Correlation between RNA N6-methyladenosine and ferroptosis in cancer: current status and prospects.

N6-methyladenosine (m6A) is the most abundant chemical modification in eukaryotic cells. It is a post-transcriptional modification of mRNA, a dynamic reversible process catalyzed by methyltransferase, demethylase, and binding proteins. Ferroptosis, a unique iron-dependent cell death, is regulated by various cell metabolic events, including many disease-related signaling pathways. And different ferroptosis inducers or inhibitors have been identified that can induce or inhibit the onset of ferroptosis through various targets and mechanisms. They have potential clinical value in the treatment of diverse diseases. Until now, it has been shown that in several cancer diseases m6A can be involved in the regulation of ferroptosis, which can impact subsequent treatment. This paper focuses on the concept, function, and biological role of m6A methylation modification and the interaction between m6A and ferroptosis, to provide new therapeutic strategies for treating malignant diseases and protecting the organism by targeting m6A to regulate ferroptosis.

Solamargine improves the therapeutic efficacy of anti-PD-L1 in lung adenocarcinoma by inhibiting STAT1 activation.

OBJECTIVE: The effect of solamargine on lung adenocarcinoma and its effect on STAT1 signaling pathway mediated immune escape were studied through network pharmacology and in vitro and in vivo experiments. METHODS: The solamargine targets were screened using the TCMSP and the LUAD targets were screened using the GeneCard, OMIM, PharmGkb, TTD and DrugBank databases. PPI network analysis and target prediction were performed using GO and KEGG. Colony formation assay, EDU staining, wound healing, transwell assay, Hoechst and flow cytometry were used to detect the effects of solamargine on the proliferation, migration and apoptosis of LUAD. Western blotting (WB) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect P-STAT1 and PD-L1 expression. And immunofluorescence was used to detect P-STAT1 expression. In vivo experiments, C57BL/6 mice were divided into control group, low concentration group, high concentration group, positive control group and combination group. Every other day, following seven consecutive doses, the size of the tumor was assessed. Finally, the expressions of P-STAT1, STAT1, PD-L1 and apoptosis index proteins were detected by WB. RESULTS: The anti-LUAD effect of solamargine was found by wound healing, colony formation assay, transwell assay, hoechst and EdU staining. The results of network pharmacological analysis showed that solamargine could suppress STAT1 expression level. Further enrichment assay of STAT1 showed that STAT1 was associated with immune-related pathways. In addition, molecular signal analysis by WB and RT-qPCR indicated that solamargine could reduce the expression levels of P-STAT1 and PD-L1 in a concentration-dependent manner. According to the results of in vivo assays, combination of solamargine and immune checkpoint inhibitors (ICIs) durvalumab could significantly inhibit the growth of Lewis transplanted tumors in C57BL/6 mice, and no toxic side effect was recoded. CONCLUSION: These results indicated that solamargine could inhibit the proliferation and promote the apoptosis of LUAD. It also could reduce the expression level of P-STAT1 protein and inhibit the expression level of PD-L1. At the same time, the combination with the ICIs can better block the expression of PD-L1 in cells, thereby inhibiting the immune escape pathway of tumor cells and achieving anti-tumor effects. This study proposed a novel combined therapeutic approach, involving the inhibition of STAT1 by solamargine in conjunction with ICIs.

Optimized fuzzy K-nearest neighbor approach for accurate lung cancer prediction based on radial endobronchial ultrasonography.

Radial endobronchial ultrasonography (R-EBUS) has been a surge in the development of new ultrasonography for the diagnosis of pulmonary diseases beyond the central airway. However, it faces challenges in accurately pinpointing the location of abnormal lesions. Therefore, this study proposes an improved machine learning model aimed at distinguishing between malignant lung disease (MLD) from benign lung disease (BLD) through R-EBUS features. An enhanced manta ray foraging optimization based on elite perturbation search and cyclic mutation strategy (ECMRFO) is introduced at first. Experimental validation on 29 test functions from CEC 2017 demonstrates that ECMRFO exhibits superior optimization capabilities and robustness compared to other competing algorithms. Subsequently, it was combined with fuzzy k-nearest neighbor for the classification prediction of BLD and MLD. Experimental results indicate that the proposed modal achieves a remarkable prediction accuracy of up to 99.38%. Additionally, parameters such as R-EBUS1 Circle-dense sign, R-EBUS2 Hemi-dense sign, R-EBUS5 Onionskin sign and CCT5 mediastinum lymph node are identified as having significant clinical diagnostic value.

Long Noncoding RNA ZBED5-AS1 Facilitates Tumor Progression and Metastasis in Lung Adenocarcinoma via ZNF146/ATR/Chk1 Axis.

Long noncoding RNAs (lncRNAs) have been implicated in tumorigenesis, including lung adenocarcinoma (LUAD). However, the functional and regulatory mechanisms of lncRNAs in LUAD remain poorly understood. In this study, we investigated the role of lncRNA ZBED5-AS1 in LUAD. We found that ZBED5-AS1 was upregulated in LUAD specimens and overexpressed in LUAD cell lines. ZBED5-AS1 promoted LUAD cell proliferation, migration, and invasion in vitro and promoted LUAD cell growth in vivo. ZBED5-AS1 promoted ZNF146 expression, activating the ATR/Chk1 pathway and leading to LUAD progression. We observed that exosomes from LUAD cells have a higher expression of ZBED5-AS1 compared with exosomes from the normal cell line BEAS-2B. Coculture experiments with exosomes showed that ZBED5-AS1 expression was downregulated after coculture with Si-ZBED5-AS1 exosomes, and coculture with exosomes with low ZBED5-AS1 expression inhibited proliferation and invasion of LUAD cells. Our results indicate that ZBED5-AS1 functions as an oncogenic factor in LUAD cells by targeting the ZNF146/ATR/Chk1 axis.

GPR37 promotes cancer growth by binding to CDK6 and represents a new theranostic target in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is associated with poor prognosis. Identifying novel cancer targets and helpful therapeutic strategies remains a serious clinical challenge. This study detected differentially expressed genes in The Cancer Genome Atlas (TCGA) LUAD data collection. We also identified a predictive DNA biomarker, G protein-coupled receptor 37 (GPR37), which was verified as a prognostic biomarker with a critical role in tumor progression. In human LUAD specimens and microarray analyses, we determined that GPR37 was significantly upregulated and associated with a poor prognosis. GPR37 downregulation markedly inhibited the proliferation and migration of LUAD both in vitro and in vivo. Mechanistically, GPR37 could bind to CDK6, thereby facilitating tumor progression in LUAD by inducing cell cycle arrest at the G1 phase. GPR37 also facilitates tumorigenesis in xenograft tumors in vivo. High-throughput screening for GPR37-targeted drugs was performed using the Natural Products Library, which revealed the potential of Hypocrellin B to inhibit GPR37 and cell growth in LUAD. We demonstrated that Hypocrellin B suppressed LUAD cell proliferation and migration both in vitro and in vivo via GPR37 inhibition. Collectively, our findings reveal the role of GPR37 in LUAD progression and migration and the potential of GPR37 as a target for the treatment of LUAD. Thus, the specific inhibition of GPR37 by the natural product Hypocrellin B may possess the potential for the treatment of LUAD.

Tuberculous pleural effusion prediction using ant colony optimizer with grade-based search assisted support vector machine.

Introduction: Although tuberculous pleural effusion (TBPE) is simply an inflammatory response of the pleura caused by tuberculosis infection, it can lead to pleural adhesions and cause sequelae of pleural thickening, which may severely affect the mobility of the chest cavity. Methods: In this study, we propose bGACO-SVM, a model with good diagnostic power, for the adjunctive diagnosis of TBPE. The model is based on an enhanced continuous ant colony optimization (ACOR) with grade-based search technique (GACO) and support vector machine (SVM) for wrapped feature selection. In GACO, grade-based search greatly improves the convergence performance of the algorithm and the ability to avoid getting trapped in local optimization, which improves the classification capability of bGACO-SVM. Results: To test the performance of GACO, this work conducts comparative experiments between GACO and nine basic algorithms and nine state-of-the-art variants as well. Although the proposed GACO does not offer much advantage in terms of time complexity, the experimental results strongly demonstrate the core advantages of GACO. The accuracy of bGACO-predictive SVM was evaluated using existing datasets from the UCI and TBPE datasets. Discussion: In the TBPE dataset trial, 147 TBPE patients were evaluated using the created bGACO-SVM model, showing that the bGACO-SVM method is an effective technique for accurately predicting TBPE.

Neobavaisoflavone Demonstrates Valid Anti-tumor Effects in Non-Small- Cell Lung Cancer by Inhibiting STAT3.

AIM AND OBJECTIVE: Lung cancer is the most commonly occurring cancer, which contributes to the majority of death caused by cancer, where non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. To treat NSCLC, STAT3 has been identified as a target with therapeutic potential. The neobavaisoflavone (NBIF) is one of the flavonoids of traditional Chinese medicine Psoralea corylifolial. MATERIALS AND METHODS: Human NSCLC cell lines, PC-9, H460, and A549, were applied to determine NBIF's anti-proliferative effects through cell viability and colony formation detection. The effect of NBIF on cell apoptosis was determined through flow cytometry-based assay. Western blotting was used in this study to confirm the levels of P-STAT3, Bcl-2, and Bax, which are apoptotic proteins. RESULTS: It was observed that NBIF could decrease the cell viability and its migration and induce apoptosis in human NSCLC cell lines dose-dependently. Levels of P-STAT3, as well as the downstream signals of the STAT3 pathway, were downregulated, suggesting that the tumorsuppression effects of NBIF might be related to the inhibition of STAT3 signaling. Furthermore, NBIF could contribute to the upregulation of BAX and downregulation of BCL2. CONCLUSION: NBIF might perform the anti-NSCLC efficacy as a result of the inhibition of the STAT3 pathway. Besides, our work suggests that NBIF could provide therapeutic alternatives for NSCLC.

An Effective Machine Learning Approach for Identifying Non-Severe and Severe Coronavirus Disease 2019 Patients in a Rural Chinese Population: The Wenzhou Retrospective Study.

This paper has proposed an effective intelligent prediction model that can well discriminate and specify the severity of Coronavirus Disease 2019 (COVID-19) infection in clinical diagnosis and provide a criterion for clinicians to weigh scientific and rational medical decision-making. With indicators as the age and gender of the patients and 26 blood routine indexes, a severity prediction framework for COVID-19 is proposed based on machine learning techniques. The framework consists mainly of a random forest and a support vector machine (SVM) model optimized by a slime mould algorithm (SMA). When the random forest was used to identify the key factors, SMA was employed to train an optimal SVM model. Based on the COVID-19 data, comparative experiments were conducted between RF-SMA-SVM and several well-known machine learning algorithms performed. The results indicate that the proposed RF-SMA-SVM not only achieves better classification performance and higher stability on four metrics, but also screens out the main factors that distinguish severe COVID-19 patients from non-severe ones. Therefore, there is a conclusion that the RF-SMA-SVM model can provide an effective auxiliary diagnosis scheme for the clinical diagnosis of COVID-19 infection.

Titin Mutation Is Associated With Tumor Mutation Burden and Promotes Antitumor Immunity in Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LUSC) is a leading cause of mobidity and mortality worldwide. Recently, there was a shift in the treatment pattern of immune therapy in LUSC patients; merely a small number of patients with non-small cell lung cancer (NSCLC) at advanced stages respond well to immune checkpoint blockade (ICB) therapy, and tumor mutation burden (TMB) is a valuable independent indicator of response to immune therapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immunocytes in LUSC are still unclear. In the present paper, our team analyzed the somatically mutated genes from the ICGC (International Cancer Genome Consortium) and TCGA (The Cancer Genome Atlas) datasets and discovered that 15 frequent gene mutations occurred in both cohorts, including ZFHX4, MUC16, FLG, TP53, LRP1B, TTN, SYNE1, RYR2, CSMD3, USH2A, MUC17, DNAH5, FAM135B, COL11A1, and RYR3. Interestingly, only mutated TTN was related to higher TMB and prognostic outcomes among the 15 mutated genes. Moreover, according to the CIBERSORT algorithm, we revealed that TTN mutation enhanced the antitumor immune response. In conclusion, TTN may have important clinical implications for relevant immune therapy of lung squamous carcinoma.

Flubendazole Elicits Antitumor Effects by Inhibiting STAT3 and Activating Autophagy in Non-small Cell Lung Cancer.

Non-small cell lung carcinoma (NSCLC) is a major neoplastic disease with a high mortality worldwide; however, effective treatment of this disease remains a challenge. Flubendazole, a traditional anthelmintic drug, possesses potent antitumor properties; however, the detailed molecular mechanism of flubendazole activity in NSCLC needs to be further explored. In the present study, flubendazole was found to exhibit valid antitumor activity in vitro as well as in vivo. Flubendazole blocked phosphorylation of STAT3 in a dose- and time-dependent manner and regulated the transcription of STAT3 target genes encoding apoptotic proteins. Further, flubendazole inhibited STAT3 activation by inhibiting its phosphorylation and nuclear localization induced by interleukin-6 (IL-6). Notably, the autophagic flux of NSCLC cell lines was increased after flubendazole treatment. Furthermore, flubendazole downregulated the expression of BCL2, P62, and phosphorylated-mTOR, but it upregulated LC3-I/II and Beclin-1 expression, which are the main genes associated with autophagy. Collectively, these data contribute to elucidating the efficacy of flubendazole as an anticancer drug, demonstrating its potential as a therapeutic agent via its suppression of STAT3 activity and the activation of autophagy in NSCLC.

Erratum: Astaxanthin prevents against lipopolysaccharide-induced acute lung injury and sepsis via inhibiting activation of MAPK/NF-κB.

[This corrects the article on p. 1884 in vol. 11, PMID: 30972212.].

L6H9 attenuates LPS-induced acute lung injury in rats through targeting MD2.

Acute lung injury (ALI) is a clinical syndrome characterized by respiratory failure and acute inflammatory response. Myeloid differentiation protein 2 (MD2) has been reported to play a pivotal role in the recognition of LPS and LPS-mediates inflammatory response. There have been no clinically effective therapeutic drugs for ALI. L6H9, an inhibitor of MD2, showed anti-inflammatory effects and cardiac protective activity. However, its effect on ALI has not been elucidated. In this study, intratracheal instillation of LPS was employed to induce ALI in rats. L6H9 pretreatment attenuates LPS-induced pathological variations in lung tissue and pulmonary edema. LPS instillation enhanced lung microvascular permeability, thereby causing inflammatory cells flow into bronchoalveolar lavage fluid (BALF). However, L6H9 inhibited the LPS-induced upregulation of total protein concentration and the number of inflammatory cells in BALF. In the meantime, macrophages infiltration in lung tissue induced by LPS was also mitigated by L6H9 treatment. Furthermore, L6H9 suppressed LPS-induced inflammatory cytokines expression in BALF, serum, and lung tissue. It is noteworthy that LPS-induced MD2/TLR4 complex formation was inhibited by L6H9 in lung tissue. On the whole, these results show that L6H9 can attenuate LPS-induced ALI in vivo by targeting MD2. Our study provide new candidate for the treatment of ALI.

Associations of cigarette smoking with memory decline and neurodegeneration among cognitively normal older individuals.

Cigarette smoking is associated with a higher risk of Alzheimer's disease (AD), but the underlying mechanisms remain to be clarified. In this study, we aimed to examine the effects of cigarette smoking on multiple AD biomarkers among older individuals with normal cognition (NC). Among 415 older individuals with NC from the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort, we examined the associations between smoking status (non-smokers vs smokers) and global cognition, verbal memory, hippocampal volumes, cerebral glucose metabolism and CSF AD pathologies. The primary findings of this study were: (1) In NC, smokers showed worse performance on verbal memory tests [Rey Auditory Verbal Learning Test (RAVLT) total learning score and delayed recall] than non-smokers; (2) Compared with non-smokers, smokers had significantly lower HpVR; (3) Smokers, relative to non-smokers, demonstrated lower levels of cerebral glucose metabolism as measured by FDG-PET; and (4) there were no significant differences in CSF AD pathologies (CSF Aß42, t-tau or p-tau) between non-smokers and smokers. Longitudinal studies are needed to investigate the relationship between cigarettes smoking and changes in AD-related markers over time. Further, ADNI participants were highly educated and predominantly white. This may limit the generalizability of our results. In summary, among individuals with NC, cigarette smoking was associated with memory impairment, hippocampal atrophy and cerebral glucose hypometabolism, but not CSF AD pathologies.

Astaxanthin prevents against lipopolysaccharide-induced acute lung injury and sepsis via inhibiting activation of MAPK/NF-κB.

BACKGROUND: Endotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various pro-inflammatory cytokines remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through Mitogen activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB), increase the production of inflammatory mediators. Astaxanthin (ASX), a xanthophyll carotenoid, exerts beneficial effects against oxidation, inflammation, and cancer. But poor evidence has been reported that whether it has protective effects on LPS-induced injury. This study aims to investigate the effects of ASX on LPS-induced sepsis and acute lung injury and to demonstrate its mechanisms. METHODS: Mouse prime macrophage (MPM) challenged with LPS were used for in vitro pharmacological activity and mechanistic studies. Inflammatory facors (tumor necrosis factor-alpha and interleukin-6 levels) in MPM were determined. The mouse models of LPS-induced sepsis and acute lung injury administrated with or without the compound were used for in vivo studies. RESULTS: Pre-treatment of MPM with ASX inhibited MAPK/NF-κB signaling pathway, and attenuated LPS-increased inflammatory factors in vitro. In animal models of LPS-induced sepsis and acute lung injury, administration of ASX significantly improved survival and protected lung injury. Subsequently, ASX was shown to suppress LPS-induced inflammatory factors increase, MAPK phosphorylation, and NF-κB activation in vivo. CONCLUSIONS: ASX exerts impressively protective effects on LPS-induced injury in vitro and in vivo. Taken together, it might be used as a potential candidate for clinical sepsis.

Baicalin promotes apoptosis and inhibits proliferation and migration of hypoxia-induced pulmonary artery smooth muscle cells by up-regulating A2a receptor via the SDF-1/CXCR4 signaling pathway.

BACKGROUND: Baicalin is a flavonoid compound that exerts specific pharmacological effect in attenuating the proliferation, migration, and apoptotic resistance of hypoxia-induced pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanism has not been fully elucidated yet. Although our previous studies had indicated that activation of A2aR attenuates CXCR expression, little is known about the relationship between A2aR and SDF-1/CXCR4 axis in hypoxic PASMCs. In this study, we aimed to investigate the effect of A2aR on the SDF-1/CXCR4 axis in hypoxic PASMCs, the mechanism underlying this effect, and whether baicalin exerts its protective functions though A2aR. METHODS: Rat PASMCs were cultured under normoxia/hypoxia and divided into nine groups: normoxia, hypoxia, hypoxia + AMD3100 (a CXCR4 antagonist), hypoxia + baicalin, hypoxia + negative virus, normoxia + A2aR knockdown, hypoxia + A2aR knockdown, hypoxia + CGS21680 (an A2aR agonist), and hypoxia + A2aR knockdown + baicalin. Lentiviral transfection methods were used to establish the A2aR knockdown model in PASMCs. Cells were incubated under hypoxic conditions for 24 h. Expression levels of A2aR, SDF-1, and CXCR4 were detected using RT-qPCR and western blot. The proliferation and migration rate were observed via CCK-8 and Transwell methods. Cell cycle distribution and cell apoptosis were measured by flow cytometry (FCM) and the In-Situ Cell Death Detection kit (Fluorescein). RESULTS: Under hypoxic conditions, levels of A2aR, SDF-1, and CXCR4 were significantly increased compared to those under normoxia. The trend of SDF-1 and CXCR4 being inhibited when A2aR is up-regulated was more obvious in the baicalin intervention group. Baicalin directly enhanced A2aR expression, and A2aR knockdown weakened the function of baicalin. SDF-1 and CXCR4 expression levels were increased in the hypoxia + A2aR knockdown group, as were the proliferation and migration rates of PASMCs, while the apoptotic rate was decreased. Baicalin and CGS21680 showed opposite effects. CONCLUSIONS: Our data indicate that baicalin efficiently attenuates hypoxia-induced PASMC proliferation, migration, and apoptotic resistance, as well as SDF-1 secretion, by up-regulating A2aR and down-regulating the SDF-1/CXCR4 axis.

Fungemia caused by Penicillium marneffei in an immunocompetent patient with COPD: A unique case report.

RATIONALE: This report describes a rare case in Wenzhou city of Zhejiang province that a non-HIV infected male recovering from fungemia caused by Penicillium marneffei (P. marneffei). Interestingly, it's very easy to misdiagnose with aspergillosis, a fungal disease prevalent in Wenzhou, during the whole procedure. PATIENT CONCERNS: An 80-year-old Chinese male subject with pre-existing chronic obstructive pulmonary disease (COPD) presented with symptoms of chest tightness and high fever for a month. DIAGNOSES: Fungal culture from the blood isolated P marneffei. Naturally, the patient was diagnosed with P marneffei fungemia. However, he was proven serologically to be negative for human immunodeficiency virus (HIV). INTERVENTIONS: The patient was treated with voriconazole at 200mg/dL every 12 hours via intravenous administration. OUTCOMES: The fever returned to normal and chest tightness disappeared gradually after a week of voriconazole treatment. LESSONS: A high level of clinical suspicion and awareness is necessary for early diagnosis of P marneffei fungemia, especially in elder patients with underlying diseases.

Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries.

Clinical analysis of pulmonary cryptococcosis in non-HIV patients in south China.

AIMS: The aim of this study was to investigate the clinical characteristics of pulmonary cryptococcosis occurring in non-HIV patients, and to develop early diagnosis of pulmonary cryptococcosis in immunocompetent cases as well. METHODS: We retrospectively reviewed the clinical data of 41 non-HIV infected patients with pulmonary cryptococcosis who were admitted to the First Affiliated Hospital of Wenzhou Medical University from January 2006 to April 2014. RESULTS: The study included a total of 41 patients (23 males and 18 females) with mean age of 47 years. 12.19% of patients had a history of direct exposure to pigeon droppings; 31.70% of the patients' working or living environments were potentially contaminated by fungal spores. Almost one-third of the patients involved into the study were asymptomatic. The most common clinical manifestations were cough, expectoration and hemoptysis. The most common radiological manifestation was single node or mass in lung, which was described as untypical. Of all cases, 11 patients were diagnosed by CT-guided percutaneous cutting needle biopsy (PCNB), 5 patients were diagnosed by operation, and Crytococcus spore was found in 7 patients' cerebrospinal fluid. 8 patients' blood Cryptococcus Neoformans capsular polysaccharide antigens latex agglutination tests were positive. 36 patients received antifungal therapy. 5 patients underwent surgical resection. During 6 to 24 months follow-up, 40 cases showed total recovery and 1 cases showed improvement. CONCLUSIONS: Pulmonary cryptococcosis in non-HIV subjects might be related to fungus-contaminated environmental exposure. The great variations and protean manifestations of its clinical features often lead to misdiagnosis. Recognition and invasive examination of non-HIV infected patients' pulmonary cryptococcosis in the early stage may help with improvement of its diagnosis and prognosis.

Salidroside attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2a receptor related mitochondria-dependent apoptosis pathway.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial remodeling mainly due to excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Salidroside, an active ingredient isolated from Rhodiola rosea is proposed to exert protective effects against PAH. However, the function of salidroside in PAH has not been investigated systematically and the underlying mechanisms are not clear. To investigate the effects of salidroside on PAH, the mice in chronic hypoxia model of PAH were given by an increasing concentration of salidroside (0, 16 mg/kg, 32 mg/kg, and 64 mg/kg). After salidroside treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodeling were attenuated, suggesting a protective role played by salidroside in PAH. To explore the potential mechanisms, the apoptosis of PASMCs after salidroside treatment under hypoxia conditions were determined in vivo and in vitro, and also the mitochondria-dependent apoptosis factors, Bax, Bcl-2, cytochrome C, and caspase 9 were examined. The results revealed that salidroside reversed hypoxia-induced cell apoptosis resistance at least partially via a mitochondria-dependent pathway. In addition, salidroside upregulated the expression of adenosine A2a receptor (A2aR) in lung tissues of mice and in PASMCs in vitro after hypoxia exposure. Combined the evidence above, we conclude that salidroside can attenuate chronic hypoxia-induced PAH by promoting PASMCs apoptosis via an A2aR related mitochondria dependent pathway.