A novel therapeutic outlook: Classification, applications and challenges of inhalable micron/nanoparticle drug delivery systems in lung cancer (Review).

Lung cancer represents a marked global public health concern. Despite existing treatment modalities, the average 5­year survival rate for patients with patients with lung cancer is only ~20%. As there are numerous adverse effects of systemic administration routes, there is an urgent need to develop a novel therapeutic strategy tailored specifically for patients with lung cancer. Non­invasive aerosol inhalation, as a route of drug administration, holds unique advantages in the context of respiratory diseases. Nanoscale materials have extensive applications in the field of biomedical research in recent years. The present study provides a comprehensive review of the classification, applications summarized according to existing clinical treatment modalities for lung cancer and challenges associated with inhalable micron/nanoparticle drug delivery systems (DDSs) in lung cancer. Achieving localized treatment of lung cancer preclinical models through inhalation is deemed feasible. However, further research is required to substantiate the efficacy and long­term safety of inhalable micron/nanoparticle DDSs in the clinical management of lung cancer.

Early-onset alcohol, tobacco, and illicit drug use with age at onset of hypertension: a survival analysis.

PURPOSE: To examine the associations of age when first substance use and early-onset substance use before age 18 with age at onset (AAO) of hypertension. METHODS: This study included 19,270 individuals with AAO of hypertension from the 2015-2019 National Survey on Drug Use and Health. Age when first use of 10 substance use variables included alcohol, daily cigarettes, cigars, smokeless tobacco, marijuana, cocaine, hallucinogens, lysergic acid diethylamide (LSD), inhalants, and methamphetamine use. The outcome was AAO of hypertension and variable cluster analysis was used to classify the exposures and outcome. Substance use status was classified into three categories: early-onset substance use (first used substance before age 18), late-onset substance use (first used substance after age 18), and never used. RESULTS: The mean AAO of hypertension was 42.7 years. Age when first use of 10 substance use variables had significant correlations with AAO of hypertension (all p values < 0.001). Individuals with early-onset alcohol, cigars, smokeless tobacco, marijuana, hallucinogens, inhalants, cocaine, LSD, and methamphetamine use revealed significantly earlier onset of hypertension than those never used. Compared with never used substances, the Cox regression model showed that early-onset alcohol, smokeless tobacco, marijuana, inhalants, and methamphetamine use had an increased risk of AAO of hypertension [hazard ratio (HR) (95%CI) = 1.22 (1.13, 1.31), 1.36 (1.24, 1.49), 1.85 (1.75, 1.95), 1.41 (1.30, 1.52), and 1.27 (1.07,1.50), respectively]. CONCLUSION: These findings suggest that intervention strategies or programs focusing on preventing early-onset substance use before age 18 may delay the onset of adult hypertension.

Differences in smoking behaviors and readiness to change for patients with COPD and differing categories of depressive symptoms: a descriptive cross-sectional design.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the world with nearly 90% of cases caused by tobacco smoking. Nearly 40% of people with COPD are diagnosed with depression which impacts quality of life and smoking cessation. The purpose of this study was to describe factors influencing smoking behaviors and readiness to change in people with comorbid COPD and depression. METHODS: A descriptive cross-sectional design was used. A convenience sample of 222 participants self-reported and/or had a documented diagnosis of COPD. Participants completed study measures which included the PHQ-9 for depressive symptoms, assessment of smoking behaviors using The Cigarette Dependence Scale, report of readiness to change using The Smoking Stage of Change Questionnaire, The Smoking Decisional Balance Questionnaire, and The Processes of Change Questionnaire. Electronic and paper questionnaires were used. Data was stored in RedCap and analyzed using SPSS version 26. Based on variable type, descriptive and comparative analyses were conducted using ANOVA, t-test, chi-square, Pearson correlation, linear regression, and multiple linear regression to determine the relationships between smoking behaviors, COPD, and depressive symptoms. RESULTS: Only 18 participants were classified as having no depressive symptoms. Participants who smoked had high nicotine dependence and wanted to quit smoking. Overall, participants saw more cons to smoking and were engaged in the processes of change. The majority of participants were in the maintenance or contemplation stage. Cigarette dependence could decrease by 9% if depressive symptoms are treated. CONCLUSIONS: There is a need to assess COPD patients for depression and to assess COPD patients' smoking behaviors and readiness to change. Adequate treatment of depression could promote an individual to move through the stages of change from chronic contemplation to action, thus improving smoking cessation efforts for individuals with COPD. Understanding patients' smoking behaviors and readiness to change can aid in developing personalized interventions to achieve smoking cessation and improve long-term outcomes.

Clusters of substance use and mental health variables with emergency room visits in U.S. adults: The 2020 National Survey on Drug Use and Health.

BACKGROUND: This study evaluated the prevalence of emergency room (ER) visits, given numerous substance use and mental health variables in the past year. METHODS: Data from 5206 emergency room visits out of 27,170 adults were extracted from the 2020 National Survey on Drug Use and Health. Oblique principal component cluster analysis was used to classify 39 substance use and mental health variables into disjoint clusters. RESULTS: In 2020, the overall prevalence of ER visits was 21.9 %. Being female, age above 65 years, with insurance, low income and low education levels, and being African American increased the risk of ER visit. Nine clusters were made out of 39 substance use and mental health variables. Multivariate stepwise logistic regression analysis showed 15 substance use and mental health variables were significantly associated with ER visits including heavy alcohol use past 30 days in cluster 3, nicotine dependence and cigarettes use in cluster 4, major depressive episode, serious psychological distress, and suicidal plans in past year in cluster 5, any psychotherapeutics use in cluster 7, tranquilizers use and lorazepam products use in cluster 8, and any pain reliever, pain reliever misuse, hydrocodone products use, oxycodone products use, tramadol products use, and codeine products use in cluster 9. CONCLUSIONS: Several substance use and mental health problems, including nicotine dependence, illicit drugs, and serious mental health problems were among the common reasons for ER visits. These findings suggest the effective use of ER as the venue to implement interventions for substance use and mental health.

Network Pharmacology Combined with Experimental Validation Reveals the Anti-tumor Effect of Duchesnea indica against Hepatocellular Carcinoma.

Context: Duchesnea indica is effective against hepatocellular carcinoma (HCC); however, its underlying mechanism of action remains unclear. Objective: The present study aimed to investigate the potential mechanism of action and effects of D. indica components against HCC. Materials and methods: First, the effects of D. indica against HCC were investigated in vitro and in vivo. For in vitro experiments, HCC cell lines were treated with D. indica solutions at different concentrations (0, 1, 2 mg/mL) and then assessed for cell apoptosis, proliferation, migration, invasion, and angiogenic ability. For in vivo experiments, 24 mice were randomly divided into the following four groups: model group and D. indica low-, medium-, and high-dose groups. Tumor growth and CD34 and Ki67 expression levels were assessed to determine the effects of D. indica on cell proliferation and angiogenic ability. Furthermore, transcriptome sequencing and differential expression analyses were used to identify D. indica-induced differentially expressed genes (DEGs) in HCC cells. Additionally, mass spectrometry was conducted to identify the chemical components of D. indica. Four databases were used to predict the target proteins of these chemical components in HCC. HCC-associated genes were identified from two databases. By intersecting the identified DEGs; target proteins; and HCC-associated genes, key D. indica-regulated HCC-related genes were identified. Subsequently, protein-protein interaction network, network pharmacology, and molecular docking were used to identify the active compounds in D. indica and their likely gene targets. Results: In vitro experiments demonstrated that D. indica induced tumor cell apoptosis and inhibited cell proliferation, migration, invasion, and angiogenic potential. In vivo experiments demonstrated that D. indica inhibited tumor growth in a dose-dependent manner. Bioinformatic analyses identified 49 key D. indica-regulated HCC-related genes, of which FOS, SERPINE1, AKR1C3, and FGF2 were the most significant. Mass spectrometry identified the following five molecules in D. indica with potential anti-HCC activity: 4', 5, 7-trihydroxyflavone; ethyl protocatechuate; 3, 5-dihydroxy-benzoic acid; curculigosaponin A; and curculigine G. Molecular docking validated the interaction between D. indica active compounds and their target proteins in HCC. Conclusions: The present study confirmed the therapeutic effects of D. indica against HCC and identified the key genes and active components that may contribute to its mechanism of action, thereby providing a basis for further research on targeted therapeutics for HCC.

ROS Scavenging and inflammation-directed polydopamine nanoparticles regulate gut immunity and flora therapy in inflammatory bowel disease.

Dysfunction of the intestinal mucosal immune system and dysbiosis of the intestinal microflora can induce inflammatory bowel disease. However, drug-mediated clinical treatment remains a challenge due to its poor therapeutic efficacy and severe side effects. Herein, a ROS scavenging and inflammation-directed nanomedicine is designed and fabricated by coupling polydopamine nanoparticles with mCRAMP, an antimicrobial peptide, while wrapping macrophage membrane in the outer layer. The designed nanomedicine reduced the secretion of pro-inflammatory cytokines and elevate the expression of anti-inflammatory cytokine in vivo and in vitro inflammation models, demonstrating its significant ability of improving inflammatory responses. Importantly, the macrophage membrane encapsulated nanoparticles exhibit the obviously enhanced targeting performance in local inflamed tissues. Furthermore, the 16S rRNA sequencing of fecal microorganisms showed that probiotics increased and pathogenic bacteria were inhibited after oral delivery the nanomedicine, indicating that the designed nano platform played a significant role in optimizing intestinal microbiome. Taken together, the designed nanomedicine are not only easy to prepare and exhibit high biocompatibility, but also show the inflammatory targeting property, anti-inflammatory function and positive regulation of intestinal flora, thus providing a new idea for the intervention and treatment of colitis. STATEMENT OF SIGNIFICANCE: Inflammatory bowel disease (IBD), a chronic and intractable disease, may lead to colon cancer in severe cases without effective treatment. However, clinical drugs are largely ineffective owing to insufficient therapeutic efficacies and side effects. Herein, we constructed a biomimetic polydopamine nanoparticle for oral administration to treat the IBD by modulating mucosal immune homeostasis and optimizing intestinal microorganisms. In vitro and in vivo experiments showed that the designed nanomedicine not only exhibits the anti-inflammatory function and inflammatory targeting property but also positively regulate the gut microflora. Taken together, the designed nanomedicine combined immunoregulation and intestinal microecology modulation to significantly enhance the therapeutic effect on colitis in mice, thus providing a new approach for the clinical treatment of colitis.

The association between early onset of alcohol, smokeless tobacco and marijuana use with adult binge drinking in United States.

Binge drinking is a deadly pattern of excessive alcohol use that is associated with multiple diseases in the United States. To date, little is known about the associations between the early onset of substance use and other factors with the severity of adult binge drinking. The 2018 National Survey on Drug Use and Health data was used to identify binge drinking (binary and in number of days in the past month). Age at onset was categorized into four groups as 1-12, 13-14, 15-17, or beyond 18. Weighted multivariate logistic regression and Poisson regression analyses were performed to examine the associations between early onset of alcohol, smokeless tobacco, and marijuana use with binge drinking. The severity of binge drinking was statistically significantly associated with substance use (4.15 days in a month), early onset of alcohol, smokeless tobacco, and marijuana use (2.15-4.93 days, all p-values < 0.0001), after accounting for the covariates. Past year substance use disorder is strongly associated with binge drinking. The severity of adult binge drinking is significantly associated with early onset of substance use including alcohol, smokeless tobacco, and marijuana. Continued efforts are warranted to improve substance use prevention and treatment tailored for adolescents and youths to prevent development of adult binge drinking.

Income Disparities in Obesity Trends among U.S. Adults: An Analysis of the 2011-2014 California Health Interview Survey.

The aim of this study was to examine income disparities in obesity trends among California adults. Data were obtained from the 2011−2014 California Health Interview Survey (n = 83,175 adults). Obesity for adults was defined as a body mass index of 30 kg/m2 or above. Family income was categorized as below 100%, 100% to 299%, or 300% and above of the federal poverty level (FPL). Weighted multiple logistic regression analyses were used to examine the association between family income and obesity across survey years after controlling for age, sex, race/ethnicity, smoking status, marital status, education, physical activity, and healthy diet. Obesity prevalence among California adults increased slightly from 25.1% in 2011 to 27.0% in 2014. Compared to 300% FPL or above, <100% FPL and 100−299% FPL were associated with increased odds of obesity, respectively (OR = 1.35, 95% CI = 1.22−1.50, for 100−299% FPL; OR = 1.18, 95% CI = 1.10−1.27, for 300% FPL or above). Each year, lower FPL was associated with higher odds of obesity, except for the year 2014. An inverse association between obesity and family income in each survey year was observed, with the magnitude of the income disparity decreasing from 2011 to 2014. The findings of this study show that family income was negatively associated with obesity among adults in California from 2011−2014, and the magnitude of the income disparity in obesity prevalence decreased over this period. Future studies need to examine potential risk factors associated with the decreasing trend.

Internal heating method of loop-mediated isothermal amplification for detection of HPV-6 DNA.

Loop-mediated isothermal amplification (LAMP) is a promising diagnostic tool for genetic amplification, which is known for its rapid process, simple operation, high amplification efficiency, and excellent sensitivity. However, most of the existing heating methods are external for completion of molecular amplification with possibility of contamination of specimens. The present research provided an internal heating method for LAMP using magnetic nanoparticles (MNPs), which is called nano-LAMP. Near-infrared light with an excitation wavelength of 808 nm was employed as the heating source; hydroxy naphthol blue (HNB) was used as an indicator to conduct methodological research. We demonstrate that the best temperature was controlled at a working power of 2 W and 4.8 µg/µL concentration of nanoparticles. The lowest limit for the detection of HPV by the nano-LAMP method is 102 copies/mL, which was confirmed by a gel electrophoresis assay. In the feasibility investigation of validated clinical samples, all 10 positive HPV-6 specimens amplified by nano-LAMP were consistent with conventional LAMP methods. Therefore, the nano-LAMP detection method using internal heating of MNPs may bring a new vision to the exploration of thermostatic detection in the future.

Exendin-4 Reversed the PC12 Cell Damage Induced by circRNA CDR1as/miR-671/GSK3ß Signaling Pathway.

The purpose of this paper is to study the effect of circRNA cerebellar degeneration-related protein 1 antisense RNA(CDR1as)/miR-671/GSK3ß signaling pathway on PC12 cell injury and the mechanism of Exendin-4 (Ex-4) in PC12 cell injury protection. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to detect the expression levels of circular RNA CDR1as and miR-671 in PC12 cells. By overexpressing or knocking out CDR1as, miR-671, and GSK3ß, the role of CDR1as, miR-671, and GSK3ß in PC12 cell injury was analyzed. The binding of CDR1as to miR-671 and GSK3ß to miR-671 was verified by dual luciferase reporter assay. PC12 cells were treated with 1-methyl-4 phenyl-pyridine ion (MPP+) to construct a PC12 cell damage model. PC12 cell transfection experiments were used to confirm the role of CDR1as/miR-671/GSK3ß signal axis in PC12 cell damage, and the role of Ex-4 in the association of circRNA CDR1as/miR-671/GSK3ß signaling axis and PC12 cell damage. PC12 cell damage was detected by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cellular lactate dehydrogenase (LDH) release. Ex-4 reversed the phosphorylation levels of PI3K, AKT, and GSK-3ß in MPP+-treated PC12 cells, and reduced MPP+-induced PC12 cell damage. CircRNA CDR1as upregulated the expression of GSK3ß by sponge miR-671. Ex-4 downregulated CDR1as expression and upregulated miR-671 expression in MPP+-induced PC12 cell. Silencing of CDR1as reduced MPP+-induced PC12 cell damage. CDR1as transfection downregulated the expression of miR-671 in PC12 cells, promoted the expression and phosphorylated of GSK3ß, and induced PC12 cell damage. GSK3ß silencing reversed CDR1as-induced PC12 cell damage. CDR1as promoted the phosphorylation level of GSK3ß in PC12 cells to cause cell damage; Ex-4 reversed the phosphorylation of GSK3ß caused by CDR1as in PC12 cells and reduced the PC12 cell damage caused by CDR1as. Ex-4 reverses the damage of PC12 cells induced by CDR1as/miR-671/GSK3ß signaling pathway.

Gender differences in the associations of early onset poly tobacco and drug use prior to age 18 with the prevalence of adult bronchitis in the United States.

PURPOSE: We investigated the associations of early onset polysubstance use prior to age 18 with the prevalence of bronchitis among U.S. adults and tested whether the associations differ by gender. METHODS: A total of 77,950 adults, of them 2,653 with bronchitis in the past year, were from the combined 2013 and 2014 National Survey on Drug Use and Health data. The variable cluster analysis was used to classify nine variables about substance use prior to age 18 (cigarettes, cigars, smokeless tobacco, marijuana, cocaine, heroin, methamphetamines, ecstasy, and phencyclidine). Weighted multivariate logistic regression analysis (MLR) was used to examine the associations with bronchitis. RESULTS: Nine variables were divided into two clusters: early onset poly tobacco use (three tobacco use variables) and early onset poly drug use (six drug use variables). The overall prevalence of bronchitis was 3.8% (5.1% for females and 2.3% for males). MLR analysis showed that being female, elderly (ages 65 and above), obese, and early onset poly tobacco use were associated with increased odds of bronchitis (p < 0.05). Gender-stratified analyses showed that early-onset poly tobacco use was significantly associated with bronchitis only in males, whereas early onset poly drug use was associated with bronchitis only in females. Moreover, obesity and tobacco use in the past year revealed associations with bronchitis regardless of gender. CONCLUSIONS: Obesity, early onset poly tobacco use prior to age 18, and tobacco use in the past year were positively associated with bronchitis; furthermore, the associations of early onset polysubstance use with bronchitis differed by gender, which indicated that gender differences should be considered in developing effective prevention strategies.

Smokefree home rules and cigarette smoking intensity among smokers in different stages of smoking cessation from 20 low-and-middle income countries.

Smokefree environment created by smokefree policies is associated with smoking reduction; however, there is paucity of literature on the relationship between smokefree home rules and smoking intensity in low-and-middle income countries (LMICs), and how smokefree policy affects smoking behavior of smokers at different stages of smoking cessation. This study examined the relationship between smokefree home rules and average number of cigarettes smoked per day (CPD) among daily smokers at different stages of the transtheoretical model (TTM) of change. Data from 18,718 current daily cigarette smokers from the Global Adult Tobacco Survey (GATS) conducted from 2011 to 2017 in 20 LMICs were analyzed. Weighted multivariable linear regression analyses were conducted using the log of CPD as the outcome variable with smokefree home rules as the exposure variable, controlling for selected covariates. Approximately 15% of the participants were in precontemplation, 5% were in preparation, 15% lived in partial smokefree homes, and 30% lived in complete smokefree homes. The average number of CPD was 12.3, 12.0, and 10.6 among participants living in homes where smoking was allowed, partial smokefree homes, and complete smokefree homes, respectively. Compared to living in homes where smoking was allowed, living in complete smokefree homes were associated with 22.5% (95%CI = 18.4%-26.5%), 17.9% (95%CI = 8.4%-27.3%), and 29.3% (95% CI = 17.1%-41.5%) fewer CPD among participants in precontemplation, contemplation, and preparation stages, respectively. These findings suggest that complete smokefree home policy will benefit smokers in LMICs irrespective of their intention to quit smoking in addition to protecting non-smokers from secondhand smoke exposure.

Replicated risk CACNA1C variants for major psychiatric disorders may serve as potential therapeutic targets for the shared depressive endophenotype.

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and major psychiatric disorders (MPDs) including schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD) and others. We reviewed all of the published GWASs, and extracted the genome-wide significant (p<10-6) and replicated associations between risk SNPs and MPDs. We found the associations of 6 variants located in 6 genes, including L type voltage-gated calcium channel (LTCCs) subunit alpha1 C gene (CACNA1C), that were genome-wide significant (2.0×10 -8 ≤p≤1.0×10 -6 ) and replicated at single-point level across at least two GWASs. Among them, the associations between MPDs and rs1006737 within CACNA1C are most robust. Thus, as a next step, the expression of the replicated risk genes in human hippocampus was analyzed. We found CACNA1C had significant mRNA expression in human hippocampus in two independent cohorts. Finally, we tried to elucidate the roles of venlafaxine and ω-3 PUFAs in the mRNA expression regulation of the replicated risk genes in hippocampus. We used cDNA chip-based microarray profiling to explore the transcriptome-wide mRNA expression regulation by ω-3 PUFAs (0.72/kg/d) and venlafaxine (0.25/kg/d) treatment in chronic mild stress (CMS) rats. ω-3 PUFAs and venlafaxine treatment elicited significant CACNA1C up-regulation. We concluded that CACNA1C might confer the genetic vulnerability to the shared depressive symptoms across MPDs and CACNA1C might be the therapeutic target for depressive endophenotype as well.

Identification of Key Hydroxymethylated Genes and Transcription Factors Associated with Alpha-Fetoprotein-Negative Hepatocellular Carcinoma.

DNA hydroxymethylation is one of the major epigenetic mechanisms mediating the development of several human cancers. This study aimed to identify key hydroxymethylated genes and transcription factors (TFs) associated with alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC) using whole-genome DNA hydroxymethylation profiling. A total of 615 differentially hydroxymethylated regions (DHMRs) were identified from AFP-negative HCC tissues compared to adjacent normal tissues. DHMR-associated genes were significantly enriched in gene ontology functions associated with actin binding, cell leading edge, and blood vessel morphogenesis and pathways such as MAPK signaling pathway, neuroactive ligand-receptor interaction, and axon guidance. Moreover, protein-protein interaction (PPI) network analysis showed that PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) had higher degrees and were hub nodes. Furthermore, TF prediction analysis showed that TFs, such as nuclear factor I C (NFIC) and GATA binding protein 3 (GATA3), regulated many DHMR-associated genes. Our findings reveal that key hydroxymethylated genes such as PHLPP1 and SMARCA2, as well as TFs such as NFIC and GATA, may be involved in the development of AFP-negative HCC. These molecules may be potential biomarkers for AFP-negative HCC.

Variable reduction for past year alcohol and drug use in unmet need for mental health services among US adults.

BACKGROUND: No previous study has focused on the inter-relationship among alcohol and drug use variables in the past year. This study aimed to classify the past year alcohol and drug use variables and investigate the selected variables in past year alcohol and drug use with the unmet need for mental health services among US adults. METHODS: Data came from the 2015 National Survey on Drug Use and Health (NSDUH). Oblique principal component cluster analysis (OPCCA) was used to classify 37 variables on alcohol and drug use in the past year into disjoint clusters. Weighted multiple logistic regression analysis was used to examine the associations of selected variables with the unmet need. RESULTS: 37 alcohol and drug use variables were divided into 7 clusters. The variable with the lowest 1-R2 ratio (R2 is the squared correlation) from each cluster was selected as follows: tobacco use, pain reliever use, tranquilizer use, stimulant use, zolpidem products use, illicit drug and alcohol use, and benzodiazepine tranquilizers misuse. Multiple logistic regression analysis showed that pain reliever use (OR = 1.33, 95% CI = 1.17-1.50), tranquilizer use (OR = 2.49, 95% CI = 2.16-2.86), stimulant use (OR = 1.22, 95% CI = 1.01-1.47), and illicit drug and alcohol use (OR = 1.54, 95% CI = 1.34-1.77) revealed positive associations with the unmet need for mental health services. CONCLUSION: This is the first study using OPCCA to reduce the dominations of alcohol and drug use; several alcohol and drug use variables in the past year were associated with unmet need of mental health services.

Suppressed hepatocyte proliferation via a ROS-HNE-P21 pathway is associated with nicotine- and cotinine-enhanced alcoholic fatty liver in mice.

CYP2A5 is a major enzyme responsible for nicotine and cotinine metabolism in mice. Nicotine and cotinine enhance alcoholic fatty liver in wild type (WT) mice but not in CYP2A5 knockout (KO) mice, and reactive oxygen species (ROS) generated during the CYP2A5-mediated metabolism contributes to the enhancing effect. In combination with ethanol, nicotine and cotinine increased lipid peroxidation end product 4-hydroxynonenal (HNE) in WT mice but not in KO mice. In ethanol-fed KO mice, only 5 and 10 genes were regulated by nicotine and cotinine, respectively. However, in ethanol-fed WT mice, 59 and 104 genes were regulated by nicotine and cotinine, respectively, and 7 genes were up-regulated by both nicotine and cotinine. Plin 2 and Cdkn1a are among the 7 genes. Plin2 encodes adipose differentiation-related protein (ADRP), a lipid droplet-associated protein, which was confirmed to be increased by nicotine and cotinine in WT mice but not in KO mice. Cdkn1a encodes P21 and elevated P21 in nuclei was also confirmed. HNE can increase P21 and P21 inhibit cell proliferation. Consistently, hepatocyte proliferation markers proliferating cell nuclear antigen (PCNA) and Ki67 were decreased in WT mice but not in KO mice by nicotine/ethanol and cotinine/ethanol, respectively. These results suggest that inhibition of liver proliferation via a ROS-HNE-P21 pathway is involved in nicotine- and cotinine-enhanced alcoholic fatty liver.

The influence of immigrant generation on obesity among Asian Americans in California from 2013 to 2014.

OBJECTIVES: We aimed to examine the association between immigrant generation and obesity among Californian adults and Asian Americans. METHODS: We pooled weighted data (n = 2,967) on Asian Americans from the 2013-2014 California Health Interview Survey. Overweight and obesity were defined using body mass indices (BMI) of 25 kg/m2 and 30 kg/m2, respectively, in non-Asians, compared with BMI of 23 kg/m2 (for being overweight) and 27.5 kg/m2 (for being obese) in Asians. First-generation or immigrant Asian Americans were defined as those born outside of the U.S. Second-generation Asian Americans were defined as those born in the U.S. with at least one foreign-born parent. All other Asian participants were classified as third-generation or higher. Multiple logistic regression analyses were used with adjustment for age, sex, family income, smoking status, marital status, education, physical activity, and fast food consumption. RESULTS: Overall, 23.3% of the Asian population was obese, and 40.0% was overweight. The percentage of 1st, 2nd, and 3rd generation were 72.7%, 22.6%, and 4.6%, respectively. Overall, 1st generation of Asians had lower odds of being obese compared to Whites (OR = 0.34, 95%CI = 0.26-0.45). Multiple logistic regression analyses showed that overall, 2nd generation (OR = 1.69, 95%CI = 1.10-2.60) and 3rd generation (OR = 2.33, 95%CI = 1.29-4.22) Asians had higher odds of being obese compared to 1st generation Asians. Among Chinese, compared to the 1st generation, the 3rd generation had increased likelihood of being obese (OR = 6.29, 95%CI = 2.38-16.6). CONCLUSION: Compared to Whites, Hispanics, and Blacks, Asian immigrants are less likely to be obese. Among Asians, 2nd and 3rd generations were more likely to be obese compared to 1st generation. The obesity rate seems to increase the longer Asian immigrants remain in the U.S.

CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model.

BACKGROUND/OBJECTIVES: CYP2A6 (CYP2A5 in mice) is mainly expressed in the liver. Hepatic CYP2A6 expression is increased in patients with non-alcoholic fatty liver disease (NAFLD). In mice, hepatic CYP2A5 is induced by high fat diet (HFD) feeding. Hepatic CYP2A5 is also increased in monosodium glutamate-induced obese mice. NAFLD is associated with obesity. In this study, we examined whether obesity is related to CYP2A6. SUBJECTS/METHODS: Obesity genetic association study: The SAGE is a comprehensive genome-wide association study (GWAS) with case subjects having a lifetime history of alcohol dependence and control subjects never addicted to alcohol. We used 1030 control individuals with self-reported height and weight. A total of 12 single nucleotide polymorphisms (SNP) within the CYP2A6 gene were available. Obesity was determined as a BMI ≥30: 30-34.9 (Class I obesity) and ≥35 (Class II and III obesity). Animal experiment study: CYP2A5 knockout (cyp2a5-/-) mice and wild type (cyp2a5+/+) mice were fed HFD for 14 weeks. Body weight was measured weekly. After an overnight fast, the mice were sacrificed. Liver and blood were collected for biochemical assays. RESULTS: Single marker analysis showed that three SNPs (rs8192729, rs7256108, and rs7255443) were associated with class I obesity (p < 0.05). The most significant SNP for obesity was rs8192729 (odds ratio (OR) = 1.94, 95% confidence intervals = 1.21-3.10, p = 0.00582). After HFD feeding, body weight was increased in cyp2a5-/- mice to a greater extent than in cyp2a5+/+ mice, and fatty liver was more pronounced in cyp2a5-/- mice than in cyp2a5+/+ mice. PPARα deficiency in cyp2a5-/- mice developed more severe fatty liver, but body weight was not increased significantly. CONCLUSION: CYP2A6 is associated with human obesity; CYP2A5 protects against obesity and NAFLD in mice. PPARα contributes to the CYP2A5 protective effects on fatty liver but it opposes to the protective effects on obesity.

Health Care Provider Intervention and Utilization of Cessation Assistance in 12 Low- and Middle-Income Countries.

Background and Aim: There is a need to improve utilization of cessation assistance in low- and middle-income countries (LMICs), and tobacco cessation research has been identified as priority in LMICs. This study evaluates the relationship between health care provider intervention and cessation assistance utilization in LMICs. Methods: Data from 13 967 participants (aged ≥15 years, 90.3% males) of the Global Adults Tobacco Survey conducted in 12 LMICs (74.3%-97.3% response rates) were analyzed with utilization of counseling/cessation clinic, WHO-recommended medications, and quitline as outcome variables. Health care provider intervention ("no intervention," only "tobacco screening," "quit advice") was the exposure variable. Weighted multiple logistic regression models were used to examine the relationship between each outcome variable and the exposure variable, adjusting for other covariates. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are reported. Results: Approximately 52%, 8%, and 40% of participants received no intervention, only tobacco screening, and advice to quit, respectively. Overall, 0.4%, 1.9%, 3.0%, and 4.5% used quitline, WHO-recommended medications, counseling/cessation clinic, and any cessation assistance, respectively. Compared with no intervention, quit advice was associated with increased utilization of quitline (OR = 2.24, 95% CI = 1.2 to 4.4), WHO-recommended medications (OR = 1.67, 95% CI = 1.2 to 2.3), counseling/cessation clinic (OR = 4.41, 95% CI = 3.2 to 6.1), and any assistance (any of the three types) (OR = 2.80, 95% CI = 2.2 to 3.6). Conclusion: The findings of this study suggest that the incorporation of quit advice by health care providers in tobacco control programs and health care systems in LMICs could potentially improve utilization of cessation assistance to improve smoking cessation in LMICs. Implications: This first study of association between health care provider intervention and the utilization of cessation assistance in LMICs reports that there was a missed opportunity to provide quit advice to about 60% of smokers who visited a health care provider in the past year. The odds of utilization of counseling/cessation clinic, WHO-recommended medications, and quitline were significantly increased in participants who were advised to quit smoking. The results suggest that effective integration and implementation of advice to quit in tobacco control programs and the national health care systems may increase the use of cessation assistance to quit smoking.

Transcriptome-wide piRNA profiling in human brains for aging genetic factors.

OBJECTIVE: Piwi-interacting RNAs (piRNAs) represent a molecular feature shared by all nonaging biological systems, including the germline and somatic cancer stem cells, which display an indefinite renewal capacity and lifespan-stable genomic integrity and are potentially immortal. Here, we tested the hypothesis that piRNA is a critical genetic determinant of aging in humans. METHODS: Expression of transcriptome-wide piRNAs (n=24k) was profiled in the human prefrontal cortex of 12 subjects (84.9±9.5, range 68-100, years of age) using microarray technology. We examined the correlation between these piRNAs' expression levels and age, adjusting for covariates including disease status. RESULTS: A total of 9,453 piRNAs were detected in brain. Including seven intergenic and three intronic piRNAs, ten piRNAs were significantly associated with age after correction for multiple testing (|r|=0.9; 1.9×10-5≤p≤9.9×10-5). CONCLUSION: We conclude that piRNAs might play a potential role in determining the years of survival of humans. The underlying mechanisms might involve the suppression of transposable elements (TEs) and expression regulation of aging-associated genes.