Youth participation in substance use prevention: A national profile, 2011-2019.

PURPOSE: Prevention efforts are critical to avoid the negative consequences of substance use in adolescents. This study aimed to examine national trends and sociodemographic differences in adolescents' participation in school-based substance use prevention (SUP) education, community-based SUP programs, as well as family conversations about substance use. METHODS: Publicly available data for adolescents aged 12-17 from the annual cross-sectional surveys of the National Survey on Drug Use and Health 2011-2019 were analyzed. RESULTS: Across the survey years, up to 74.9%, 12.2%, and 58.1% of adolescents reported having participated in school-based SUP education, community-based SUP programs, and family conversations about the danger of substance use in the past-year, respectively. From 2011 to 2019, statistically significant decreases were observed in adolescents' participation in school-based SUP education (OR = 0.97, 95% CI: 0.96, 0.98, p < 0.001) and community-based SUP programs (OR = 0.98, 95% CI: 0.97, 0.99, p < 0.001). Meanwhile, no significant changes were observed in adolescents' participation in family conversations about the dangers of substance use. Overall, lower levels of participation in school-based and community-based SUP programs were found in adolescents aged 16-17. Adolescents living in rural areas showed lower levels of participation in school-based SUP programs and family conversations about SUP. Racial/ethnic minority adolescents overall were less likely to participate in conversations with parents about SUP than Whites. CONCLUSIONS: Further development and implementation of developmentally appropriate, gender-specific, culturally sensitive, and contextually informed SUP programs at school, community, and family levels are needed.

The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism.

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.

An In-Depth Study of Phytopathogenic Ganoderma: Pathogenicity, Advanced Detection Techniques, Control Strategies, and Sustainable Management.

Phytopathogenic Ganoderma species pose a significant threat to global plant health, resulting in estimated annual economic losses exceeding USD (US Dollars) 68 billion in the agriculture and forestry sectors worldwide. To combat this pervasive menace effectively, a comprehensive understanding of the biology, ecology, and plant infection mechanisms of these pathogens is imperative. This comprehensive review critically examines various aspects of Ganoderma spp., including their intricate life cycle, their disease mechanisms, and the multifaceted environmental factors influencing their spread. Recent studies have quantified the economic impact of Ganoderma infections, revealing staggering yield losses ranging from 20% to 80% across various crops. In particular, oil palm plantations suffer devastating losses, with an estimated annual reduction in yield exceeding 50 million metric tons. Moreover, this review elucidates the dynamic interactions between Ganoderma and host plants, delineating the pathogen's colonization strategies and its elicitation of intricate plant defense responses. This comprehensive analysis underscores the imperative for adopting an integrated approach to Ganoderma disease management. By synergistically harnessing cultural practices, biological control, and chemical treatments and by deploying resistant plant varieties, substantial strides can be made in mitigating Ganoderma infestations. Furthermore, a collaborative effort involving scientists, breeders, and growers is paramount in the development and implementation of sustainable strategies against this pernicious plant pathogen. Through rigorous scientific inquiry and evidence-based practices, we can strive towards safeguarding global plant health and mitigating the dire economic consequences inflicted by Ganoderma infections.

Patterns and Factors Associated With Alcohol Misuse Among Young Black Men Who Have Sex With Men in New York City.

Alcohol misuse is a significant health concern among gay, bisexual, same-gender-loving, and other men who have sex with men (MSM). Yet, little is known about the severity and predictors of alcohol misuse among self-reported young Black MSM. This study aimed to identify patterns of and factors associated with alcohol misuse in a sample of young Black MSM living in New York City. Baseline data from a randomized controlled trial aimed at improving the uptake of HIV testing among 250 MSM aged 18 to 29 were analyzed. Log-binominal regression analyses were conducted to assess the association of demographic and psychosocial factors with alcohol misuse in the past year and past 3 months among young Black MSM. Overall, 33.2% and 28.0% of young Black MSM in the study experienced alcohol misuse in the past year and past 3 months, respectively. In the adjusted model, factors positively associated with past-year alcohol misuse included marijuana use, a history of drug use, and having one-two or more than two male sex partners. Likewise, participants who used marijuana and those with one-two or more than two male partners were more likely to report past 3-month alcohol misuse. No significant association was found between positive screening for depressive symptoms, chemsex, internalized homophobia, and the likelihood of having alcohol misuse. The high prevalence of alcohol misuse underscores the importance of raising awareness of alcohol misuse and designing alcohol risk reduction programs that jointly address HIV risk among young Black MSM.

Overexpression of TNFSF11 reduces GPX4 levels and increases sensitivity to ferroptosis inducers in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD), the most common and lethal subtype of lung cancer, continues to be a major health concern worldwide. Despite advances in targeted and immune therapies, only a minority of patients derive substantial benefits. As a result, the urgent need for novel therapeutic strategies to improve lung cancer treatment outcomes remains undiminished. METHODS: In our study, we employed the TIMER database to scrutinize TNFSF11 expression across various cancer types. We further examined the differential expression of TNFSF11 in normal and tumor tissues utilizing the TCGA-LUAD dataset and tissue microarray, and probed the associations between TNFSF11 expression and clinicopathological parameters within the TCGA-LUAD dataset. We used the GSE31210 dataset for external validation. To identify genes strongly linked to TNFSF11, we engaged LinkedOmics and conducted a KEGG pathway enrichment analysis using the WEB-based Gene SeT AnaLysis Toolkit. Moreover, we investigated the function of TNFSF11 through gene knockdown or overexpression approaches and explore its function in tumor cells. The therapeutic impact of ferroptosis inducers in tumors overexpressing TNFSF11 were also investigated through in vivo and in vitro experiments. Through these extensive analyses, we shed light on the potential role of TNFSF11 in lung adenocarcinoma, underscoring potential therapeutic targets for this malignancy. RESULTS: This research uncovers the overexpression of TNFSF11 in LUAD patients and its inverse correlation with peroxisome-related enzymes. By utilizing gene knockdown or overexpression assays, we found that TNFSF11 was negatively associated with GPX4. Furthermore, cells with TNFSF11 overexpression were relatively more sensitive to the ferroptosis inducers. CONCLUSIONS: Our research has provided valuable insights into the role of TNFSF11, revealing its negative regulation of GPX4, which could be influential in crafting therapeutic strategies. These findings set the stage for further exploration into the mechanisms underpinning the relationship between TNFSF11 and GPX4, potentially opening up new avenues for precision medicine in the treatment of LUAD.

Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.

Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.

YBX1 as a prognostic biomarker and potential therapeutic target in hepatocellular carcinoma: A comprehensive investigation through bioinformatics analysis and in vitro study.

BACKGROUNDS: Y-box binding protein 1 (YBX1) is a DNA/RNA binding protein known to contribute to the progression of various malignancies, however, a comprehensive pan-cancer analysis to investigate YBX1 across a broad spectrum of cancer types has not yet been conducted. METHODS: We utilized the TIMER database for a comprehensive pan-cancer analysis and assessed YBX-1 expression via the TCGA and GEO databases. The relationship between YBX-1 expression and tumor-infiltrating cells was examined using TIMER and the R programming language. To evaluate the prognostic value of YBX1, we performed Kaplan-Meier plots and Cox regression analyses. Through LinkedOmics, we identified genes significantly correlated with YBX-1. The WEB-based Gene SeT AnaLysis Toolkit was used for KEGG pathway enrichment analysis. Additionally, using shRNA-mediated knockdown, we explored the potential role of YBX1 in tumor cell biology. RESULTS: Our study identifies pronounced overexpression of YBX-1 across multiple cancer types, correlating with adverse outcomes, notably in liver hepatocellular carcinoma (LIHC). A distinct association between elevated YBX-1 expression and heightened immune cell infiltration suggests YBX-1's potential role in reshaping the tumor microenvironment. Intriguingly, our KEGG pathway analysis indicated a tight nexus between YBX-1 expression and lipid metabolism. Moreover, the suppression of YBX-1 via shRNA revealed diminished cellular proliferation and marked reductions in crucial molecules steering the fatty acid synthesis pathway, implicating YBX-1's potential regulatory role in lipid metabolism within LIHC. CONCLUSIONS: YBX-1 serves as a favorable prognostic indicator in various cancers, particularly in liver hepatocellular carcinoma. Targeting YBX1 in HCC offers potential therapeutic strategies. This work paves the way for fresh insights into targeted therapeutic approaches for cancers, especially benefiting liver hepatocellular carcinoma patients.

Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells.

Mitochondria are promising drug target for cancer treatment. We previously demonstrated that a bi-gold compound BGC2a was more potent than the mono-gold drug auranofin in suppressing cancer cells due to increased gold atom number that led to higher drug accumulation in and thereby inhibition of mitochondria. To exploit the potential of this new strategy, we further designed and synthesized a series of bi-gold mitocans, the compounds targeting mitochondria. The results showed that most of the newly synthesized mitocans exhibited obviously lower IC50 than auranofin, an old drug that is repurposed in clinical trials for cancer treatment. The best mitocan C3P4 was nearly 2-fold more potent than BGC2a in human non-small cell lung cancer A549 cells and mantle cell lymphoma Jeko-1 cells, exhibiting substantial colony formation-suppressing and tumor-suppressing effects in A549 cells xenograft model. C3P4 induced apoptosis in a dose-dependent manner and arrested cell cycle at G0/G1 phase. The mechanistic study showed that C3P4 significantly increased the global reactive oxygen species and mitochondrial superoxide level, and reduced the mitochondrial membrane potential. C3P4 preferentially accumulated in mitochondria as measured by the gold content and substantially inhibited oxygen consumption rate and ATP production. These results further validated our hypothesis that targeting mitochondria would be promising to develop more potent anticancer agents. C3P4 may be further evaluated as a drug candidate for lung cancer treatment.

Perfluorooctanoic acid-induced metabolic disorder via enhancing metabolism of glutamine and fatty acids in human intestinal cells.

Intestinal cell metabolism plays an important role in intestine health. Perfluorooctanoic acid (PFOA) exposure could disorder intestinal cell metabolism. However, the mechanisms regarding how the three carbon sources interact under PFOA stress remined to be understood. The present study aimed to dissect the interconnections of glucose, glutamine, and fatty acids in PFOA-treated human colorectal cancer (DLD-1) cells using 13C metabolic flux analysis. The abundance of glycolysis and tricarboxylic acid (TCA) cycle metabolites was decreased in PFOA-treated cells except for succinate, whereas most of amino acids were more abundant. Beside serine and glycine, the levels of metabolites derived from 13C glucose were reduced in PFOA-treated cells, and the pentose phosphate pathway flux was 1.4-fold higher in PFOA-treated cells than in the controls. In reductive glutamine pathway, higher labeled enrichment of citrate, malate, fumarate, and succinate was observed for PFOA-treated cells. The contribution of glucose to fatty acid synthesis in PFOA-treated cells decreased while the contribution of glutamine to fatty acid synthesis increased. Additionally, synthesis of TCA intermediates from fatty acid ß-oxidation was promoted in PFOA-treated cells. All results suggested that metabolic remodeling could happen in intestinal cells exposed to PFOA, which was potentially related to PFOA toxicity relevant with the loss of glucose in biomass synthesis and energy metabolism.

Population-based examination of substance use disorders and treatment use among US young adults in the National Survey on Drug Use and Health, 2011-2019.

Background: Compared with adults of other age groups, young adults are more likely to have substance use disorders (SUDs) but less likely to receive treatment. Untreated SUDs can lead to lethal consequences, particularly deaths related to drug overdose. Objectives: This study aimed to examine trends and sociodemographic differences in the prevalence and treatment use of SUDs among US young adults aged 18 to 25 in the National Survey on Drug Use and Health 2011-2019. Methods: Bivariable logistic regression analyses were conducted to examine annual changes in the prevalence and treatment use of SUDs, and multivariable logistic regression was used to examine sociodemographic differences in SUD prevalence and treatment use in the pooled sample of young adults from 2011 to 2019. Results: From 2011 to 2019, the overall SUD prevalence increased significantly from 5.4% to 6.2%. Cannabis use disorder was the most common SUD annually. Groups with lower prevalence of SUDs included females, young adults aged 22-25, and Hispanic, Black, and Asian participants. Across the survey years, the prevalence of treatment use fluctuated insignificantly between 10.9% and 16.9% among young adults with SUDs, and most young adults received SUD treatment in self-help groups and residential and outpatient rehabilitation facilities. Compared to White participants, treatment use was lower in Hispanic, Black, Asian participants, as well as young adults of two or more races. Young adults covered by Medicaid/CHIP were more likely to use treatment. Conclusions: This study revealed an alarming level of unmet treatment need and significant disparities in treatment use among young adults with SUDs. To reduce barriers to treatment utilization, more coordinated efforts that leverage policy and structural changes alongside innovations to engage young adults with SUD care are needed.

Major depression with co-occurring suicidal thoughts, plans, and attempts: An increasing mental health crisis in US adolescents, 2011-2020.

This study aimed to examine national trends and disparities in the prevalence and treatment of adolescent 12-month major depressive episode (MDE) with co-occurring suicidal thoughts, plans, and attempts. Publicly available data for adolescents aged 12-17 in the 2011-2020 National Survey on Drug Use and Health were analyzed. Bivariate and multivariable logistic regression analyses were conducted. In 2011, 4.6%, 2.1%, and 1.7% of adolescents had 12-month MDE with co-occurring suicidal thoughts, plans, and attempts, and the prevalence increased steadily to 9.8%, 5.3%, and 3.5% in 2019, respectively. In 2011, 45% of adolescents with MDE and suicidal thoughts received any mental health treatment, and the prevalence increased slightly to 46.6% in 2019. Meanwhile, the prevalence of treatment use among adolescents with MDE and suicidal plans remained stable at below 54%. Lastly, the prevalence of treatment use increased significantly from 53.6% in 2011 to 60.8% in 2019 among those with MDE and suicidal attempts. Continued high prevalence and low treatment use were observed in 2020. Disparities in treatment use were found in older adolescents, adolescents without insurance, Hispanics, and Asians. Concerted efforts are needed to prioritize evidence-based interventions, enhance outreach to high-risk groups, and expand service provisions to underserved adolescents.

Corrigendum: NanoSIMS analysis of water content in bridgmanite at the micron scale: an experimental approach to probe water in Earth's deep mantle.

[This corrects the article DOI: 10.3389/fchem.2023.1166593.].

NanoSIMS analysis of water content in bridgmanite at the micron scale: An experimental approach to probe water in Earth's deep mantle.

Water, in trace amounts, can greatly alter chemical and physical properties of mantle minerals and exert primary control on Earth's dynamics. Quantifying how water is retained and distributed in Earth's deep interior is essential to our understanding of Earth's origin and evolution. While directly sampling Earth's deep interior remains challenging, the experimental technique using laser-heated diamond anvil cell (LH-DAC) is likely the only method available to synthesize and recover analog specimens throughout Earth's lower mantle conditions. The recovered samples, however, are typically of micron sizes and require high spatial resolution to analyze their water abundance. Here we use nano-scale secondary ion mass spectrometry (NanoSIMS) to characterize water content in bridgmanite, the most abundant mineral in Earth's lower mantle. We have established two working standards of natural orthopyroxene that are likely suitable for calibrating water concentration in bridgmanite, i.e., A119(H2O) = 99 ± 13 µg/g (1SD) and A158(H2O) = 293 ± 23 µg/g (1SD). We find that matrix effect among orthopyroxene, olivine, and glass is less than 10%, while that between orthopyroxene and clinopyroxene can be up to 20%. Using our calibration, a bridgmanite synthesized by LH-DAC at 33 ± 1 GPa and 3,690 ± 120 K is measured to contain 1,099 ± 14 µg/g water, with partition coefficient of water between bridgmanite and silicate melt ∼0.025, providing the first measurement at such condition. Applying the unique analytical capability of NanoSIMS to minute samples recovered from LH-DAC opens a new window to probe water and other volatiles in Earth's deep mantle.

Metabolomic differentiation of benign vs malignant pulmonary nodules with high specificity via high-resolution mass spectrometry analysis of patient sera.

Differential diagnosis of pulmonary nodules detected by computed tomography (CT) remains a challenge in clinical practice. Here, we characterize the global metabolomes of 480 serum samples including healthy controls, benign pulmonary nodules, and stage I lung adenocarcinoma. The adenocarcinoma demonstrates a distinct metabolomic signature, whereas benign nodules and healthy controls share major similarities in metabolomic profiles. A panel of 27 metabolites is identified in the discovery cohort (n = 306) to distinguish between benign and malignant nodules. The discriminant model achieves an AUC of 0.915 and 0.945 in the internal validation (n = 104) and external validation cohort (n = 111), respectively. Pathway analysis reveals elevation in glycolytic metabolites associated with decreased tryptophan in serum of lung adenocarcinoma vs benign nodules and healthy controls, and demonstrates that uptake of tryptophan promotes glycolysis in lung cancer cells. Our study highlights the value of the serum metabolite biomarkers in risk assessment of pulmonary nodules detected by CT screening.

Human Capital Development Factors and Black Adolescent Tobacco and Cannabis Use.

INTRODUCTION: This study examined the association of four domains of human capital development (cognitive development, social and emotional development, physical health, and mental health) and exclusive and concurrent tobacco and cannabis use (TCU) among black youth. AIMS AND METHODS: Nationally representative annual cross-sectional data for black adolescents (12-17 years; N = 9017) in the National Survey on Drug Use and Health 2015-2019 were analyzed. Analyses examined the influence of human capital factors (cognitive development, social and emotional development, physical health, and mental health) on exclusive and concurrent TCU. RESULTS: In total, 50.4% were males; prevalence of 12-month tobacco use fluctuated insignificantly between 5.6% and 7.6% across survey years. Similarly, prevalence of 12-month cannabis use remained relatively stable around 13%, with no significant linear change. Prevalence of concurrent TCU also fluctuated insignificantly between 3.5% and 5.3%. Investment in cognitive development decreased the odds of tobacco (aOR = 0.58, p < .001), cannabis (aOR = 0.64, p < .001), and concurrent tobacco and cannabis (aOR = 0.58, p < .001) use. Similarly, investment in social and emotional development reduced the odds of tobacco (aOR = 086, p < .001), cannabis (aOR = 0.83, p < .001), and concurrent tobacco and cannabis (aOR = 0.81, p < .001) use. Good physical health reduced the odds of tobacco (aOR = 0.52, p < .1), cannabis (aOR = 0.63, p < .05), and concurrent TCU (aOR = 0.54, p < .05). Major depressive episodes increased the likelihood of cannabis use (aOR = 1.62, p < .001). CONCLUSIONS: Investment in cognitive, social, and emotional aspects of human capital development, and physical health among black youth is protective against TCU. Efforts to sustain human capital development among black adolescents may contribute to reducing TCU disparities. IMPLICATIONS: This is one of few studies to examine human capital development factors and their associations with TCU among black youth. Efforts to eliminate tobacco/cannabis-related disparities among black youth should also invest in social, emotional, cognitive, and physical health development opportunities.

Photocatalytic synthesis of alkyl-alkyl sulfones via direct C(sp3)-H bond functionalization.

We report a highly efficient one-pot, three-component strategy for the construction of alkyl-alkyl sulfones through a photoinduced TBADT-catalyzed C(sp3)-H sulfonylation of unactivated hydrocarbon compounds. A wide range of commercially available hydrocarbon compounds and bioactive molecules can be successfully applied to the catalytic system, affording the corresponding alkyl-alkyl sulfones in good to excellent yields (>50 examples, up to 87% yield).

Constructing interactive networks of functional genes and metabolites to uncover the cellular events related to colorectal cancer cell migration induced by arsenite.

Tumor cell migration induced by arsenite (iAsIII) is closely associated with cancer progression. However, transcriptomic and metabolic traits of migrative human cells exposed to iAsIII remain to be well characterized. Here, the combination of transcriptomics and metabolomics approaches were employed to construct interactive networks of functional genes and metabolites in human colorectal cancer (DLD-1) cells exposed to iAsIII. The number of DLD-1 cells passing through the Transwell membrane was at least 6 times greater in the iAsIII-treated groups than in controls. Following iAsIII treatment, the expression of ZEB1 and SLUG protein was significantly upregulated while the expression of CRB2 was downregulated (p < 0.05), indicating the onset of epithelial to mesenchymal transition (EMT). Meanwhile, integrin- and collagen-mediated biological adhesion were enhanced by SLUG under iAsIII treatment. The expression of matrix metallopeptidase (MMP) genes was fostered by iAsIII, which have the functions to degrade extracellular matrix. Glutamine metabolism could be considerably interfered by iAsIII, and in turn glutamine supplementation could effectively enhance DLD-1 cell movement. Overall, our results suggested that DLD-1 cell migration could be promoted by iAsIII via a series of cellular events, including EMT activation, altered cell adhesion, MMP-dependent matrix degradation, accompanying with a metabolic focus on glutamine.

Widening Gaps and Disparities in the Treatment of Adolescent Alcohol and Drug Use Disorders.

INTRODUCTION: The overall prevalence of alcohol use disorders and drug use disorders in adolescents has been declining in recent years, yet little is known about treatment use for these disorders among adolescents. This study aimed to examine the patterns and demographics of treatment of alcohol use disorders, drug use disorders, and both conditions among U.S. adolescents. METHODS: This study used publicly available data for adolescents aged 12-17 years from the annual cross-sectional surveys of the National Survey on Drug Use and Health, 2011-2019. Data were analyzed between July 2021 and November 2022. RESULTS: From 2011 to 2019, fewer than 11%, 15%, and 17% of adolescents with 12-month alcohol use disorders, drug use disorders, and both conditions received treatment, respectively, with significant decreases in treatment use for drug use disorders (OR=0.93; CI=0.89, 0.97; p=0.002). Overall, treatment use in outpatient rehabilitation facilities and self-help groups was most common but decreased over the course of the study period. Extensive disparities in treatment use were further identified on the basis of adolescents' gender, age, race, family structure, and mental health. CONCLUSIONS: To improve adolescent treatment use for alcohol and drug use disorders, assessments and engagement interventions that are gender specific, developmentally appropriate, culturally sensitive, and contextually informed are especially needed.

Targeting Mitochondrial IDH2 Enhances Antitumor Activity of Cisplatin in Lung Cancer via ROS-Mediated Mechanism.

Mitochondrial isocitrate dehydrogenase 2 (IDH2) is an important metabolic enzyme in the tricarboxylic acid cycle (TCA) cycle. Our previous study showed that high expression of wild-type IDH2 promotes the proliferation of lung cancer cells. This study aims to test the potential of targeting IDH2 as a therapeutic strategy to inhibit lung cancer in vitro and in vivo. First, we analyzed the available data from the databases gene expression omnibus (GEO) database to evaluate the clinical relevance of IDH2 expression in affecting lung cancer patient survival. We then generated a stable IDH2-knockdown lung cancer cell line using a lentivirus-based method for in vitro and in vivo study. Cell growth, apoptosis, cell viability, and colony formation assays were conducted to test the sensitivity of lung cancer cells with different IDH2 expression status to cisplatin or radiation treatment in vitro. For mechanistic study, Cellular oxygen consumption and extracellular acidification rates were measured using a Seahorse metabolic analyzer, and reactive oxygen species (ROS) generation was analyzed using flow cytometry. An animal study using a xenograft tumor model was performed to further evaluate the in vivo therapeutic effect on tumor growth. We found that high IDH2 expression was associated with poor survival in lung cancer patients undergoing chemotherapy. Inhibition of IDH2 significantly enhanced the anticancer activity of cisplatin and also increased the effect of radiation against lung cancer cells. IDH2 was upregulated in cisplatin-resistant lung cancer cells, which could be sensitized by targeted inhibition of IDH2. Mechanistic study showed that abrogation of IDH2 caused only minimal changes in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in lung cancer cells, but induced a significant increase in ROS, which rendered the cancer cells more sensitive to cisplatin. Pretreatment of lung cancer cells with the ROS scavenger N-acetyl-cysteine could partially rescue cells from the cytotoxic effect of cisplatin and IDH2 inhibition. Importantly, abrogation of IDH2 significantly increased the sensitivity of lung cancer cells to cisplatin in vivo.