Do alternative tobacco products induce less adverse respiratory risk than cigarettes?

RATIONALE: Due to the relatively short existence of alternative tobacco products, gaps exist in our current understanding of their long-term respiratory health effects. We therefore undertook the first-ever side-by-side comparison of the impact of chronic inhalation of aerosols emitted from electronic cigarettes (EC) and heated tobacco products (HTP), and combustible cigarettes (CC) smoke. OBJECTIVES: To evaluate the potential differential effects of alternative tobacco products on lung inflammatory responses and efficacy of vaccination in comparison to CC. METHODS: Mice were exposed to emissions from EC, HTP, CC, or air for 8 weeks. BAL and lung tissue were analyzed for markers of inflammation, lung damage, and oxidative stress. Another group was exposed for 12 weeks and vaccinated and challenged with a bacterial respiratory infection. Antibody titers in BAL and sera and pulmonary bacterial clearance were assessed. MAIN RESULTS: EC- and HTP-aerosols significantly augmented lung immune cell infiltrates equivalent to that achieved following CC-exposure. HTP and CC significantly increased neutrophil numbers compared to EC. All products augmented numbers of B cells, T cells, and pro-inflammatory IL17A+ T cells in the lungs. Decreased lung antioxidant activity and lung epithelial and endothelial damage was induced by all products. EC and HTP differentially augmented inflammatory cytokines/chemokines in the BAL. Generation of immunity following vaccination was impaired by EC and HTP but to a lesser extent than CC, with a CC > HTP > EC hierarchy of suppression of pulmonary bacterial clearance. CONCLUSIONS: HTP and EC-aerosols induced a proinflammatory pulmonary microenvironment, lung damage, and suppressed efficacy of vaccination.

Does the urinary microbiome profile change after treatment of bladder cancer?

INTRODUCTION: We sought to investigate the change in the urinary microbiome profile after transurethral resection of bladder tumor (TURBT). METHODS: Urine specimens were collected from consecutive patients with bladder cancer. Patients were divided into those with bladder tumors ("Tumor group": de novo tumors or recurrent/progressed after TURBT ± intravesical therapy) versus those without evidence of recurrence after treatment "No Recurrent Tumor group". Samples were analyzed using 16S rRNA sequencing. Alteration in the urinary microbiome was described in terms of alpha (diversity within a sample measured by Observed, Chao, Shannon, and Simpson indices), beta diversities (diversity among different samples measured by Brady Curtis Diversity index), and differential abundance of bacteria at the genus level. Analyses were adjusted for gender, method of preservation (frozen vs preservative), and method of collection (mid-stream vs. catheter). RESULTS: Sixty-eight samples were analyzed (42 in "Tumor" vs 26 in "No Recurrent Tumor" groups). The median age was 70 years (IQR 64-74) and 85% were males. All patients in the "No Recurrent Tumor" group had non-muscle invasive bladder cancer and 85% received BCG compared to 69% and 43% for the "Tumor" group, respectively. There was no significant difference in alpha diversity (p > 0.05). Beta diversity was significantly different (p = 0.04). Veillonella and Bifidobacterium were more abundant in the "Tumor" group (> 2FC, p = 0.0002), while Escherichia-Shigella (> 2FC, p = 0.0002) and Helococcus (> 2FC, p = 0.0008) were more abundant in the "No Recurrent Tumor" group. CONCLUSION: Bladder cancer patients with no recurrence and/or progression exhibited a different urinary microbiome profile compared to those with tumors.

The Urinary Microbiome and Bladder Cancer.

Bladder cancer is the 10th most common cancer worldwide. Approximately 75% of patients with bladder cancer will present with non-muscle invasive disease. Patients are usually treated with transurethral resection of bladder tumor (TURBT), in addition to adjuvant intravesical therapy (chemotherapy or anti-cancer immunotherapy with Bacillus Calmette Guerin- BCG) for those at intermediate-risk and high-risk of recurrence and progression. For many years, urine has been thought to be "sterile"; however, advanced microbiological and molecular techniques, including 16S ribosomal RNA (16S rRNA) sequencing, have negated that previous paradigm and confirmed the presence of a urinary microbiome. The urinary microbiome has been associated with several urological diseases, including interstitial cystitis, urgency urinary incontinence, neurogenic bladder dysfunction, and others. More recently, many reports are emerging about the role of the urinary microbiome in urothelial carcinogenesis, including gender disparity in bladder cancer and responses to treatments. The urinary microbiome may serve as a biomarker that can help with risk stratification as well as prediction of the response to intravesical therapies. However, the microbiome literature has been hampered by the lack of a unified standardized methodology for sample collection, type, preservation, processing, as well as bioinformatics analysis. Herein we describe and critique the literature on the association between urinary microbiome and bladder cancer and highlight some of the future directions.

Not all vaping is the same: differential pulmonary effects of vaping cannabidiol versus nicotine.

RATIONALE: Vaping has become a popular method of inhaling various psychoactive substances. While evaluating respiratory effects of vaping have primarily focused on nicotine-containing products, cannabidiol (CBD)-vaping is increasingly becoming popular. It currently remains unknown whether the health effects of vaping nicotine and cannabinoids are similar. OBJECTIVES: This study compares side by side the pulmonary effects of acute inhalation of vaporised CBD versus nicotine. METHODS: In vivo inhalation study in mice and in vitro cytotoxicity experiments with human cells were performed to assess the pulmonary damage-inducing effects of CBD or nicotine aerosols emitted from vaping devices. MEASUREMENTS AND MAIN RESULTS: Pulmonary inflammation in mice was scored by histology, flow cytometry, and quantifying levels of proinflammatory cytokines and chemokines. Lung damage was assessed by histology, measurement of myeloperoxidase activity and neutrophil elastase levels in the bronchoalveolar lavage fluid and lung tissue. Lung epithelial/endothelial integrity was assessed by quantifying BAL protein levels, albumin leak and pulmonary FITC-dextran leak. Oxidative stress was determined by measuring the antioxidant potential in the BAL and lungs. The cytotoxic effects of CBD and nicotine aerosols on human neutrophils and human small airway epithelial cells were evaluated using in vitro air-liquid interface system. Inhalation of CBD aerosol resulted in greater inflammatory changes, more severe lung damage and higher oxidative stress compared with nicotine. CBD aerosol also showed higher toxicity to human cells compared with nicotine. CONCLUSIONS: Vaping of CBD induces a potent inflammatory response and leads to more pathological changes associated with lung injury than vaping of nicotine.

Decursin inhibits EGFR-ERK1/2 signaling axis in advanced human prostate carcinoma cells.

We have shown that decursin, a coumarin compound, induces cell cycle arrest and apoptosis in human prostate cancer cells (PCa); however, its molecular mechanisms are largely unexplored. We studied the mechanisms associated with its anticancer activity in advanced human prostate carcinoma cells. We found that decursin inhibited epidermal growth factor receptor (EGFR) signaling by inhibiting its activating phosphorylation at tyrosine 1068 residue in DU145 and 22Rv1 cells. This inhibition of EGFR was associated with the downregulation of ERK1/2 phosphorylation. Both EGFR and ERK1/2 are known to be deregulated/activated in many human malignancies. Consistent with our earlier study, decursin (25-100 µM) treatment for 24-72 h inhibited DU145 cell proliferation by 49%-87% (p < 0.001) which was associated with strong G1 phase arrest and cell death. It also decreased (p < 0.001) the number of surviving colonies. Decursin moderately increased the expression of Rb-related proteins p107 and p130 but decreased the levels of E2F family transcription factors including E2F-3, E2F-4 and E2F-5. Further, decursin strongly inhibited the growth of androgen-dependent prostate carcinoma 22Rv1 cells from 61% to 79% (p < 0.001) and arrested these cells at G1 phase via induction of cyclin-dependent kinase inhibitor p27/Kip1 and downregulation of CDK2 and CDK4 protein expression. Additionally, EGFR inhibitor erlotinib- and EGF ligand-modulated EGFR activation validated EGFR signaling as a target of decursin-mediated cell growth inhibition and cytotoxicity. Decursin decreased EGF ligand-induced phosphorylation of EGFR (Y-1068) as well as activation of its downstream mediator, ERK1/2. Furthermore, inhibitory targeting of EGFR-ERK1/2 axis by combinatorial treatment of decursin and erlotinib further sensitized DU145 cells for the decursin-induced growth inhibition and cell death. Overall, these findings strongly suggest that anticancer efficacy of decursin against human PCa involves inhibitory targeting of EGFR-ERK1/2 signaling axis, a pathway constitutively active in advanced PCa.

Hypertensive Phenotypes and Pattern of Ambulatory Blood Pressure in Patients of Diabetes Mellitus of Kashmir Valley.

Background: Patients of diabetes mellitus (DM) with hypertension (HTN) have a fourfold increased risk of cardiovascular disease (CVD) as compared to normotensive nondiabetic controls. However, many patients of DM who are normotensive or have controlled blood pressure on office BP measurement (OBPM) may assume that they do not have increased risk of CVD but may be having HTN or uncontrolled blood pressure on ambulatory blood pressure monitoring (ABPM). Study Design Objective: A cross-sectional observational study to compare OBPM with ABPM and thus predict various hypertensive phenotypes like masked hypertension (MH) and white coat hypertension and pattern of blood pressure in diabetic patients of our population. Materials and Methods: Two hundred patients of DM with or without HTN were included in this study. The cases were subjected to detailed history, clinical examination, OBPM, and ABPM. Results: Out of 200 patients of DM, 32 were normotensives, 46 were hypertensives controlled on antihypertensive treatment, 22 were hypertensives not on anti-hypertensive treatment, and 100 were hypertensives uncontrolled on anti-hypertensive treatment. Among 32 normotensive diabetics, 17 (53%) patients had MH on ABPM. Out of these 32 normotensive patients, 7 (21.8%) had isolated nocturnal hypertension, 3 (9.3%) had isolated day-time HTN (IDH) and 7 (21.8%) had day-time and nocturnal HTN (DNH). Patients with MH had higher BMI, an observation that was statistically significant. Non-dipping pattern was found in 53% of patients of masked HTN. Out of 46 hypertensive diabetics with controlled OBPM on antihypertensive treatment, 26 (56.5%) had masked effect or masked uncontrolled hypertension on ABPM. Out of 22 diabetics with treatment naïve HTN, 7 (32%) were found to have white coat hypertension on ABPM. Fifteen (15%) patients out of 100 hypertensive diabetics with uncontrolled OBPM despite on anti-hypertensive were found to have white coat effect on ABPM. Patients with white coat effect had higher body mass index an observation that was statistically significant (p = 0.039). Non-dipping pattern was significantly associated with longer duration of diabetes (≥ 120 months), retinopathy and neuropathy. Conclusion: To rely exclusively on OBPM to diagnose HTN and monitor blood pressure may underestimate the CVD risk especially in diabetics. ABPM is a tool that may not only help clinicians in starting anti-HTN treatment perspicuously, but also may help in avoiding unnecessary anti-hypertensive treatment and/or withdrawing anti-hypertensive treatment as indicated and thus avoiding credulity.

AT-RvD1 Mitigates Secondhand Smoke-Exacerbated Pulmonary Inflammation and Restores Secondhand Smoke-Suppressed Antibacterial Immunity.

Cigarette smoke is a potent proinflammatory trigger contributing to acute lung injury and the development of chronic lung diseases via mechanisms that include the impairment of inflammation resolution. We have previously demonstrated that secondhand smoke (SHS) exposure exacerbates bacterial infection-induced pulmonary inflammation and suppresses immune responses. It is now recognized that resolution of inflammation is a bioactive process mediated by lipid-derived specialized proresolving mediators that counterregulate proinflammatory signaling and promote resolution pathways. We therefore hypothesized that proresolving mediators could reduce the burden of inflammation due to chronic lung infection following SHS exposure and restore normal immune responses to respiratory pathogens. To address this question, we exposed mice to SHS followed by chronic infection with nontypeable Haemophilus influenzae (NTHI). Some groups of mice were treated with aspirin-triggered resolvin D1 (AT-RvD1) during the latter half of the smoke exposure period or during a period of smoking cessation and before infection. Treatment with AT-RvD1 markedly reduced the recruitment of neutrophils, macrophages, and T cells in lung tissue and bronchoalveolar lavage and levels of proinflammatory cytokines in the bronchoalveolar lavage. Additionally, treatment with AT-RvD1 improved Ab titers against the NTHI outer membrane lipoprotein Ag P6 following infection. Furthermore, treatment with AT-RvD1 prior to classically adjuvanted immunization with P6 increased Ag-specific Ab titers, resulting in rapid clearance of NTHI from the lungs after acute challenge. Collectively, we have demonstrated that AT-RvD1 potently reverses the detrimental effects of SHS on pulmonary inflammation and immunity and thus could be beneficial in reducing lung injury associated with smoke exposure and infection.

Acute Effects of Heated Tobacco Product (IQOS) Aerosol Inhalation on Lung Tissue Damage and Inflammatory Changes in the Lungs.

INTRODUCTION: Emerging heated tobacco products (HTPs) were designed to reduce exposure to toxicants from cigarette smoke (CS) by avoiding burning tobacco and instead heating tobacco. We studied the effects of short-term inhalation of aerosols emitted from HTP called IQOS, on lung damage and immune-cell recruitment to the lungs in mice. METHODS: Numerous markers of lung damage and inflammation including albumin and lung immune-cell infiltrates, proinflammatory cytokines, and chemokines were quantified in lungs and bronchoalveolar (BAL) fluid from IQOS, CS, or air-exposed (negative control) mice. RESULTS: Importantly, as a surrogate marker of lung epithelial-cell damage, we detected significantly increased levels of albumin in the BAL fluid of both HTP- and CS-exposed mice compared with negative controls. Total numbers of leukocytes infiltrating the lungs were equivalent following both IQOS aerosols and CS inhalation and significantly increased compared with air-exposed controls. We also observed significantly increased numbers of CD4+IL-17A+ T cells, a marker of a T-cell immune response, in both groups compared with air controls; however, numbers were the highest following CS exposure. Finally, the numbers of CD4+RORγt+ T cells, an inflammatory T-cell subtype expressing the transcription factor that is essential for promoting differentiation into proinflammatory Th17 cells, were significantly augmented in both groups compared with air-exposed controls. Levels of several cytokines in BAL were significantly elevated, reflecting a proinflammatory milieu. CONCLUSIONS: Our study demonstrates that short-term inhalation of aerosols from IQOS generates damage and proinflammatory changes in the lung that are substantially similar to that elicited by CS exposure. IMPLICATIONS: Exposure of mice to IQOS, one of the candidate modified-risk tobacco products, induces inflammatory immune-cell accumulation in the lungs and augments the levels of proinflammatory cytokines and chemokines in the BAL fluid. Such an exacerbated pulmonary proinflammatory microenvironment is associated with lung epithelial-cell damage in IQOS-exposed mice, suggesting a potential association with the impairment of lung function.

Specialized Proresolving Mediators Overcome Immune Suppression Induced by Exposure to Secondhand Smoke.

Tobacco smoke exposure is associated with multiple diseases including, respiratory diseases like asthma and chronic obstructive pulmonary disease. Tobacco smoke is a potent inflammatory trigger and is immunosuppressive, contributing to increased susceptibility to pulmonary infections in smokers, ex-smokers, and vulnerable populations exposed to secondhand smoke. Tobacco smoke exposure also reduces vaccine efficacy. Therefore, mitigating the immunosuppressive effects of chronic smoke exposure and improving the efficacy of vaccinations in individuals exposed to tobacco smoke, is a critical unmet clinical problem. We hypothesized that specialized proresolving mediators (SPMs), a class of immune regulators promoting resolution of inflammation, without being immunosuppressive, and enhancing B cell Ab responses, could reverse the immunosuppressive effects resulting from tobacco smoke exposure. We exposed mice to secondhand smoke for 8 wk, followed by a period of smoke exposure cessation, and the mice were immunized with the P6 lipoprotein from nontypeable Haemophilus influenzae, using 17-HDHA and aspirin-triggered-resolvin D1 (AT-RvD1) as adjuvants. 17-HDHA and AT-RvD1 used as adjuvants resulted in elevated serum and bronchoalveolar lavage levels of anti-P6-specific IgG and IgA that were protective, with immunized mice exhibiting more rapid bacterial clearance upon challenge, reduced pulmonary immune cell infiltrates, reduced production of proinflammatory cytokines, and less lung-epithelial cell damage. Furthermore, the treatment of mice with AT-RvD1 during a period of smoke-cessation further enhanced the efficacy of SPM-adjuvanted P6 vaccination. Overall, SPMs show promise as novel vaccine adjuvants with the ability to overcome the tobacco smoke-induced immunosuppressive effects.

Cytochrome c Deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer.

Although African-American (AA) patients with prostate cancer tend to develop greater therapeutic resistance and faster prostate cancer recurrence compared with Caucasian-American (CA) men, the molecular mechanisms of this racial prostate cancer disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and prostate cancer aggressiveness in AA men. In AA prostate cancer cells, decreased nuclear accumulation of nuclear respiration factor 1 (Nrf1) and its subsequent loss of binding to the cytochrome c promoter mediated cytochrome c deficiency. The activation of cellular Myc (c-Myc) and NF-κB or inhibition of AKT prevented nuclear translocation of Nrf1. Genetic and pharmacologic inhibition of c-Myc and NF-κB or activation of AKT promoted Nrf1 binding to cytochrome c promoter, cytochrome c expression, caspase activation, and cell death. The lack of p-Drp1S616 in AA prostate cancer cells contributed to defective cytochrome c release and increased resistance to apoptosis, indicating that restoration of cytochrome c alone may be insufficient to induce effective apoptosis. Cytochrome c deficiency promoted the acquisition of glycolytic phenotypes and mitochondrial dysfunction, whereas cytochrome c restoration via inhibition of c-Myc and NF-κB or activation of AKT attenuated glycolysis in AA prostate cancer cells. Inhibition of c-Myc and NF-κB enhanced the efficacy of docetaxel in tumor xenografts. Therefore, restoring cytochrome c may overcome therapeutic resistance and prostate cancer aggressiveness in AA men. Overall, this study provides the first comprehensive experimental, mechanistic, and clinical evidence for apoptosome and mitochondrial dysfunction in prostate cancer racial disparity. SIGNIFICANCE: Mechanistic insights on prostate cancer health disparity among American men provide novel approaches to restore mitochondrial function, which can address therapeutic resistance and aggressiveness in African-American men with prostate cancer.

Secondhand Smoke Induces Inflammation and Impairs Immunity to Respiratory Infections.

Despite advocacy to reduce smoking-related diseases, >1 billion people worldwide continue to smoke. Smoking is immunosuppressive and an important etiological factor in the development of several human disorders including respiratory diseases like chronic obstructive pulmonary disease. However, there is a critical gap in the knowledge of the role of secondhand smoke (SHS) in inflammation and immunity. We therefore studied the influence of SHS on pulmonary inflammation and immune responses to respiratory infection by nontypeable Haemophilus influenzae (NTHI) recurrently found in chronic obstructive pulmonary disease patients. Chronic SHS-exposed mice were chronically infected with NTHI and pulmonary inflammation was evaluated by histology. Immune cell numbers and cytokines were measured by flow cytometry and ELISA, respectively. Chronic SHS exposure impaired NTHI P6 Ag-specific B and T cell responses following chronic NTHI infection as measured by ELISPOT assays, reduced the production of Abs in serum and bronchoalveolar lavage, and enhanced albumin leak into the bronchoalveolar lavage as determined by ELISA. Histopathological examination of lungs revealed lymphocytic accumulation surrounding airways and bronchovasculature following chronic SHS exposure and chronic infection. Chronic SHS exposure enhanced the levels of inflammatory cytokines IL-17A, IL-6, IL-1ß, and TNF-α in the lungs, and impaired the generation of adaptive immunity following either chronic infection or P6 vaccination. Chronic SHS exposure diminished bacterial clearance from the lungs after acute NTHI challenge, whereas P6 vaccination improved clearance equivalent to the level seen in air-exposed, non-vaccinated mice. Our study provides unequivocal evidence that SHS exposure has long-term detrimental effects on the pulmonary inflammatory microenvironment and immunity to infection and vaccination.

Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer.

Abrogation of endoplasmic reticulum (ER) protein folding triggered by exogenous or endogenous factors, stimulates a cellular stress response, termed ER stress. ER stress re-establishes ER homeostasis through integrated signaling termed the ER-unfolded protein response (UPRER). In the presence of severe toxic or prolonged ER stress, the pro-survival function of UPRER is transformed into a lethal signal transmitted to and executed through mitochondria. Mitochondria are key for both apoptotic and autophagic cell death. Thus ER is vital in sensing and coordinating stress pathways to maintain overall physiological homeostasis. However, this function is deregulated in cancer, resulting in resistance to apoptosis induction in response to various stressors including therapeutic agents. Here we review the connections between ER stress and mitochondrial apoptosis, describing potential cancer therapeutic targets.

Mitochondrial dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African-American men with prostate cancer.

BACKGROUND: African-American (AA) patients with prostate cancer (PCa) respond poorly to current therapy compared with Caucasian American (CA) PCa patients. Although underlying mechanisms are not defined, mitochondrial dysfunction is a key reason for this disparity. METHODS: Cell death, cell cycle, and mitochondrial function/stress were analysed by flow cytometry or by Seahorse XF24 analyzer. Expression of cellular proteins was determined using immunoblotting and real-time PCR analyses. Cell survival/motility was evaluated by clonogenic, cell migration, and gelatin zymography assays. RESULTS: Glycolytic pathway inhibitor dichloroacetate (DCA) inhibited cell proliferation in both AA PCa cells (AA cells) and CA PCa cells (CA cells). AA cells possess reduced endogenous reactive oxygen species, mitochondrial membrane potential (mtMP), and mitochondrial mass compared with CA cells. DCA upregulated mtMP in both cell types, whereas mitochondrial mass was significantly increased in CA cells. DCA enhanced taxol-induced cell death in CA cells while sensitising AA cells to doxorubicin. Reduced expression of heat shock proteins (HSPs) was observed in AA cells, whereas DCA induced expression of CHOP, C/EBP, HSP60, and HSP90 in CA cells. AA cells are more aggressive and metastatic than CA cells. CONCLUSIONS: Restoration of mitochondrial function may provide new option for reducing PCa health disparity among American men.

A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy.

X-chromosome-linked inhibitor of apoptosis protein (XIAP) has an important regulatory role in programmed cell death by inhibiting the caspase cascade. Activation of XIAP-dependent signaling culminates into regulation of multiple cellular processes including apoptosis, innate immunity, epithelial-to-mesenchymal transition, cell migration, invasion, metastasis and differentiation. Although XIAP localizes to the cytosolic compartment, XIAP-mediated cellular signaling encompasses mitochondrial and post-mitochondrial levels. Recent findings demonstrate that XIAP also localizes to mitochondria and regulates mitochondria functions. XIAP acts upstream of mitochondrial cytochrome c release and modulates caspase-dependent apoptosis. The new function of XIAP has potential to enhance mitochondrial membrane permeabilization and other cellular functions controlling cytochrome c release. These findings could exploit the overexpression of XIAP in human tumors for therapeutic benefits.

Immune Dysfunction in Patients with Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a complex chronic disease. Chronic inflammation is the hallmark of COPD, involving the interplay of a wide variety of cells in the lung microenvironment. Cigarette smoke (CS) induces chronic lung inflammation and is considered a key etiological factor in the development and pathogenesis of COPD. Structural and inflammatory cells in the lung respond to CS exposure by releasing proinflammatory mediators that recruit additional inflammatory immune cells, which collectively contribute to the establishment of a chronic inflammatory microenvironment. Chronic inflammation contributes to lung damage, compromises innate and adaptive immune responses, and facilitates the recurrent episodes of respiratory infection that punctuate and further contribute to the pathological manifestations of the stable disease. A number of studies support the conclusion that immune dysfunction leads to exacerbations and disease severity in COPD. Our group has clearly demonstrated that CS exacerbates lung inflammation and compromises immunity to respiratory pathogens in a mouse model of COPD. We have also investigated the phenotype of immune cells in patients with COPD compared with healthy control subjects and found extensive immune dysfunction due to the presence and functional activity of T regulatory cells, CD4(+)PD-1(+) exhausted effector T cells and myeloid-derived suppressor cells. Manipulation of these immunosuppressive networks in COPD could provide a rational strategy to restore functional immune responses, reduce exacerbations, and improve lung function. In this review, we discuss the role of immune dysfunction in COPD that may contribute to recurrent respiratory infections and disease severity.

Restoration of mitochondria function as a target for cancer therapy.

Defective oxidative phosphorylation has a crucial role in the attenuation of mitochondrial function, which confers therapy resistance in cancer. Various factors, including endogenous heat shock proteins (HSPs) and exogenous agents such as dichloroacetate, restore respiratory and other physiological functions of mitochondria in cancer cells. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents. Here, we summarize the key reasons contributing to mitochondria dysfunction in cancer cells and how restoration of mitochondrial function could be exploited for cancer therapeutics.

Acacetin inhibits in vitro and in vivo angiogenesis and downregulates Stat signaling and VEGF expression.

Angiogenesis is an effective target in cancer control. The antiangiogenic efficacy and associated mechanisms of acacetin, a plant flavone, are poorly known. In the present study, acacetin inhibited growth and survival (up to 92%; P < 0.001), and capillary-like tube formation on Matrigel (up to 98%; P < 0.001) by human umbilical vein endothelial cells (HUVEC) in regular condition, as well as VEGF-induced and tumor cells conditioned medium-stimulated growth conditions. It caused retraction and disintegration of preformed capillary networks (up to 91%; P < 0.001). HUVEC migration and invasion were suppressed by 68% to 100% (P < 0.001). Acacetin inhibited Stat-1 (Tyr701) and Stat-3 (Tyr705) phosphorylation, and downregulated proangiogenic factors including VEGF, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2), and basic fibroblast growth factor (bFGF) in HUVEC. It also suppressed nuclear localization of pStat-3 (Tyr705). Acacetin strongly inhibited capillary sprouting and networking from rat aortic rings and fertilized chicken egg chorioallantoic membrane (CAM; ∼71%; P < 0.001). Furthermore, it suppressed angiogenesis in Matrigel plugs implanted in Swiss albino mice. Acacetin also inhibited tyrosine phosphorylation of Stat-1 and -3, and expression of VEGF in cancer cells. Overall, acacetin inhibits Stat signaling and suppresses angiogenesis in vitro, ex vivo, and in vivo, and therefore, it could be a potential agent to inhibit tumor angiogenesis and growth.

Guillain-barré syndrome in pregnancy: an unusual case.

Guillain-Barré syndrome (GBS) is rare in pregnancy with an estimated incidence between 1.2 and 1.9 cases per 100,000 people annually, and it carries a high maternal risk. We report a 29-year-old primigravida who had pain and progressive heaviness of both lower limbs in her third trimester of pregnancy. The attending gynecologist ascribed these symptoms to ongoing pregnancy. The intrapartum period (lower segment caesarian section) passed uneventfully. On third postpartum day, the patient developed weakness of all the four limbs. A detailed history and physical examination pointed toward GBS although there was no antecedent infective episode. Subsequent nerve conduction velocity studies and cerebrospinal fluid analysis confirmed GBS. All other investigations including electrolytes were normal. The patient improved without the introduction of immunomodulating therapy.

Fisetin inhibits various attributes of angiogenesis in vitro and in vivo--implications for angioprevention.

Studies have shown that fisetin, a small phytochemical molecule, has antitumor activity; however, its antiangiogenic activity has not yet been examined. Accordingly, herein, we investigated the antiangiogenic efficacy and associated mechanisms of fisetin in human umbilical vein endothelial cells (HUVECs). Fisetin (10-50 µM) strongly inhibited the regular serum plus growth supplement- and vascular endothelial growth factor (VEGF)-induced growth (up to 92%, P < 0.001) and survival (up to 16%, P < 0.001) of HUVEC in a dose- and time-dependent manner. Fisetin also caused cell cycle arrest at G(1) (strong) and G(2)/M (moderate) phases together with a decrease in cyclin D1 and an increase in p53 levels. Fisetin-caused cell death was accompanied by decreased expression of survivin and an increase in cleaved levels of caspases-3 and -7 and poly-(ADP-ribose) polymerase along with an increased ratio of Bax to Bcl-2. Furthermore, fisetin inhibited capillary-like tube formation on Matrigel (up to 85%, P < 0.001) as well as migration (up to 66%, P < 0.001), which were associated with decreased expression of endothelial nitric oxide synthase (eNOS) and VEGF in HUVEC. It also decreased the expression of eNOS, VEGF, inducible nitric oxide synthase, matrix metalloproteinase-2 and -9 in A549 and DU145 human cancer cells. In vivo matrigel plug assay in mice showed significant decrease in size (up to 43%, P < 0.001), vascularization and hemoglobin content (up to 94%, P < 0.001) in the plugs from fisetin-treated, compared with control mice. Overall, these results suggest that fisetin inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects, and therefore, fisetin warrants further investigation for its angiopreventive potential toward cancer control.