Prognostic Significance of the Coagulation and Complement Systems in Critical COVID-19 Infection.

Infection with the SARS-CoV-2 virus (COVID-19 disease) can cause a wide range of clinical situations - from an asymptomatic state to fatal outcomes. In cases of serious clinical manifestations, the underlying mechanisms involve a number of immune cells and stromal cells as well as their products such as pro-inflammatory interleukin-6 and tumour necrosis factor-alpha that ultimately cause the cytokine storm. The situation of overproduction of pro-inflammatory cytokines is somewhat similar to, though in a mild form, health conditions in obesity and related metabolic disorders like type-2 diabetes, which are also considered important risk factors for severe illness in COVID-19. Interestingly, neutrophils perhaps play a significant role in this pathogenesis. On the other hand, it is thought that COVID-19-related critical illness is associated with pathological hyperactivity of the complement system and coagulopathy. Although the precise molecular interactions between the complement and coagulation systems are not clear, we observe an intimate cross-talk between these two systems in critically ill COVID-19 patients. It is believed that both of these biological systems are connected with the cytokine storm in severe COVID-19 disease and actively participate in this vicious cycle. In order to hinder the pathological progression of COVID-19, a number of anticoagulation agents and complement inhibitors have been used with varying success. Among these drugs, low molecular weight heparin enoxaparin, factor Xa inhibitor apixaban, and complement C5 inhibitor eculizumab have been commonly used in patients with COVID-19. Our overall experience might help us in the future to tackle any such conditions.

Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway.

BACKGROUND: In menopausal women, one of the critical risk factors for breast cancer is obesity/adiposity. It is evident from various studies that leptin, a 16 kDa protein hormone overproduced in obese people, plays the critical role in neovascularization and tumorigenesis in breast and other organs. However, the mechanisms by which obesity influences the breast carcinogenesis remained unclear. In this study, by analyzing different estrogen receptor-α (ER-α)-positive and ER-α-negative BC cell lines, we defined the role of CCN5 in the leptin-mediated regulation of growth and invasive capacity. METHODS: We analyzed the effect of leptin on cell viability of ER-α-positive MCF-7 and ZR-75-1 cell lines and ER-α-negative MDA-MB-231 cell line. Additionally, we also determined the effect of leptin on the epithelial-mesenchymal transition (EMT) bio-markers, in vitro invasion and sphere-formation of MCF-7 and ZR-75-1 cell lines. To understand the mechanism, we determined the impact of leptin on CCN5 expression and the functional role of CCN5 in these cells by the treatment of human recombinant CCN5 protein(hrCCN5). Moreover, we also determined the role of JAK-STAT and AKT in the regulation of leptin-induced suppression of CCN5 in BC cells. RESULTS: Present studies demonstrate that leptin can induce cell viability, EMT, sphere-forming ability and migration of MCF-7 and ZR-75-1 cell lines. Furthermore, these studies found that leptin suppresses the expression of CCN5 at the transcriptional level. Although the CCN5 suppression has no impact on the constitutive proliferation of MCF-7 and ZR-75-1 cells, it is critical for leptin-induced viability and necessary for EMT, induction of in vitro migration and sphere formation, as the hrCCN5 treatment significantly inhibits the leptin-induced viability, EMT, migration and sphere-forming ability of these cells. Mechanistically, CCN5-suppression by leptin is mediated via activating JAK/AKT/STAT-signaling pathways. CONCLUSIONS: These studies suggest that CCN5 serves as a gatekeeper for leptin-dependent growth and progression of luminal-type (ER-positive) BC cells. Leptin may thus need to destroy the CCN5-barrier to promote BC growth and progression via activating JAK/AKT/STAT signaling. Therefore, these observations suggest a therapeutic potency of CCN5 by restoration or treatment in obese-related luminal-type BC growth and progression.

Biological characteristics of CCN proteins in tumor development.

The extracellular membrane (ECM) is no longer regarded as inert, rather it has multiple versatile physiologic functions. Its diverse composition is implicated in each step of cancer progression including inflammation, angiogenesis, tumor invasion and metastasis. In addition to structural proteins, the ECM also contains a family of non-structural proteins called matricellular proteins. The six secreted CCN proteins, which belong to the matricellular protein family, include the following: Cyr61 (CCN1), CTGF (CCN2), Nov (CCN3), WISP- 1 (CCN4), WISP-2 (CCN5) and WISP-3(CCN6). These proteins are capable of modulating a variety of biological processes in health as well as in disease conditions. In tumor development and in tumor microenvironment, CCN proteins can influence multiple facets of pathophysiological processes including cellular proliferation, invasion and metastasis. This review has attempted a cohesive look at the CCN family protein functions in a tumor-specific manner.

Small Circular DNAs in Human Pathology.

In general, human pathogen-related small circular deoxyribonucleic acid (DNA) molecules are bacterial plasmids and a group of viral genomes. Plasmids are extra-chromosomal small circular DNAs that are capable of replicating independently of the host, and are present throughout a variety of different microorganisms, most notably bacteria. While plasmids are not essential components of the host, they can impart an assortment of survival enhancing genes such as for fertility, drug resistance, and toxins. Furthermore, plasmids are of particular interest to molecular biology especially in relation to gene-cloning. Among viruses, genomes of anelloviruses, papillomaviruses, and polyomaviruses consist of small circular DNA. The latter two virus families are known for their potential roles in a number of pathogenic processes. Human papillomaviruses (HPV) are now widely recognised to be associated with a greatly increased risk of cervical cancer, especially oncogenic strains 16 and 18. On the other hand, human cells may contain several types of small circular DNA molecules including mitochondrial DNA (mtDNA). The mitochondrial genome consists of 37 genes that encode for proteins of the oxidation phosphorylation system, transfer ribonucleic acids (tRNAs), and ribosomal RNAs (rRNAs). Though mitochondria can replicate independently of the host; nuclear DNA does encode for several mitochondrial proteins. Mutations in mtDNA contribute to some well characterised diseases; mtDNA is also implicated in several diseases and malignancies with poorly elucidated aetiologies. Furthermore, mtDNA can function as a diagnostic tool. Other extra-chromosomal circular DNAs are usually detected in cancer. This review article is intended to provide an overview of four broad categories of small circular DNAs that are present in non-eukaryotic (plasmids and relevant viral genomes) and eukaryotic (mtDNA and other extra-chromosomal DNAs) systems with reference to human diseases, particularly cancer. For this purpose, a literature search has been carried out mainly from PubMed. Improved understanding of the significance of small circular DNA molecules is expected to have far reaching implications in many fields of medicine.

An Overview of Selected Bacterial Infections in Cancer, Their Virulence Factors, and Some Aspects of Infection Management.

In cancer development and its clinical course, bacteria can be involved in etiology and secondary infection. Regarding etiology, various epidemiological studies have revealed that Helicobacter pylori can directly impact gastric carcinogenesis. The Helicobacter pylori-associated virulence factor cytotoxin-associated gene A perhaps plays an important role through different mechanisms such as aberrant DNA methylation, activation of nuclear factor kappa B, and modulation of the Wnt/ß-catenin signaling pathway. Many other bacteria, including Salmonella and Pseudomonas, can also affect Wnt/ß-catenin signaling. Although Helicobacter pylori is involved in both gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma, its role in the latter disease is more complicated. Among other bacterial species, Chlamydia is linked with a diverse range of diseases including cancers of different sites. The cellular organizations of Chlamydia are highly complex. Interestingly, Escherichia coli is believed to be associated with colon cancer development. Microorganisms such as Escherichia coli and Pseudomonas aeruginosa are frequently isolated from secondary infections in cancer patients. In these patients, the common sites of infection are the respiratory, gastrointestinal, and urinary tracts. There is an alarming rise in infections with multidrug-resistant bacteria and the scarcity of suitable antimicrobial agents adversely influences prognosis. Therefore, effective implementation of antimicrobial stewardship strategies is important in cancer patients.

Infections and immunity: associations with obesity and related metabolic disorders.

About one-fourth of the global population is either overweight or obese, both of which increase the risk of insulin resistance, cardiovascular diseases, and infections. In obesity, both immune cells and adipocytes produce an excess of pro-inflammatory cytokines that may play a significant role in disease progression. In the recent coronavirus disease 2019 (COVID-19) pandemic, important pathological characteristics such as involvement of the renin-angiotensin-aldosterone system, endothelial injury, and pro-inflammatory cytokine release have been shown to be connected with obesity and associated sequelae such as insulin resistance/type 2 diabetes and hypertension. This pathological connection may explain the severity of COVID-19 in patients with metabolic disorders. Many studies have also reported an association between type 2 diabetes and persistent viral infections. Similarly, diabetes favors the growth of various microorganisms including protozoal pathogens as well as opportunistic bacteria and fungi. Furthermore, diabetes is a risk factor for a number of prion-like diseases. There is also an interesting relationship between helminths and type 2 diabetes; helminthiasis may reduce the pro-inflammatory state, but is also associated with type 2 diabetes or even neoplastic processes. Several studies have also documented altered circulating levels of neutrophils, lymphocytes, and monocytes in obesity, which likely modifies vaccine effectiveness. Timely monitoring of inflammatory markers (e.g., C-reactive protein) and energy homeostasis markers (e.g., leptin) could be helpful in preventing many obesity-related diseases.

Evaluation of cancer awareness, cancer education, and prevention intervention techniques among university-level students in the United States and India.

BACKGROUND: Cancer is one of the leading causes of death globally. A considerable number of different cancer types may be preventable, using primary intervention techniques, such as health education, cancer awareness, behaviors and lifestyle modifications. The present study conducted a comparative assessment of cancer awareness among undergraduate students of the United States and India. MATERIALS AND METHODS: Students from an Institution in India (KC) (55 females, 33 males), and an Institution in the United States of America (SHU) (226 female, 58 male) during 2019-2020 participated in this study. Participants (n = 372) across all majors and all years (first through fourth year) completed an online questionnaire and answered the questions on their demographic characteristics (e.g., gender, age, and location), academic status (e.g., year of study, major), multiple-choice questions about cancer knowledge, and opinion questions (e.g., "where would you find info," "should therapies be free"). Student responses were collected using Qualtrics Survey Software. Excel was used to analyze responses. We conducted statistical Χ2 tests for independence to determine whether there is a statistically significant difference between the expected frequencies and the observed frequencies in one or more categories of a contingency table, with a significance of ɑ = 0.01. While small sizes due to the small institutions and the response pool, we note that we achieved the necessary "n" for all tests reported. RESULTS: Our research shows a few important statistically significant differences, including knowledge of cancer and breast lumps is dependent on location, ranking of global cancer deaths is dependent on location, and that cancer knowledge is dependent on the information source. All for Χ2 tests with P < 0.001. CONCLUSIONS: Further encouragement of education for young people in various aspects of cancer and cancer prevention, as well as information facility and sources of reliable data, could be helpful for improving the overall health and primary prevention. A thorough assessment is needed to understand the responsible factors for the observed cancer knowledge variations among students of two different places.

Obesity and breast cancer: status of leptin and adiponectin in pathological processes.

It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin's growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin.

Mammary tumor development from T47-D human breast cancer cells in obese ovariectomized mice with and without estradiol supplements.

Obesity is a risk factor for postmenopausal breast cancer, particularly for development of estrogen-receptor (ER)-positive tumors. Additionally, obesity is implicated in breast cancer progression. However, few studies address mechanisms of action of how obesity mediates these responses. Our goal was to address how obesity and/or elevated serum leptin affects tumor formation from ER-positive T47-D cells. In Study 1 ovariectomized CD-1 nude female mice were injected with goldthioglucose (GTG) at 0.5 mg/g body weight in saline or the vehicle at 6 weeks of age. At 10 weeks of age mice were inoculated with T47-D cells and implanted with estrogen pellets. In Study 2 mice were injected with 0.3 mg/g GTG or the vehicle. At 10 weeks of age cells were inoculated and mice were implanted with estrogen or placebo pellets. Mice were followed until 30 weeks of age. Some GTG mice became obese and others were non-responders. In Study 1 no mice developed tumors. In Study 2 mice with placebo pellets developed more tumors than mice with estrogen pellets, 50% vs. 13%. GTG-obese mice with placebo pellets had a 100% tumor incidence compared to 50% and 20% for GTG-lean and controls without estrogen. Serum leptin was higher in obese compared to lean mice and adiponectin was not affected by body weight. Adiponectin:leptin ratio was significantly reduced in obese compared to lean mice. Leptin, leptin receptor and signaling protein expression were determined in mammary and tumor tissue. Leptin and STAT3 were most abundant in tumors. These findings suggest that in vivo estrogen suppressed proliferation of T47-D cells but without supplemental estrogen obesity enhanced tumor development. The exact reason for this is not presently clear.

Role of the adiponectin leptin ratio in prostate cancer.

We hypothesize that adiponectin and leptin may be capable of mediating some of the effects that body weight has on prostate cancer and that a mouse model may be effective to examine this hypothesis. We found that tumors from the TRAMP prostate cancer model expressed adiponectin and leptin receptors. TRAMP-C2 prostate cancer cell proliferation was reduced by adiponectin. Leptin was able to block the ability of adiponectin to reduce cell proliferation through altered signaling of the ERK pathway. Overall, this work suggests that adiponectin, leptin, and their receptors may play an important role in prostate cancer.

Effects of adiponectin and leptin co-treatment on human breast cancer cell growth.

Obesity is a risk factor for postmenopausal breast cancer (BC), but the specific mechanisms for this relationship are not well understood. Studies on adipocyte-derived adiponectin and leptin reveal opposing effects on BC cell proliferation in vitro, suggesting they may play a role in BC pathogenesis. In the current study we examined effects on proliferation of five BC cell lines treated with varying adiponectin:leptin (A/L) ratios. A decrease in proliferation was noted for MCF-7 and T47-D cells with increasing ratios (2-500), while an increase was seen in similarly treated MDA-MB-231 and MDA-MB-361 cells. For SK-BR-3 cells, an increase was seen at a ratio of 8. We identified differential effects on some pro-mitogenic, survival and apoptosis-related proteins in MCF-7 and T47-D cells treated at an A/L ratio of 100. Specifically, the AKT and MAPK pathways were not activated in MCF-7 cells, but AKT activation occured within 30 min and MAPK activation was sustained at 48 h in T47-D cells. p53 and Bax were elevated in MCF-7, but were below basal in T47-D cells at 30 min. While co-treatment enhanced apoptosis in MCF-7, similar treatment had the opposite effect in T47-D cells. There were no differences in cell cycle distribution between treated or untreated MCF-7 or T47-D, although T47-D cells had a slightly higher proportion in the G1/G0 phase after co-treatment. The effects of A/L ratio on mediating proliferation may have some specificity since the cell lines exhibited different responses. This may explain previous inconsistencies for the relationship of serum leptin with BC. More studies are needed to better understand the complex interactions that exist between these two adipokines.

Sex hormone binding globulin in breast cancer.

The present study was undertaken to determine the significance of sex hormone binding globulin, the major and specific binding protein for testosterone and estradiol, in breast cancer. Among breast cancer patients, lower serum levels of Sex hormone binding globulin and higher levels of testosterone were observed. Sex hormone binding globulin showed an inverse relationship with testosterone and total cholesterol, and a direct relation with HDL-cholesterol. By the western blot analyses, Sex hormone binding globulin was detected in all biological samples that we examined. In the breast tumor tissue sections, immuno-staining for Sex hormone binding globulin was confined in cell cytoplasm and 29% cases were positive, which showed no association with the investigated prognostic markers of breast cancer such as ER and HER-2/neu over-expression. In this study, decreased circulating levels of Sex hormone binding globulin in breast cancer patients possibly indicate higher bioavailable estrogens.

Cancer and comorbidity: The role of leptin in breast cancer and associated pathologies.

Obesity is an important risk factor for postmenopausal breast cancer and also a poor prognostic factor among cancer patients. Moreover, obesity is associated with a number of health disorders such as insulin resistance/type-2 diabetes mellitus, hypertension, and other cardiovascular diseases. Frequently, these health disorders exhibit as components/complications of the metabolic syndrome. Nevertheless, obesity-related diseases may coexist with postmenopausal breast cancer; and these comorbid conditions could be substantial. Therefore, it may be assumed that different diseases including breast cancer could originate from a common pathological background in excessive adipose tissue. Adipocyte-released hormone-like cytokine (or adipokine) leptin behaves differently in a normal healthy state and obesity. A growing body of evidence suggests an important role of leptin in our major obesity-related health issues such as insulin resistance, hypertension, and neoplasia. In this context, this review describes the relationships of the abovementioned pathologies with leptin.

Diet-induced obesity and mammary tumor development in relation to estrogen receptor status.

Leptin enhances proliferation of estrogen receptor (ER)-positive breast cancer cells in vitro. Here, we compared mammary tumor (MT) formation from ER-positive (MCF-7) and ER-negative (MDA-MB-231) breast cancer cells in athymic mice fed a High-Fat diet to elevate serum leptin. Neither body weight, diet or serum leptin levels impacted MT latency, burden or tumor grade. However, protein expression in mammary fat pads exhibited elevated PCNA and Cyclin D1 while in MTs, Ob-Rb, IGF-IR, Bcl-2, and Bax were lower in Low-Fat versus High-Fat mice. In conclusion, diet rather than serum leptin impacted breast cancer cell tumor metabolism.

Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status.

Obesity is a risk factor for postmenopausal breast cancer and is associated with poor prognosis. Leptin, a cytokine synthesized in adipose tissue, has been implicated as a link between obesity and breast cancer. In the present study, the effects of leptin on cell proliferation and proteins associated with leptin signaling and/or breast cell growth were investigated in ER-positive, MCF-7, T47-D and MDA-MB-361, and ER-negative, MDA-MB-231 and SK-BR-3, breast cancer cell lines. MDA-MB-361 and SK-BR-3 also overexpress HER2/neu. For proliferation assays, 96-well plates were used and for protein determinations cells were synchronized in 6-well plates for 18-24 h in serum-free medium. Leptin was added at 0, 5, 10, 25, 50 and 100 ng/ml for 24 and 48 h. For Western blot analyses, protein extracts were probed for Ob-Rb, Ob-R, leptin, Jak2, PI3K, Stat3, p-Stat3, PCNA, cyclin D1, Cox-2, VEGF, Bcl-2, Bcl-xL, Bax, insulin, IGF-I, IGFBP3, IGF-IRalpha, aromatase, CYP1A1 and CYP1B1. Overall, except for MCF-7 cells, leptin stimulated proliferation in all lines. MCF-7 cells expressed higher levels of Ob-Rb, Jak2, PI3K, Stat3 and p-Stat3 in a dose-dependent manner to 50 ng/ml at 24 h; and IGF-IRalpha increased at 24 h. Cyclin D1 and Cox-2 levels increased with leptin treatment. Higher CYP1B1 expression was observed at both 24 and 48 h. In MDA-MB-231 cells, p-Stat3 and Bcl-xL were increased at 48 h; whereas PCNA and cyclin D1 expression increased in leptin-treated cells at 24 and 48 h. In T47-D cells, Jak2 and Stat3 were elevated at higher leptin concentrations at 24 and 48 h. However, p-Stat3 and PCNA demonstrated an increase only in 48-h leptin-treated cells. Furthermore, cyclin D1 exhibited higher expression at both 24 and 48 h, while Bcl-xL expression was lower with increasing concentrations of leptin at 48 h. In MDA-MB-361 cells, Ob-Rb and VEGF increased at 24 and 48 h; whereas PI3K, Stat3, PCNA and insulin levels increased in leptin-treated MDA-MB-361 cells after 48 h. Bcl-2 and IGF-IRalpha were decreased at 24 h and a dose-dependent increase at 48 h was noted. Higher expression of CYP1B1 was observed with leptin for 24 h. In SK-BR-3 cells, Ob-R increased at both 24 and 48 h. A similar trend was found for IGF-I and IGFBP3 expression. Higher levels of Jak2 and PI3K were observed after 24 h. Interestingly, there was a gradual increase of leptin expression at 24 h, but a gradual decrease at 48 h in relation to the dose of leptin. In contrast, PCNA and IGF-IRalpha showed a decline at 24 h and an increase at 48 h. Elevated levels of cyclin D1, VEGF and Bax were detected at 48 h in cells and increased Cox-2 expression was observed at 24 h. These data indicate that leptin may influence breast cancer development in relation to ER status as well as to the presence or absence of HER2. Continued study on leptin may be helpful for a better understanding of breast cancer development in obese women.

Effects of paraquat on anti-oxidant system in rats.

The toxic effects of paraquat on the anti-oxidant defense system of male albino rats were evaluated, after administering either a single dose (1.5 and 7.5 mg/kg of body weight) or continuous daily doses (same as above, i.e., 1.5 mg/kg and 7.5 mg/kg of body weight) for 3 and 7 days. Glutathione levels in blood cells, liver, lung and kidney tissues decreased in a dose and time dependent manner. Glutathione reductase and glucose-6-phosphate dehydrogenase activity decreased, whereas the activity of glutathione-S-transferase, glutathione peroxidase, catalase and superoxide dismutase increased in paraquat exposure. Malondialdehyde formation also increased in a dose and time dependent manner. The alterations of anti-oxidant system particularly glutathione can be utilized as biomarkers during management of paraquat poisoning.

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment.

Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

The potential role of leptin in tumor invasion and metastasis.

The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin's association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-ß signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin's potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

The influence of different calorie restriction protocols on serum pro-inflammatory cytokines, adipokines and IGF-I levels in female C57BL6 mice: short term and long term diet effects.

Calorie restriction (CR) is an effective intervention to prevent chronic diseases including cancer. Although many factors, i.e., sex hormones, IGF-I and mTOR have been studied in response to CR, the molecular mechanisms of CR remain to be identified. Our objective was to determine the short and long-term effects of different CR protocols on pro-inflammatory cytokines. Our hypothesis was that Intermittent CR (ICR) would result in greater inhibition of pro-inflammatory serum cytokines compared to Chronic CR (CCR) as we previously found ICR to be more protective in the prevention of mammary tumor development. From ten weeks of age female C57BL6 mice were maintained on either ad libitum (AL) fed, ICR or CCR protocols (overall CR of ~75% of AL) for up to 74 weeks of age. Blood samples were collected for measurements of serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), adiponectin, leptin, IGF-I and insulin at specified ages. For ICR mice samples were collected following 3 weeks of restriction (ICR-R) and after one week of refeeding (ICR-RF). In general, both modes of CR significantly reduced serum IL-6, TNF-α, IGF-I and leptin levels compared to AL with IL-6 levels 24 and 3.5 fold and TNF-α levels t 11 and 1.5 fold lower in ICR and CCR groups, respectively at study termination. There was a trend for adiponectin and insulin to be highest in ICR-RF mice. Body weights were positively correlated with IL-6, TNF-α, insulin and leptin but negatively correlated with adiponectin-to-leptin ratio. Moreover, there was a positive correlation between IL-6 and TNF-α. Beneficial effects of ICR may function through pro-inflammatory cytokine pathways.

Environmental contaminants in pathogenesis of breast cancer.

This review is an attempt to comprehend the diverse groups of environmental chemical contaminants with a potential for pathogenesis of breast cancer, their probable sources and the possible mechanisms by which these environmental contaminants act and interplay with other risk factors. Estrogens are closely related to the pathogenesis of breast cancer. Oxidative catabolism of estrogen, mediated by various cytochrome P450 enzymes, generates reactive free radicals that can cause oxidative damage. The same enzymes of estrogenic metabolic pathways catalyze biological activation of several environmental (xenobiotic) chemicals. Xenobiotic chemicals may exert their pathological effects through generation of reactive free radicals. Breast tissue can be a target of several xenobiotic agents. DNA-reactive metabolites of different xenobiotic compounds have been detected in breast tissue. Many phase I and II xenobiotic metabolizing enzymes are expressed in both normal and cancerous breast tissues. These enzymes play a significant role in the activation/detoxification of xenobiotic and endogenous compounds including estrogens. More than 30 carcinogenic chemicals are present in tobacco smoke; many of them are fat-soluble, resistant to metabolism and can be stored in breast adipose tissue. Similarly, pesticides are also known to cause oxidative stress; while some act as endocrine disruptor, some are shown to suppress apoptosis in estrogen sensitive cell lines. Reports have shown an association of smoking (both active and passive) and pesticides with breast cancer risk. However, the issues have remained controversial. Different mutagenic substances that are generated in the cooking process e.g., heterocyclic amines and polycyclic aromatic hydrocarbons (PAHs) can be a threat to breast tissue. PAHs and dioxins exert their adverse effects through the aryl hydrocarbon receptor (AhR), which activates several genes involved in the metabolisms of xenobiotic compounds and endogenous estrogens. These chemicals also induce AhR-dependent mitochondrial dysfunction. Many of the environmental pollutants suppress the immune system, which are implicated to risk. A better understanding about the biological effects of different environmental carcinogenic compounds and determination of their impact on rising incidence of breast cancer will be beneficial in improving preventive policy against breast cancer.