivative of (-)-lobeline (6: ). Moreover, the absolute configuration of norlobeline (5: ) was established by single-crystal X-ray diffraction analysis. Three major secondary metabolites (6: -8: ) were evaluated for their neuroprotective effect against paclitaxel-induced neurotoxicity. Consequently, pretreatment with compound 8: at a concentration of 1.0 µM displayed significant attenuation on paclitaxel-damaged neurite outgrowth of dorsal root ganglion neurons without interfering with the cytotoxicity of paclitaxel on cervical cancer SiHa cells.

[Governor vessel moxibustion combined with warming acupuncture for knee osteoarthritis with yang deficiency and cold congelation based on the supporting-yang theory].

OBJECTIVE: To compare the clinical efficacy between governor vessel moxibustion combined with warming acupuncture based on the supporting-yang theory and simple warming acupuncture for knee osteoarthritis (KOA) with yang deficiency and cold congelation. METHODS: A total of 64 patients with KOA of yang deficiency and cold congelation were randomized into a combination group (32 cases, 2 cases dropped off) and a warming acupuncture group (32 cases, 1 case dropped off). In the warming acupuncture group, warming acupuncture was applied at Zusanli (ST 36), Guanyuan (CV 4) and Dubi (ST 35), Neixiyan (EX-LE 4), etc. on the affected side, once a day. On the basis of the treatment in the warming acupuncture group, governor vessel moxibustion was applied in the combination group, once a week. The 14-day treatment was taken as one course, and totally 2 courses with 2-day interval were required in the two groups. The clinical symptom score, the visual analogue scale (VAS) score and the Western Ontario and McMaster Universities arthritis index (WOMAC) score were observed before treatment, after treatment and in the follow-up of 12 weeks after treatment; the volume of suprapatellar bursa effusion was detected before and after treatment; the clinical efficacy was evaluated after treatment and in the follow-up in the two groups. RESULTS: After treatment and in the follow-up, the scores of clinical symptom, VAS and WOMAC were decreased compared before treatment in both groups (P<0.05), and those in the combination group were lower than the warming acupuncture group (P<0.05). After treatment, the volume of suprapatellar bursa effusion was decreased compared before treatment in both groups (P<0.05). After treatment and in the follow-up, the total effective rates were 93.3% (28/30) and 86.7% (26/30) in the combination group, which were superior to 87.1% (27/31) and 74.2% (23/31) in the warming acupuncture group respectively (P<0.05). CONCLUSION: Governor vessel moxibustion combined with warming acupuncture can improve the clinical symptoms i.e. pain and dysfunction and reduce the volume of suprapatellar bursa effusion in KOA patients with yang deficiency and cold congelation, its short-term effect and long-term effect are both superior to simple warming acupuncture.

Prognosis and treatment pattern of advanced hepatocellular carcinoma after failure of first-line atezolizumab and bevacizumab treatment.

BACKGROUND: The combination of atezolizumab and bevacizumab (Atezo-Bev) has become the standard first-line therapy for patients with advanced hepatocellular carcinoma (HCC), but the prognosis and treatment pattern after its treatment failure are unclear. METHODS: We reviewed the medical records of patients who failed first-line Atezo-Bev treatment for advanced HCC from January 2018 to May 2021 in four Taiwan medical centers. Post-first-line survival (PFLS) was defined as the date from the failure of Atezo-Bev treatment to the date of death or last follow-up. RESULTS: A total of 41 patients were included in the study. All patients had Child-Pugh A liver reserve before the initiation of Atezo-Bev treatment, but the liver reserve of 6 (15%) and 7 (17%) patients deteriorated to Child-Pugh B and C, respectively, after treatment failure. The median PFLS was 5.9 months. PFLS significantly differed among patients with various liver reserves after the failure of Atezo-Bev treatment (median 9.6 vs 3.8 vs 1.2 months, for Child-Pugh A, B, and C; p < 0.001). In total, 30 (73%) patients received second-line systemic therapy, and they exhibited significantly longer PFLS (median 8.0 vs 1.8 months, p = 0.033) than patients who did not. Deteriorated liver function and not receiving second-line therapy remained associated with inferior PFLS in multivariate analysis. The most common second-line therapies were sorafenib (n = 19, 63%) and lenvatinib (n = 9, 30%), with no significant differences in efficacies. CONCLUSION: Receiving second-line therapy and good liver reserve were associated with favorable PFLS after the failure of first-line Atezo-Bev treatment.

CuS Nanoparticles-Loaded and Cisplatin Prodrug Conjugated Fe(III)-MOFs for MRI-Guided Combination of Chemotherapy and NIR-II Photothermal Therapy.

Ovarian cancer has become an urgent threat to global female healthcare. Cisplatin, as the traditional chemotherapeutic agent against ovarian cancer, retains several limitations, such as drug resistance and dose-limiting toxicity. In order to solve the above problems and promote the therapeutic effect of chemotherapy, combining chemotherapy and phototherapy has aroused wide interest. In this study, we constructed a versatile cisplatin prodrug-conjugated therapeutic platform based on ultrasmall CuS-modified Fe(III)-metal-organic frameworks (MIL-88) (named M-Pt/PEG-CuS) for tumor-specific enhanced synergistic chemo-/phototherapy. After intravenous injection, M-Pt/PEG-CuS presented obvious accumulation in tumor and Fe(III)-MOFs possessed magnetic resonance imaging (MRI) to guide synergy therapy. Both in vitro and in vivo experimental results showed that M-Pt/PEG-CuS could not only successfully inhibit tumor growth by combining chemotherapy and NIR-II PTT but also avoid the generation of liver damage by the direct treatment of cisplatin(II). Our work presented the development of the nanoplatform as a novel NIR-II photothermal agent, as well as gave a unique combined chemo-photothermal therapy strategy, which might provide new ways of ovarian cancer therapy for clinical translation.

Effects of Collagen Antibacterial Functional Dressing plus Continuous Nursing on Lower Extremity Skin Injury Caused by Norepinephrine in Patients with Septic Shock.

Background: This study was designed to explore the effects of collagen antibacterial functional dressing plus continuous care on norepinephrine-induced lower extremity skin injury in patients with septic shock. Methods: In this prospective, randomized, controlled study, 120 patients with septic shock receiving norepinephrine in our hospital from February 2020 to February 2021 were recruited. All the enrollments were randomized into the experimental group (n = 60) and the control group (n = 60). The control group received continuous care, while the experimental group additionally received collagen antibacterial functional dressing. Outcome measures included skin sensation scores, incidence of lower extremity skin injuries, recovery time, inflammatory factor levels, and care satisfaction. Results: Collagen antibacterial functional dressing plus continuous care resulted in significantly lower skin sensation scores and a lower incidence of skin injuries versus continuous care alone. Patients in the experimental group had faster recovery of lower extremity skin injury than those in the control group. Collagen antibacterial functional dressing plus continuous care was associated with significantly lower levels of inflammatory factors and a higher satisfaction rate than continuous care alone. Conclusion: Collagen antibacterial functional dressing plus continuous care improves the local skin condition of patients with septic shock receiving norepinephrine, regulates the levels of inflammatory factors, reduces the risk of skin injuries, and enhances care satisfaction.

[Effect of electroacupuncture on renal vascular microcirculation in diabetic mice based on in vivo two-photon microscopy imaging].

OBJECTIVE: To investigate the protective effect of electroacupuncture (EA) at "Zusanli"(ST36)and "Weiwanxiashu"(EX-B3) on capillary function around the renal tubule and renal tubule structure in diabetic mice based on two-photon microscopy (TPM) imaging, so as to providing visualizable evidence for the regulatory effect of EA on diabetic renal vascular microcirculation. METHODS: Spontaneous type Ⅱ diabetes mellitus mice (db/db) were employed for this study. Twenty db/db mice were randomly divided into model group (n=10) and EA group (n=10), and 10 db/m mice used as the control group. EA was applied to bilateral ST36 and EX-B3 for 20 min/time, 6 times a week for 6 weeks. The body weight was recorded and the fasting blood glucose measured before and after the intervention. The urine production and water consumption of mice in each cage were recorded after EA. The renal in vivo imaging method based on TPM was established to display the morphological structure of renal tubules, and the mouse renal blood flow velocity was detected by injecting 500 kDa dextran-fluorescein into femoral vein after the intervention. RESULTS: Compared with the control group, the proportion of mice with decreased body mass in the model group was increased, accounting for 40%, while that in the control group was 0%; and fasting blood glucose, urine production and water consumption were significantly increased in the model group (P<0.001, P<0.000 1). A renal in vivo imaging method based on TPM was successfully established, which can be applied to quantitatively analyze the renal blood flow and renal tubular diameter of mice. Based on this method, the results showed that compared with the control group, the blood flow velocity of peritubular capillary in the model group was significantly decreased (P<0.000 1, P<0.001), renal tubular cells were slightly exfoliated and the diameter of renal tubular was significantly increased (P<0.000 1). Compared with the model group, EA reduced the body weight loss ratio from 40% to 0%, and significantly decreased the fasting blood glucose, urine production and water consumption (P<0.01, P<0.000 1, P<0.001), and the blood flow velocity of peritubular capillary in the EA group was significantly increased (P<0.001, P<0.05) and tubule dilatation significantly alleviated (P<0.0 1). CONCLUSION: EA at ST36 and EX-B3 can ameliorate renal vascular microcirculation disorder to relieve the renal structure damage and improve renal function in diabetes mice.

Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism.

The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease-specific mechanisms due to a paucity of animal models. Here, we generated homozygous (Slc25a32Y174C/Y174C and Slc25a32K235R/K235R) and compound heterozygous (Slc25a32Y174C/K235R) knock-in mice by mimicking the missense mutations identified from our patient. A homozygous knock-out (Slc25a32-/-) mouse was also generated. The Slc25a32K235R/K235R and Slc25a32Y174C/K235R mice presented with mild motor impairment and recapitulated the biochemical disturbances of the patient. While Slc25a32-/- mice die in utero with NTDs. None of the Slc25a32 mutations hindered the mitochondrial uptake of folate. Instead, the mitochondrial uptake of flavin adenine dinucleotide (FAD) was specifically blocked by Slc25a32Y174C/K235R, Slc25a32K235R/K235R, and Slc25a32-/- mutations. A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency was observed. Besides the flavoenzymes involved in fatty acid ß-oxidation and amino acid metabolism being impaired, Slc25a32-/- embryos also had a subunit of glycine cleavage system-dihydrolipoamide dehydrogenase damaged, resulting in glycine accumulation and glycine derived-formate reduction, which further disturbed folate-mediated one-carbon metabolism, leading to 5-methyltetrahydrofolate shortage and other folate intermediates accumulation. Maternal formate supplementation increased the 5-methyltetrahydrofolate levels and ameliorated the NTDs in Slc25a32-/- embryos. The Slc25a32K235R/K235R and Slc25a32Y174C/K235R mice had no glycine accumulation, but had another formate donor-dimethylglycine accumulated and formate deficiency. Meanwhile, they suffered from the absence of all folate intermediates in mitochondria. Formate supplementation increased the folate amounts, but this effect was not restricted to the Slc25a32 mutant mice only. In summary, we established novel animal models, which enabled us to understand the function of SLC25A32 better and to elucidate the role of SLC25A32 dysfunction in human disease development and progression.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-glucoside Attenuates Reactive Oxygen Species-Dependent Inflammation and Apoptosis in Porphyromonas gingivalis-Infected Brain Endothelial Cells.

We recently reported that the periodontopathic bacteria Porphyromonas gingivalis (P. gingivalis) initiates an inflammatory cascade that disrupts the balance of reactive oxygen species (ROS), resulting in apoptotic cell death in brain endothelial cells. An extract from Polygonum multiflorum Thunb., 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-glucoside (THSG) has been well-reported to diminish the inflammation in many disease models. However, the effects of THSG in the area of the brain-oral axis is unknown. In this study, we examined the effects of THSG in P. gingivalis-stimulated inflammatory response and apoptotic cell death in brain endothelial cells. THSG treatment remarkably lessened the upregulation of IL-1ß and TNF-α proteins in bEnd.3 cells infected with P. gingivalis. Treatment of THSG further ameliorated brain endothelial cell death, including apoptosis caused by P. gingivalis. Moreover, the present study showed that the inhibitory effects on NF-κB p65 and antiapoptotic properties of THSG is through inhibiting the ROS pathway. Importantly, the ROS inhibitory potency of THSG is similar to a ROS scavenger N-Acetyl-L-Cysteine (NAC) and NADPH oxidase inhibitor apocynin. Furthermore, the protective effect of THSG from P. gingivalis infection was further confirmed in primary mouse brain endothelial cells. Taken together, this study indicates that THSG attenuates an ROS-dependent inflammatory response and cell apoptosis in P. gingivalis-infected brain endothelial cells. Our results also suggest that THSG could be a potential herbal medicine to prevent the risk of developing cerebrovascular diseases from infection of periodontal bacteria.

Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation.

BACKGROUND: Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4-(2-aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. RESULTS: ABS and PEG-NH2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. CONCLUSION: Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility.