Selective inhibition of overactive warmth-sensitive Ca2+-permeable TRPV3 channels by antispasmodic agent flopropione for alleviation of skin inflammation.

The temperature-sensitive Ca2+-permeable TRPV3 ion channel is robustly expressed in the skin keratinocytes, and its gain-of-function mutations are involved in the pathology of skin lesions. Here, we report the identification of an antispasmodic agent flopropione that alleviates skin inflammation by selective inhibition of TRPV3. In whole-cell patch clamp recordings, flopropione selectively inhibits macroscopic TRPV3 currents in a concentration-dependent manner with an IC50 value of 17.8 ± 3.5 µM. At the single-channel level, flopropione inhibits TRPV3 channel open probability without alteration of its unitary conductance. In an in vivo mouse model of skin inflammation induced by the skin sensitizer DNFB, flopropione also alleviates dorsal skin lesions and ear skin swelling. Further molecular docking combined with site-directed mutagenesis reveals that two residues E501 and I505 in the channel S2-helix are critical for flopropione-mediated inhibition of TRPV3. Taken together, our findings demonstrate that the spasmolytic drug flopropione as a selective inhibitor of TRPV3 channel not only provides a valuable tool molecule for understanding of TRPV3 channel pharmacology but also holds repurposing potential for therapy of skin disorders, such as dermatitis and pruritus.

Discovery of flavone-derivatives as the new skeleton of transient receptor potential vanilloid 3 channel antagonists.

Transient receptor potential vanilloid 3 (TRPV3) channel is a temperature-sensitive and Ca2+-permeable nonselective cation channel, which is abundantly expressed in skin keratinocyte and plays an important role in skin homeostasis and repair. However, only a few TRPV3 inhibitors were reported. Few selective and potent modulators of the TRPV3 channel have hindered the progress of the investigation and clinical application. TRPV3 channel research still faces challenges and requires the new inhibitors. Flavonoids are a kind of natural compounds with various biological and pharmacological activities including anti-inflammatory and anti allergic effects, which is associated with some physiological effects mediated by TRPV3 channel. Herein, our group designed and synthesized a range of flavone derivatives, and investigated their inhibitory properties on the human TRPV3 channel by electrophysiology technique. Then, we identified a new potent TRPV3 antagonist 2d with IC50 of 0.62 µM. It also showed good selectivity on TRPV1, TRPV4, TRPA1 and TRPM8.

Genome-Wide Identification and Expression Analysis of Kiwifruit Leucine-Rich Repeat Receptor-Like Proteins Reveal Their Roles in Biotic and Abiotic Stress Responses.

Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we performed family identification, characterization, transcriptome data analysis, and differential gene expression analysis of kiwifruit LRR-RLPs. We identified totals of 101, 164, and 105 LRR-RLPs in Actinidia chinensis 'Hongyang', Actinidia eriantha 'Huate', and Actinidia chinensis 'Red5', respectively. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Based on RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

Regulation of phagolysosomal activity by miR-204 critically influences structure and function of retinal pigment epithelium/retina.

MicroRNA-204 (miR-204) is expressed in pulmonary, renal, mammary and eye tissue, and its reduction can result in multiple diseases including cancer. We first generated miR-204-/- mice to study the impact of miR-204 loss on retinal and retinal pigment epithelium (RPE) structure and function. The RPE is fundamentally important for maintaining the health and integrity of the retinal photoreceptors. miR-204-/- eyes evidenced areas of hyper-autofluorescence and defective photoreceptor digestion, along with increased microglia migration to the RPE. Migratory Iba1+ microglial cells were localized to the RPE apical surface where they participated in the phagocytosis of photoreceptor outer segments (POSs) and contributed to a persistent build-up of rhodopsin. These structural, molecular and cellular outcomes were accompanied by decreased light-evoked electrical responses from the retina and RPE. In parallel experiments, we suppressed miR-204 expression in primary cultures of human RPE using anti-miR-204. In vitro suppression of miR-204 in human RPE similarly showed abnormal POS clearance and altered expression of autophagy-related proteins and Rab22a, a regulator of endosome maturation. Together, these in vitro and in vivo experiments suggest that the normally high levels of miR-204 in RPE can mitigate disease onset by preventing generation of oxidative stress and inflammation originating from intracellular accumulation of undigested photoreactive POS lipids. More generally, these results implicate RPE miR-204-mediated regulation of autophagy and endolysosomal interaction as a critical determinant of normal RPE/retina structure and function.

IL-6/STAT3-mediated autophagy participates in the development of age-related glomerulosclerosis.

The standard of age-related glomerulosclerosis is unclear. Both signal transducer and activator of transcription 3 (STAT3) and autophagy are involved in age-related kidney disease. Therefore, we aimed to explore the standard, as well as the potential mechanism(s). A total of 44 patients who underwent radical nephrectomy were enrolled. Pearson analysis was performed to investigate the parameters with ages. The patients were divided into the young- and aged-kidney groups. Kidney morphological changes were evaluated by histology staining, senescence was evaluated by senescence-associated-ß-galactosidase (SA-ß-gal) staining, and autophagosome was measured by transmission electron microscopy. Moreover, Western blot and/or immunohistochemistry were accomplished to assess the expression of p16, STAT3, and glycoprotein130 (GP130) and autophagy-related proteins. Furthermore, human glomerular mesangial cells were administrated with tocilizumab (TCZ) and/or IL-6, and then the above indexes were tested again. Sclerotic glomerular density and glomerular sclerosis rate were significantly higher in individuals more than 40 years old, and they were strongly correlated with ages. Moreover, the expression of p16, STAT3, GP130, and p62 was significantly increased, while LC3II and autophagosome were statistically decreased in the aged-kidney. Glomeruli were hardly to stain with SA-ß-gal. For the in vitro experiments, we observed that IL-6 significantly increased p16, STAT3, GP130, and p62, induced higher SA-ß-gal staining, while downregulated LC3II and autophagosome. Furthermore, TCZ statistically reversed the effects of IL-6 on the above expression of proteins. Glomerular sclerosis rate might be one standard for natural renal aging, and IL-6/STAT3-mediated autophagy may participate in the development of age-related glomerulosclerosis.

Natural Piperine Improves Lipid Metabolic Profile of High-Fat Diet-Fed Mice by Upregulating SR-B1 and ABCG8 Transporters.

Natural piperine from black pepper is known to function as hypocholesterolemic agent, but how it lowers the blood cholesterol remains unclear. In this study, we found that intragastric administrations of piperine (25 mg/kg/day) for 8 weeks significantly reduced the plasma triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice. H&E staining indicated that piperine significantly decreased hepatic lipid accumulation compared with the control group. The Oil Red O staining further showed that piperine attenuated lipid deposition in liver HepG2 cells in a concentration-dependent manner. Mechanistically, piperine treatment caused a significant upregulation of hepatic scavenger receptor B1 (SR-B1) in the liver and transporter protein of ATP binding cassette SGM8 (ABCG8) in the small intestine. Taken together, our findings demonstrate the role of natural piperine in improving lipid metabolic profile that is involved in the reverse cholesterol transport (RCT)-mediated mechanism through upregulation of SR-B1 in the liver and ABCG8 in the small intestine.

Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes.

BACKGROUND: Aberrant microRNA (miRNA) expression affects biologic processes and downstream genes that are crucial to CKD initiation or progression. The miRNA miR-204-5p is highly expressed in the kidney but whether miR-204-5p plays any role in the development of chronic renal injury is unknown. METHODS: We used real-time PCR to determine levels of miR-204 in human kidney biopsies and animal models. We generated Mir204 knockout mice and used locked nucleic acid-modified anti-miR to knock down miR-204-5p in mice and rats. We used a number of physiologic, histologic, and molecular techniques to analyze the potential role of miR-204-5p in three models of renal injury. RESULTS: Kidneys of patients with hypertension, hypertensive nephrosclerosis, or diabetic nephropathy exhibited a significant decrease in miR-204-5p compared with controls. Dahl salt-sensitive rats displayed lower levels of renal miR-204-5p compared with partially protected congenic SS.13BN26 rats. Administering anti-miR-204-5p to SS.13BN26 rats exacerbated interlobular artery thickening and renal interstitial fibrosis. In a mouse model of hypertensive renal injury induced by uninephrectomy, angiotensin II, and a high-salt diet, Mir204 gene knockout significantly exacerbated albuminuria, renal interstitial fibrosis, and interlobular artery thickening, despite attenuation of hypertension. In diabetic db/db mice, administering anti-miR-204-5p exacerbated albuminuria and cortical fibrosis without influencing blood glucose levels. In all three models, inhibiting miR-204-5p or deleting Mir204 led to upregulation of protein tyrosine phosphatase SHP2, a target gene of miR-204-5p, and increased phosphorylation of signal transducer and activator of transcription 3, or STAT3, which is an injury-promoting effector of SHP2. CONCLUSIONS: These findings indicate that the highly expressed miR-204-5p plays a prominent role in safeguarding the kidneys against common causes of chronic renal injury.

LncRNA ARAP1-AS2 promotes high glucose-induced human proximal tubular cell injury via persistent transactivation of the EGFR by interacting with ARAP1.

The persistent transactivation of epidermal growth factor receptor (EGFR) causes subsequent activation of the TGF-ß/Smad3 pathway, which is closely associated with fibrosis and cell proliferation in diabetic nephropathy (DN), but the exact mechanism of persistent EGFR transactivation in DN remains unclear. ARAP1, a susceptibility gene for type 2 diabetes, can regulate the endocytosis and ubiquitination of membrane receptors, but the effect of ARAP1 and its natural antisense long non-coding RNA (lncRNA), ARAP1-AS2, on the ubiquitination of EGFR in DN is not clear. In this study, we verified that the expression of ARAP1 and ARAP1-AS2 was significantly up-regulated in high glucose-induced human proximal tubular epithelial cells (HK-2 cells). Moreover, we found that overexpression or knockdown of ARAP1-AS2 could regulate fibrosis and HK-2 cell proliferation through EGFR/TGF-ß/Smad3 signalling. RNA pulldown assays revealed that ARAP1-AS2 directly interacts with ARAP1. Coimmunoprecipitation, dual-immunofluorescence and ubiquitination assays showed that ARAP1 may maintain persistent EGFR activation by reducing EGFR ubiquitination through competing with Cbl for CIN85 binding. Taken together, our results suggest that the lncRNA ARAP1-AS2 may promote high glucose-induced proximal tubular cell injury via persistent EGFR/TGF-ß/Smad3 pathway activation by interacting with ARAP1.

Hyperfunction of CD4 CD25 regulatory T cells in de novo acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a common hematopoietic malignancy that has a high relapse rate, and the number of regulatory T cells (Tregs) in AML patients is significantly increased. The aim of this study was to clarify the role of Tregs in the immune escape of acute myeloid leukemia. METHODS: The frequencies of Tregs and the expression of PD-1, CXCR4 and CXCR7 were examined by flow cytometry. The expression of CTLA-4 and GITR was tested by MFI. Chemotaxis assays were performed to evaluate Treg migration. The concentrations of SDF-1α, IFN-γ and TNF-α were examined by ELISA. Coculture and crisscross coculture experiments were performed to examine Treg proliferation and apoptosis and the effect of regulatory B cells (Breg) conversion. RESULTS: The frequencies of Tregs in peripheral blood and bone marrow in AML patients were increased compared with those in healthy participants. AML Tregs had robust migration towards bone marrow due to increased expression of CXCR4. AML Treg-mediated immunosuppression of T cells was achieved through proliferation inhibition, apoptosis promotion and suppression of IFN-γ production in CD4+CD25- T cells. AML Bregs induced the conversion of CD4+CD25-T cells to Tregs. CONCLUSION: In AML patients, the Breg conversion effect and robust CXCR4-induced migration led to Treg enrichment in bone marrow. AML Tregs downregulated the function of CD4+CD25- T cells, contributing to immune escape.

Inhibition of Ca2+ -activated chloride channel ANO1 suppresses ovarian cancer through inactivating PI3K/Akt signaling.

Most common ovarian cancers are epithelial carcinoma in which the etiology for carcinogenesis remains elusive. ANO1/TMEM16A, a member of Ca2+ -activated Cl- channels (CaCCs), has been demonstrated to promote epithelium-originated cancers and whether it plays a role in the pathogenesis of ovarian cancer is unknown. In our study we found that ANO1 proteins were overexpressed in human epithelial ovarian cancer cells and tissue samples. ANO1 protein upregulation was correlated with the clinical FIGO (International Federation of Gynecology and Obstetrics) staging and poor grade in ovarian cancer tissues. Interestingly, the upregulation of ANO1 gene expression was also detected in the peripheral blood mononuclear cells (PBMCs) from preoperative patients with ovarian tumors, and the down-regulation of ANO1 in the PBMCs from postoperative patients. Silencing of ANO1 inhibited proliferation and invasion of ovarian cancer cells. Mechanistically, ANO1 knockdown attenuated phosphorylation of PI3K/Akt, and inhibition of PI3K/Akt signaling by specific inhibitor LY294002 resulted in suppression of ovarian cancer cells growth promoted by ANO1 expression. Furthermore, intratumoral injection of ANO1 siRNA suppressed subcutaneous xenograft tumor growth in nude mice implanted with ovarian cancer SKOV3 cells. Taken together, our findings demonstrate that ANO1 overexpression is involved in the pathogenesis of human epithelial ovarian cancer. Inhibition of ANO1 upregulation or inactivating PI3K/Akt signaling may have therapeutic potential for epithelial ovarian cancer, and the detection of ANO1 expression level in PBMCs from patients may also serve as a biomarker for diagnosis and prognosis of epithelial ovarian cancers.

Inhibiting MicroRNA-503 and MicroRNA-181d with Losartan Ameliorates Diabetic Nephropathy in KKAy Mice.

BACKGROUND Diabetic nephropathy (DN) is the most lethal diabetic microvascular complication; it is a major cause of renal failure, and an increasingly globally prominent healthcare problem. MATERIAL AND METHODS To identify susceptible microRNAs for the pathogenesis of DN and the targets of losartan treatment, microRNA arrays were employed to survey the glomerular microRNA expression profiles of KKAy mice treated with or without losartan. KKAy mice were assigned to either a losartan-treated group or a non-treatment group, with C57BL/6 mice used as a normal control. Twelve weeks after treatment, glomeruli from the mice were isolated. MicroRNA expression profiles were analyzed using microRNA arrays. Real-time PCR was used to confirm the results. RESULTS Losartan treatment improved albuminuria and the pathological lesions of KKAy mice. The expression of 10 microRNAs was higher, and the expression of 12 microRNAs was lower in the glomeruli of the KKAy untreated mice than that of the CL57BL/6 mice. The expression of 4 microRNAs was down-regulated in the glomeruli of the KKAy losartan-treated mice compared to that of the untreated mice. The expression of miRNA-503 and miRNA-181d was apparently higher in the glomeruli of the KKAy untreated mice, and was inhibited by losartan treatment. CONCLUSIONS The over-expression of miR-503 and miR-181d in glomeruli of KKAy mice may be responsible for the pathogenesis of DN and are potential therapeutic targets for DN.

[Analysis of hemophilia case information of Shandong province].

OBJECTIVE: To summarize the general condition, regional distribution, prevalence and clinical characteristics of Shandong province based on hemophilia case registry information. METHODS: A retrospective study was carried out on 1979 hemophilia patients registered at Shandong Hemophilia Registration Center. RESULTS: The 1979 cases have included 1704 hemophilia A and 275 hemophilia B patients. Hemophilia A was characterized as severe in 1021 patients (59.9%), moderate in 483 patients (28.4%), and mild in 200 patients (11.7%); while hemophilia B was characterized as severe in 125 patients (45.4%), moderate in 116 patients (42.2%), and mild in 34 patients (12.4%). The median age was 23 years (ranging from 1 month to 81 years), and most were young patients. Joint deformity occurred in 963 patients, and 948 patients had a family history of hemophilia. All counties of Shandong province had patients except for Changdao county and Fushan district of Yantai city. The prevalence of Heze city and Dongying city (3.39/100 000 and 3.05/100 000, respectively) were relatively higher. CONCLUSION: The above data revealed epidemiological and clinical characteristics of Shandong Province. Patient-centered registry system allowed a more detailed and accurate patient information, and promoted the comprehensive care of hemophilia, which also suggested the necessity for the establishment and improvement of the National Hemophilia Registry System.

Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway.

The senolytics dasatinib and quercetin (DQ) alleviate age­related disorders. However, limited information is available regarding the effects of DQ on diabetic kidney disease (DKD). The present study aimed to explore the effects of DQ on DKD and its potential molecular mechanism(s). Dasatinib (5 mg/kg) and quercetin (50 mg/kg) were administered to diabetic db/db mice by gavage for 20 weeks. Body weight, urine albumin­creatinine ratio (ACR), serum creatinine (Scr), and blood urea nitrogen (BUN) were recorded at the indicated time periods. Periodic acid­Schiff and Masson's staining were performed to assess the histopathological changes of kidney tissues. Immunohistochemical analysis, immunofluorescence and western blotting were performed to evaluate the expression levels of extracellular matrix (ECM) proteins, autophagic and podocyte differentiation­related proteins. In addition, mouse podocytes were administered with high­glucose, DQ and 3­methyladenine (3­MA), and the expression levels of autophagic and podocyte differentiation­related proteins were measured. Moreover, following overexpression of the Notch intracellular domain (NICD), the expression levels of NICD, autophagic and podocyte differentiation­related proteins were further assessed. DQ significantly reduced the body weight, blood glucose, ACR, Scr and BUN levels and improved the histopathological changes induced in diabetic db/db mice. In addition, DQ caused a significant downregulation of the expression levels of the ECM proteins, improved autophagy and induced an upregulation of the expression levels of podocyte differentiation­related proteins. Administration of 3­MA to mice significantly reduced podocyte differentiation, and overexpression of NICD could reverse the effects of DQ on autophagy and podocyte differentiation in vitro. The present study suggests that DQ protects against DKD by activation of autophagy to alleviate podocyte dedifferentiation via the Notch pathway.

Hyperosmotic cold shock mouse melanoma cells encapsulated with doxorubicin for targeted treatment of melanoma.

Background: The primary treatment strategies for melanoma include surgical excision, chemotherapy, and radiotherapy. However, the efficacy of these treatments is often limited by drug resistance, recurrence, and severe side effects. Therefore, we aimed to develop a targeted drug delivery system capable of selectively locating tumor sites to minimize systemic toxicity and enhance therapeutic efficacy. This cell drug delivery system can also deliver chemotherapeutic drugs to the tumor microenvironment. Methods: We treated B16F10 cells with hyperosmotic cold shock (HCS) to obtain and characterize HCS cells. We then investigated the anti-tumor effects and immune activation capabilities of these cells and explored their potential as a targeted drug delivery system. Results: HCS cells not only maintained an intact cellular structure and tumor antigens but also exhibited high expression of the homologous melanoma-associated antigen glycoprotein 100. These cells demonstrated an exceptional capacity for loading and releasing doxorubicin, which has chemotherapeutic anti-tumor effects. HCS cells can precisely target the tumor microenvironment to minimize systemic toxicity, inducing an immune response by activating CD3+ and CD4+ T cells. Conclusion: HCS cells are non-carcinogenic, with both cellular and tumor antigens intact; thus, they are suitable drug delivery carriers. Our findings highlight the potential of HCS cells for carrying doxorubicin because of their high drug-loading efficiency, effective tumor-targeting and anti-tumor effects. Therefore, our results will facilitate the development of melanoma treatments that have higher efficacy than those in the literature.

Risk factors and long-term outcomes for human herpesvirus 6 encephalitis in the early period after allogeneic stem cell transplantation.

Human herpesvirus 6 (HHV6) encephalitis is a rare but life-threatening complication for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, reports on susceptibility factors and clinical outcomes are limited. We enrolled HHV6 encephalitis patients following allo-HSCT between 2018 and 2022, then conducted a 1:4 nested case-control cohort study to evaluate risk factors and long-term outcomes. Among 1350 patients, 20 (1.48%) developed HHV6 encephalitis, with a median onset time of 25.5 days after HSCT. Patient age<30 (odds ratio [OR], 3.24, P = 0.016) and NK cell count<115/ul at 21 days (OR, 6.07, P = 0.018) were identified as independent risk factors in multivariate analysis. Moreover, the HHV6 encephalitis group was significantly associated with higher incidence of grade II-IV graft-versus-host disease (aGVHD) (hazard ratio [HR], 5.52, P < 0.001) and transplant-associated microangiopathy (HR,9.86, P < 0.001), and demonstrated a significantly higher non-relapse mortality (NRM) (HR, 5.28, P = 0.004) and a lower overall survival (HR, 4.34, P = 0.001) or progression-free survival (HR, 3.94, P = 0.001) compared to control group. In conclusion, patients <30 years old or with delayed NK cell recovery are more susceptible to HHV6 encephalitis after allo-HSCT, and patients with HHV6 encephalitis after transplantation have poorer clinical outcomes.

Increased ascorbic acid synthesis by overexpression of AcGGP3 ameliorates copper toxicity in kiwifruit.

The widespread application of copper (Cu) -based fertilizers and pesticides could increase the accumulation of Cu in kiwifruit. According to a global survey, red- and yellow-fleshed kiwifruit contained more elevated amounts of Cu than green-fleshed kiwifruit due to weaker disease resistance and higher use of Cu pesticides. Intriguingly, our research revealed that external and endogenous ascorbic acid (AsA) reduced the phenotypic and physiological injury of Cu toxicity in kiwifruit. Cu stress assays and transcriptional analysis have shown that Cu treatment for 12 h significantly increased the AsA content in kiwifruit leaves and up-regulated key genes involved in AsA biosynthesis, such as GDP-L-galactose phosphorylase3 (GGP3) and GDP-mannose-3',5'-epimerase (GME). Overexpressing GGP3 in transgenic kiwifruit significantly increased the endogenous AsA content of kiwifruit, which was beneficial in mitigating Cu toxicity by decreasing levels of reactive oxygen species, malondialdehyde, and electrolyte leakage, as well as reducing damage to the chloroplast structure and photosystem II. This study presented a novel strategy to ameliorate plant Cu stress by increasing the endogenous antioxidant (AsA) content through transgenesis.

B16 Membrane-Coated Vesicles for Combined Photodynamic Therapy and Immunotherapy Shift Immune Microenvironment of Melanoma.

Introduction: Coating of nanomedicine with cell membranes has attracted increasing attention as it can boost biocompatibility and improve the efficiency of treatment. Herein, we prepared innovative tumor cell-membrane-coated vesicles based on photodynamic therapy (PDT) drug indocyanine green (ICG) and explore the effect on melanoma in vitro and in vivo. Methods: ICG was coated with B16 cell membranes (I@BM NVs) by sonication and extrusion, and the morphological characteristics of I@BM NVs were evaluated by transmission electron microscopy (TEM) and NP-tracking analysis. Homologous cellular uptake was evaluated by flow cytometry (FCM) after staining by DiD dye. Cellular cytotoxicity was evaluated by cell counting kit-8 assay and the anti-tumor effect in vitro was assessed by FCM and western blotting. The anti-tumor effect in vivo was evaluated in a B16 xenograft model in mice. The tumor micro-environment was investigated by FCM and real-time PCR. Results: The vesicles are stable and uniform in nature, and show strong homologous targeting in vivo and in vitro. The vesicles can generate reactive oxygen species to induce apoptosis of B16 cells under near-infrared irradiation. Furthermore, the I@BM NVs induce a significant anti-tumor response in vivo, and perform better with respect to both tumor growth inhibition and lifespan extension. Analysis of immunocytes in the tumor microenvironment showed significant reductions in numbers of myeloid-derived suppressor cells and tumor-associated M2 macrophages in mice in the I@BM NVs group. This was accompanied by significant increases in numbers of M1 macrophages and proliferative CD4+/CD8+ T cells. Expression levels of IFN-γ and IL-2 increased in the I@BM NVs group, while expression of TGF-ß and IL-10 decreased. Conclusion: The results show that the I@BM NVs are feasible drugs for the treatment of melanoma by inducing cell apoptosis under NIR and shifting the immunosuppressive tumor microenvironment in vivo.

Transcriptional mapping of the macaque retina and RPE-choroid reveals conserved inter-tissue transcription drivers and signaling pathways.

The macula and fovea comprise a highly sensitive visual detection tissue that is susceptible to common disease processes like age-related macular degeneration (AMD). Our understanding of the molecular determinants of high acuity vision remains unclear, as few model organisms possess a human-like fovea. We explore transcription factor networks and receptor-ligand interactions to elucidate tissue interactions in the macula and peripheral retina and concomitant changes in the underlying retinal pigment epithelium (RPE)/choroid. Poly-A selected, 100 bp paired-end RNA-sequencing (RNA-seq) was performed across the macular/foveal, perimacular, and temporal peripheral regions of the neural retina and RPE/choroid tissues of four adult Rhesus macaque eyes to characterize region- and tissue-specific gene expression. RNA-seq reads were mapped to both the macaque and human genomes for maximum alignment and analyzed for differential expression and Gene Ontology (GO) enrichment. Comparison of the neural retina and RPE/choroid tissues indicated distinct, contiguously changing gene expression profiles from fovea through perimacula to periphery. Top GO enrichment of differentially expressed genes in the RPE/choroid included cell junction organization and epithelial cell development. Expression of transcriptional regulators and various disease-associated genes show distinct location-specific preference and retina-RPE/choroid tissue-tissue interactions. Regional gene expression changes in the macaque retina and RPE/choroid is greater than that found in previously published transcriptome analysis of the human retina and RPE/choroid. Further, conservation of human macula-specific transcription factor profiles and gene expression in macaque tissues suggest a conservation of programs required for retina and RPE/choroid function and disease susceptibility.

Prognostic significance of ANO1 expression in cancers.

BACKGROUND: Anoctamin-1 (ANO1) plays a pivotal role in cancer progression. A meta-analysis was conducted to assess the potential prognostic role of ANO1 in cancers. METHODS: A total of 1760 patients from 7 eligible studies were included into the analysis. Pooled hazard ratios or odds ratios were extracted and calculated with a random-effects model, and analyses of heterogeneity bias were conducted. RESULTS: Our results showed that over expression of ANO1 was significantly correlated with poor overall survival in all cancers (HR = 1.52; 95% CI: 1.19-1.92; P = .0006). Subgroup analysis indicated that there was a significant association between over expression of ANO1 and poor prognosis breast cancer (HR = 3.24; 95% CI: 1.74-6.04), head and neck squamous cell carcinoma (HR = 1.14; 95% CI: 1.00-1.30), esophageal squamous cell carcinoma (HR = 1.93; 95% CI: 1.07-3.50), gastric cancer (HR = 1.62; 95% CI: 1.12-2.34) and colorectal cancer (HR = 1.38; 95% CI: 1.03-1.85). In addition, over expression of ANO1 was not associated with TNM stage, histological grade, lymph node metastasis, tumor size, age and gender. However, ANO1 was significantly associated with human epidermal growth factor receptor 2, but not associated with progesterone receptor or estrogen receptor in breast cancer. CONCLUSIONS: Our results indicate that ANO1 can be a predictive factor for prognosis of cancer.