Recent development of polymer nanomicelles in the treatment of eye diseases.

The eye, being one of the most intricate organs in the human body, hosts numerous anatomical barriers and clearance mechanisms. This highlights the importance of devising a secure and efficacious ocular medication delivery system. Over the past several decades, advancements have been made in the development of a nano-delivery platform based on polymeric micelles. These advancements encompass diverse innovations such as poloxamer, chitosan, hydrogel-encapsulated micelles, and contact lenses embedded with micelles. Such technological evolutions allow for sustained medication retention and facilitate enhanced permeation within the eye, thereby standing as the avant-garde in ocular medication technology. This review provides a comprehensive consolidation of ocular medications predicated on polymer nanomicelles from 2014 to 2023. Additionally, it explores the challenges they pose in clinical applications, a discussion intended to aid the design of future clinical research concerning ocular medication delivery formulations.

Case report: an initially unresectable stage III pulmonary sarcomatoid carcinoma qith EGFR mutation achieving pathological complete response following neoadjuvant therapy with osimertinib plus chemotherapy.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) provide dramatic response to patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, the use of neoadjuvant therapy with EGFR-TKIs in EGFR-mutant NSCLC remains controversial, especially in pulmonary sarcomatoid carcinoma (PSC). One patient with initially unresectable stage III (cT4N0M0) PSC was found to carry EGFR mutation by the next generation sequencing. After neoadjuvant therapy with osimertinib plus chemotherapy, radical resection of the right upper lung lesion was achieved, and the pathological results reached pathological complete response (pCR). To the best of our knowledge, this is the first report of an EGFR-mutant patient with initially unresectable stage III PSC achieved pCR by neoadjuvant therapy with osimertinib plus chemotherapy. Therefore, neoadjuvant therapy with EGFR-TKIs may be a viable option for EGFR-mutant PSC patients.

A tumor-associated autoantibody panel for the detection of non-small cell lung cancer.

Lung cancer is the second most frequent malignancy and the leading cause of cancer-associated death worldwide. Compared with patients diagnosed at advanced disease stages, early detection of lung cancer significantly improved the 5-year survival rate from 3.3% to 48.8%, which highlights the importance of early detection. Although multiple technologies have been applied to the screening and early diagnosis of lung cancer so far, some limitations still exist so they could not fully suit the needs for clinical application. Evidence show that autoantibodies targeting tumor-associated antigens(TAAs) could be found in the sera of early-stage patients, and they are of great value in diagnosis. Methods, we identified and screened TAAs in early-stage non-small cell lung cancer(NSCLC) samples using the serological analysis of recombinant cDNA expression libraries(SEREX). We measured the levels of the 36 autoantibodies targeting TAAs obtained by preliminary screening via liquid chip technique in the training set(332 serum samples from early-stage NSCLC patients, 167 samples from patients with benign lung lesions, and 208 samples from patients with no obvious abnormalities in lungs), and established a binary logistic regression model based on the levels of 8 autoantibodies to distinguish NSCLC samples. Results, We validated the diagnostic efficacy of this model in an independent test set(163 serum samples from early-stage NSCLC patients, and 183 samples from patients with benign lung lesions), the model performed well in distinguishing NSCLC samples with an AUC of 0.8194. After joining the levels of 4 serum tumor markers into its independent variables, the final model reached an AUC of 0.8568, this was better than just using the 8 autoantibodies (AUC:0.8194) or the 4 serum tumor markers alone(AUC: 0.6948). In conclusion, we screened and identified a set of autoantibodies in the sera of early-stage NSCLC patients through SEREX and liquid chip technique. Based on the levels of 8 autoantibodies, we established a binary logistic regression model that could diagnose early-stage NSCLC with high sensitivity and specificity, and the 4 conventional serum tumor markers were also suggested to be effective supplements for the 8 autoantibodies in the early diagnosis of NSCLC.

Development and Validation of Lactate Metabolism-Related lncRNA Signature as a Prognostic Model for Lung Adenocarcinoma.

Background: Lung cancer has been a prominent research focus in recent years due to its role in cancer-related fatalities globally, with lung adenocarcinoma (LUAD) being the most prevalent histological form. Nonetheless, no signature of lactate metabolism-related long non-coding RNAs (LMR-lncRNAs) has been developed for patients with LUAD. Accordingly, we aimed to develop a unique LMR-lncRNA signature to determine the prognosis of patients with LUAD. Method: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to derive the lncRNA expression patterns. Identification of LMR-lncRNAs was accomplished by analyzing the co-expression patterns between lncRNAs and LMR genes. Subsequently, the association between lncRNA levels and survival outcomes was determined to develop an effective signature. In the TCGA cohort, Cox regression was enlisted to build an innovative signature consisting of three LMR-lncRNAs, which was validated in the GEO validation cohort. GSEA and immune infiltration analysis were conducted to investigate the functional annotation of the signature and the function of each type of immune cell. Results: Fourteen differentially expressed LMR-lncRNAs were strongly correlated with the prognosis of patients with LUAD and collectively formed a new LMR-lncRNA signature. The patients could be categorized into two cohorts based on their LMR-lncRNA signatures: a low-risk and high-risk group. The overall survival of patients with LUAD in the high-risk group was considerably lower than those in the low-risk group. Using Cox regression, this signature was shown to have substantial potential as an independent prognostic factor, which was further confirmed in the GEO cohort. Moreover, the signature could anticipate survival across different groups based on stage, age, and gender, among other variables. This signature also correlated with immune cell infiltration (including B cells, neutrophils, CD4+ T cells, CD8+ T cells, etc.) as well as the immune checkpoint blockade target CTLA-4. Conclusion: We developed and verified a new LMR-lncRNA signature useful for anticipating the survival of patients with LUAD. This signature could give potentially critical insight for immunotherapy interventions in patients with LUAD.

Selection and optimization of nutritional risk screening tools for esophageal cancer patients in China.

BACKGROUND/OBJECTIVES: Malnutrition has multiple impacts on surgical success, postoperative complications, duration of hospital stay, and costs, particularly for cancer patients. There are various nutrition risk screening tools available for clinical use. Herein, we aim to determine the most appropriate nutritional risk screening system for esophageal cancer (EC) patients in China. SUBJECTS/METHODS: In total, 138 EC patients were enrolled in this study and evaluated by experienced nurses using three different nutritional screening tools, the Nutrition Risk Screening 2002 tool (NRS2002), the Patient-generated Subjective Globe Assessment (PG-SGA), and the Nutrition Risk Index (NRI).We compared sensitivity, specificity, positive and negative likelihood ratios, and Youden index generated by each of the three screening tools. Finally, cut-off points for all three tools were re-defined to optimize and validate the best nutritional risk screening tool for assessing EC patients. RESULTS: Our data suggested that all three screening tools were 100% sensitive for EC patients, while the specificities were 44.4%, 2.96%, and 59.26% for NRS 2002, PG-SGA, and NRI, respectively. NRI had a higher positive likelihood ratio as well as a higher area under the receiver operating characteristic curve compared to those of NRS 2002 and PG-SGA; although, all three tools had null negative likelihood ratios. After adjusting the cut-off points, the specificity and accuracy for all tools were significantly improved, however, the NRI remained the most appropriate nutritional risk screening system for EC patients. CONCLUSIONS: The NRI is the most suitable (highest sensitivity and accuracy) nutritional risk screening tool for EC patients. The performance of the NRI can be significantly improved if the cut-off point is modified according to the results obtained using MedCalc software.

LncRNA H19 promotes lung cancer proliferation and metastasis by inhibiting miR-200a function.

Lung cancer is the major cause leading to cancer mortality, and the 5-year survival rate for patients with lung cancer still remains low. It is urgent to fully understand the development and progression of lung cancer to discover new therapeutic targets and develop new therapeutic approaches. H19 was documented to be upregulated in lung cancer and related to cell proliferation. However, it is still unclear if H19 has other functions in lung cancer. The mRNA levels of genes were detected by qRT-PCR, and the cell proliferation rate and cell viability were measured through cell count assay and MTT assay. Transwell assays were applied to detect cell abilities to migration and invasion, while luciferase reporter assay and RNA pull-down assay were used to examine interaction between H19 and miR-200a. H19 expression was elevated in the lung cancer tissues and cell lines, while H19 overexpression promoted the lung cancer cell growth, cell migration and invasion, as well as the epithelial mesenchymal transition (EMT). Meantime, RNA pull-down assay showed that H19 interacted with miR-200a, and miR-200a inhibited the activity of H19-fused luciferase. Furthermore, H19 overexpression inhibited miR-200a function and thereby upregulated miR-200a target genes, ZEB1 and ZEB2.H19 sponged and inhibited miR-200a to de-repress expression of ZEB1 and ZEB2, and thereby enhanced lung cancer proliferation and metastasis.

Case report: Crizotinib is effective in a patient with ROS1-rearranged pulmonary inflammatory myofibroblastic tumor.

OBJECTIVES: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor and is prevalent among children and adolescents. In recent years, following the emergence of high-throughput sequencing techniques, rearrangements in genes, such as ALK, ROS1, NTRK, RET, and PDGFRß, have been detected in a considerable proportion of IMT patients. However, the practice of targeted therapy for those patients remains extremely limited. In this study, we report about a 14-year-old boy diagnosed with pulmonary IMT with a mass measuring 12 × 8 cm in the right lower lobe. MATERIALS AND METHODS: Immunohistochemistry (IHC) assay and comprehensive next-generation sequencing (NGS) were performed on the biopsied tumor tissue. RESULTS: The IHC assay revealed an ALK-negative tumor, while NGS detected aTFG-ROS1 rearrangement. The patient achieved continuous remission after treatment with crizotinib (250 mg, bid). CONCLUSION: This case broadens the experience regarding targeted therapy forROS1-rearranged IMT and supports the use of broad molecular profiling testing for optimizing therapeutic options.

Contraction-dependent TGF-ß1 activation is required for thrombin-induced remodeling in human airway smooth muscle cells.

AIMS: Thrombin is a serine proteinase that is not only involved in coagulation cascade, but also mediates a number of biological responses relevant to tissues repair, and induces bronchoconstriction. TGF-ß plays a pivotal role in airway remodeling due to its effects on airway smooth muscle proliferation and extracellular matrix (ECM) deposition. Recently, bronchoconstriction itself is found to constitute a form of strain and is highly relevant to asthmatic airway remodeling. However, the underlying mechanisms remain unknown. Here, we investigated the role of contraction- dependent TGF-ß activation in thrombin-induced remodeling in human airway smooth muscle (HASM) cells. MATERIALS AND METHODS: Primary HASM cells were treated with or without thrombin in the absence or presence of anti-TGF-ß antibody, cytochalasin D and formoterol. CFSE labeling index or CCK-8 assay were performed to test cell proliferation. RT-PCR and Western blotting were used to examined ECM mRNA level and collagen Iα1, α-actin protein expression, respectively. Immunofluorescence was also used to confirm contraction induced by thrombin in HASM cells. KEY FINDING: Thrombin stimulation enhanced HASM cells proliferation and activated TGF-ß signaling. Thrombin induced ECM mRNA and collagen Iα1 protein expression, and these effects are mediated by TGF-ß. Abrogation of TGF-ß activation by contraction inhibitors cytochalasin D and formoterol prevents the thrombin-induced effects. SIGNIFICANCE: These findings suggest that contraction-dependent TGF-ß activation could be a mechanism by which thrombin leads to the development of asthmatic airway remodeling. Blocking physical forces with bronchodilator would be an intriguing way in reducing airway remodeling in asthma.

Different functions of DEPTOR in modulating sensitivity to chemotherapy for esophageal squamous cell carcinoma.

There have been paradoxical findings regarding the expression of DEP domain-containing mTOR-interacting protein (DEPTOR) and its role in predicting prognosis in esophageal squamous cell carcinoma (ESCC). Here we show that DEPTOR expression was significantly increased in tumor tissues and predicted good survival in early stage ESCC patients but not in advanced stage patients. In vitro，our studies showed that ESCC cell lines could be classified into relatively high and low DEPTOR-expressing subgroups according to esophageal squamous epithelial cell line Het-1A.In our study, different levels of DEPTOR expression absolutely determined the response to chemotherapy. In relatively low-expressing cell lines, DEPTOR increased chemotherapy sensitivity via deactivation of the AKT pathway. In relatively high-expressing cell lines, DEPTOR increased cell survival and chemoresistance by strong feedback activation of the IRS1-PI3K-AKT-survivin pathway that occurred after downregulation of ribosomal protein S6 kinase (S6K). Collectively, our findings highlight the dichotomous nature of DEPTOR functions in modulating chemotherapy sensitivity in different ESCC cells.

Comparison of endoscopic submucosal tunneling dissection and thoracoscopic enucleation for the treatment of esophageal submucosal tumors.

BACKGROUND AND AIMS: Endoscopic submucosal tunneling dissection (ESTD) has been proved to be safe and effective for removal of esophageal submucosal tumors (SMTs) and can maintain the mucosal integrity compared with other endoscopic methods. The aim of the study was to estimate the safety and efficacy of ESTD as well as compare its efficacy with thoracoscopic enucleation for esophageal SMTs, which is used increasingly as a minimally invasive approach. METHODS: We retrospectively collected the clinical data of patients with esophageal SMTs <40 mm who underwent ESTD or thoracoscopic enucleation at Nanfang Hospital between January 2008 and August 2016. Epidemiologic data (sex, age), tumor location, tumor size, en bloc resection rate, adverse events, pathologic results, length of postoperative hospital stay, and cost were compared between ESTD and thoracoscopic enucleation. RESULTS: A total of 126 patients were included. A total of 74 patients underwent ESTD, and the other 52 underwent thoracoscopic enucleation. There was no significant difference between the 2 groups in sex, age, tumor size, hospitalization expense, infection, adverse events, and en bloc resection rate (P < .05). However, patients in the ESTD group had a shorter operating time, less estimated blood loss, shorter length of postoperative hospital stay, and lower chest pain level (P < .05). Kaplan-Meier curves for disease-free survival also showed no statistically significant difference between ESTD and thoracoscopic enucleation groups during the median follow-up of 19.5 and 42 months, respectively. CONCLUSIONS: The treatment efficacy was comparable between the ESTD and thoracoscopic enucleation for esophageal SMTs <40 mm. However, there was a significant advantage in the ESTD group for a shorter operating time, reduced postoperative chest pain, and shorter hospitalization.

[A meta-analysis of platinum plus docetaxel or vinorelbine in the first-line treatment of advanced non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: Platinum plus a third-generation agent doublet chemotherapy is the standard regimen and first-line chemotherapy for the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy and safety of docetaxel plus platinum (DP) compared with vinorelbine plus platinum (VP) regimens in patients with advanced NSCLC. METHODS: We searched the PubMed, EMBASE, Cochrane Library, CNKI, CBM, VIP, and WanFang databases for randomized controlled trials (RCTs), in which DP regimen was compared with VP regimen. A quality assessment of qualified RCTs was performed according to Cochrane Handbook 5.1.0, and Stata 12.0 was used to perform meta-analysis. RESULTS: Seven RCTs involving 2,318 patients were included. Meta-analysis results indicated that the DP regimen increased the two-year survival rate (HR=0.887, 95%CI: 0.810-0.972, P=0.010), response rate (RR=1.276, 95%CI: 1.107 -1.450, P=0.001), and diarrhea rate (RR=3.134, 95%CI: 1.918-5.121, P<0.001) compared with the VP regimen. Anemia rate was also reduced (RR=0.386, 95%CI: 0.311-0.478, P<0.001). No statistical differences were observed between DP and VP regimens in terms of one-year survival rate, leukopenia, neutropenia, thrombocytopenia, anorexia, nausea, and vomiting. CONCLUSIONS: DP regimen reduced the rate of anemia and increased the rate of diarrhea, two-year survival rate, and response rate. Therefore, DP regimen may be a more effective option as a first-line treatment for advanced NSCLC compared with VP regimen.

Unidirectionally progressive resection of left upper pulmonary lobe under video-assisted thoracoscopy.

The case is a nodule in the upper left lobe, and intraoperative frozen section pathological diagnosis on the removed nodule confirmed well differentiated mucinous adenocarcinoma. Unidirectionally progressive resection of the left upper pulmonary lobe under video-assisted thoracoscopy is selected as the surgical method. Right below the operation hole, surgeons gradually advanced in one direction, and dissociated and divided in such order: the upper left pulmonary vein, the upper left lobe bronchus, the upper left pulmonary arterial branches and the fissures. Endoscopic linear cutters and hem-o-lok clip applicator were used to deal with the blood vessels, bronchus, and under-differentiated fissures. At last, the removed upper left lobe was put into a size eight sterile glove and taken out through the main operation hole. General anesthesia with double-lumen endotracheal intubation is used. The patient took a 90 degree decubitus on his contralateral side. The surgeons were on the ventral side of the patient, and operated with endoscope apparatus under the monitor.

Complete thoracoscopic lobectomy and mediastinal lymph node dissection.

To evaluate the complete thoracoscopic lower right lobectomy and mediastinal lymph node. During the surgery, the lower right pulmonary artery and vein, bronchi and lymph nodes were treated using a unidirectional approach. Eight stations (2, 3, 4, 7, 8, 9, 10 and 11) of lymph nodes were dissected completely en bloc. Repeated stretch and flipping was avoided in this procedure, which was beneficial for the unaffected side of the lung. The operation of lymph node dissection was completed thoroughly in accordance with standard principles.

Unidirectionally progressive resection of lower right lung cancer under video-assisted thoracoscopy.

UNLABELLED: The surgery is performed under general anesthesia with double-lumen endotracheal intubation. The patient is placed in a 90-degree position lying on the unaffected side. An approximately 1.5-cm observation port is created in the 7th intercostal space between the middle and anterior axillary lines, an approximately 4-cm working port in the 4th intercostal space between the anterior axillary line and the midclavicular line, and an approximately 1.5-cm auxiliary port in the 9th intercostal space between the posterior axillary line and the subscapular line. The operator stands in front of the patient, manipulating the endoscopic instruments while watching the monitor. SURGICAL PROCEDURE: since the patient has right lower lung cancer, a unidirectional procedure is adopted for the surgery, in which the layers of structure are treated one after another until the fissure from a single direction through the working port. Hence, the pulmonary vein, bronchi, pulmonary artery and the poorly developed fissure of the right lower lobe are treated successively during lobectomy. The vessels, bronchi and fissures are cut using an endoscopic linear stapler or the Hemolock clips. The resected lobe is placed into a size 8 sterile glove and retrieved through the working port to prevent contamination of the chest incision by any tumor tissue. Mediastinal lymph node dissection is performed at the end.

Overexpression of microRNA-1 causes atrioventricular block in rodents.

The present study was designed to investigate whether microRNAs (miRNAs) are involved in atrioventricular block (AVB) in the setting of myocardial ischemia (MI). A cardiac-specific miR-1 transgenic (Tg) mouse model was successfully established for the first time in this study using microinjection. miR-1 level was measured by real-time qRT-PCR. Whole-cell patch clamp was employed to record L-type calcium current (I Ca,L) and inward rectifier K(+) current (I K1). Expression of connexin 43 (Cx43) protein was determined by western blot analysis. Alternations of [Ca(2+)]i was detected by laser scanning confocal microscopy in ventricular myocytes. The incidence of AVB was higher in miR-1 Tg mice than that in wild-type (WT) mice. The normalized peak current amplitude of I Ca,L was lower in ventricular myocytes from miR-1 Tg mice as compared with WT mice. Similarly, the current density of I K1 was decreased in miR-1 Tg mice than that in WT mice. Compared with WT mice, miR-1 Tg mice exhibited a significant decrease of the systolic [Ca(2+)]i in ventricular myocytes but a prominent increase of the resting [Ca(2+)]i. Moreover, Cx43 protein was downregulated in miR-1 Tg mice compared to that in WT mice. Administration of LNA-modified antimiR-1 reversed all the above changes. miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias.

Inhibition of angiotensin II-induced contraction of human airway smooth muscle cells by angiotensin-(1-7) via downregulation of the RhoA/ROCK2 signaling pathway.

Sustained renin-angiotensin system (RAS) activation in asthmatic patients plays a crucial role in airway hyperresponsiveness and airflow limitation. Angiotensin II (Ang II), as a key peptide of RAS, contributes to the contraction of human airway smooth muscle by activating the RhoA/Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathway. Angiotensin-(1-7) [Ang-(1-7)], is a component of the angiotensin I converting enzyme 2 (ACE2)-Ang-(1-7)-Mas axis which counteracts the detrimental effects of the ACE- Ang II-angiotensin type 1 receptor (AT1R) axis in vivo; however, whether Ang-(1-7) can inhibit the effect of Ang II in the contraction of human airway smooth muscle cells (HASMCs) is unknown. In our study, collagen gel lattices and immunofluorescence were used to evaluate the contraction of HASMCs induced by Ang II. Real-time PCR and western blot analysis were performed to confirm the regulatory mechanism and the participating signaling pathway. Ang II caused the contraction of HASMCs; this effect was reversed by Ang­(1­7). In addition, irbesartan and A779, which are inhibitors of AT1R and Mas, respectively, attenuated the effect of Ang II and Ang-(1-7). Furthermore, Y-27632, an inhibitor of ROCK2, attenuated the Ang II-induced contraction of HASMCs by blocking the RhoA/ROCK2 signaling pathway which is involved in this contraction, and thus may be a major regulator involved in the basal maintenance of contractility in HASMCs. These data demonstrate that Ang II induces the contraction of HASMCs and that this effect can be reversed by Ang-(1-7), partially through the downregulation of of the RhoA/ROCK2 signaling pathway.

[Thoraco laparoscopic esophagectomy versus open esophagectomy: a meta-analysis of outcomes].

OBJECTIVE: To evaluate the outcomes of thoraco laparoscopic esophagectomy venus open esophagectomy for esophageal cancer. METHODS: Literature search was performed using PubMed, Embase, Cochrane Library, and Google Scholar databases, CBM, and CNKI from inception to July 2011 for comparative studies assessing thoraco laparoscopic esophagectomy and open esophagectomy. Data were extracted and evaluated by two reviewers independently according to the Cochrane Handbook for Systematic Reviews. Meta-analyses were conducted using RevMan 5.1. RESULTS: A total of 10 studies involving 1017 patients were included for the analysis. Four hundred and fifty-five patients underwent thoraco laparoscopic esophagectomy and 562 patients underwent open esophagectomy. There were no significant differences between the two groups in anastomotic leak, 30-day mortality, and number of lymph node retrieved(P>0.05). However, thoraco laparoscopic esophagectomy had lower blood loss, less operative time, and reduced respiratory complications(P<0.05). There were no significant differences between the two groups in overall complications, cardiac complications, anastomotic stricture, recurrent laryngeal nerve injury, length of stay, ICU stay, and 3-year survival(all P>0.05). CONCLUSION: Thoraco laparoscopic esophagectomy for esophageal cancer is feasible and safe as open esophagectomy.

[Video-assisted thoracoscopic removal of esophageal leiomyomas with intraoperative tumor location by endoscopy].

OBJECTIVE: To summarize our experience with video-assisted thoracoscopic (VATS) removal of esophageal leiomyoma located with endoscopy during operation. METHODS: Between January 2006 and December 2010, 55 patients with esophageal leiomyoma underwent VATS enucleation. The surgical procedure was similar to that of open thoracotomy with intraoperative endoscopic location of the tumor and examination of the mucosal integrity especially for tumors less than 1 cm in diameter. RESULTS: Of the 55 patients undergoing VATS tumor removal, 54 patients completed the procedures smoothly, and 1 patient experienced ventricular fibrillation during the operation to require an open thoracotomy. Endoscopy was used in 38 patients during the operation. VATS enucleation differed significantly from open thoracotomy in the volume of bleeding, postoperative fasting days and postoperative hospital stay (P<0.05). The symptoms were completely relieved after the operation without postoperative complications. The patients were followed up for 8 to 59 months (mean 23.0 months) and no recurrence was found. CONCLUSION: VATS removal of esophageal leiomyomas is minimally invasive, safe and effective and can serve as the primary option for surgical removal of esophageal leiomyomas.

Mild hypoxia-induced cardiomyocyte hypertrophy via up-regulation of HIF-1α-mediated TRPC signalling.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a central transcriptional regulator of hypoxic response. The present study was designed to investigate the role of HIF-1α in mild hypoxia-induced cardiomyocytes hypertrophy and its underlying mechanism. Mild hypoxia (MH, 10% O(2)) caused hypertrophy in cultured neonatal rat cardiac myocytes, which was accompanied with increase of HIF-1α mRNA and accumulation of HIF-1α protein in nuclei. Transient receptor potential canonical (TRPC) channels including TRPC3 and TRPC6, except for TRPC1, were increased, and Ca(2+)-calcineurin signals were also enhanced in a time-dependent manner under MH condition. MH-induced cardiomyocytes hypertrophy, TRPC up-regulation and enhanced Ca(2+)-calcineurin signals were inhibited by an HIF-1α specific blocker, SC205346 (30 µM), whereas promoted by HIF-1α overexpression. Electrophysiological voltage-clamp demonstrated that DAG analogue, OAG (30 µM), induced TRPC current by as much as 170% in neonatal rat cardiomyocytes overexpressing HIF-1α compared to negative control. These results implicate that HIF-1α plays a key role in development of cardiac hypertrophy in responses to hypoxic stress. Its mechanism is associated with up-regulating TRPC3, TRPC6 expression, activating TRPC current and subsequently leading to enhanced Ca(2+)-calcineurin signals.