The Effects of Apigenin in the Treatment of Diabetic Nephropathy: A Systematic Review of Non-clinical Studies.

PURPOSE: Diabetes is one of the important and growing diseases in the world. Among the most common diabetic complications are renal adverse effects. The use of apigenin may prevent the development and progression of diabetes-related injuries. The current study aims to review the effects of apigenin in the treatment of diabetic nephropathy. METHODS: In this review, a systematic search was performed based on PRISMA guidelines for obtaining all relevant studies on "the effects of apigenin against diabetic nephropathy" in various electronic databases up to September 2022. Ninety-one articles were obtained and screened in accordance with the predefined inclusion and exclusion criteria. Seven eligible articles were finally included in this review. RESULTS: The experimental findings revealed that hyperglycemia led to the decreased cell viability of kidney cells and body weight loss and an increased kidney weight of rats; however, apigenin administration had a reverse effect on these evaluated parameters. It was also found that hyperglycemia could induce alterations in the biochemical and renal function-related parameters as well as histopathological injuries in kidney cells or tissue; in contrast, the apigenin administration could ameliorate the hyperglycemia-induced renal adverse effects. CONCLUSION: The results indicated that the use of apigenin could mitigate diabetes-induced renal adverse effects, mainly through its antioxidant, anti-apoptotic, and anti-inflammatory activities. Since the findings of this study are based on experimental studies, suggesting the use of apigenin (as a nephroprotective agent) against diabetic nephropathy requires further clinical studies.

The Radiosensitizing Potentials of Silymarin/Silibinin in Cancer: A Systematic Review.

INTRODUCTION: Although radiotherapy is one of the main cancer treatment modalities, exposing healthy organs/tissues to ionizing radiation during treatment and tumor resistance to ionizing radiation are the chief challenges of radiotherapy that can lead to different adverse effects. It was shown that the combined treatment of radiotherapy and natural bioactive compounds (such as silymarin/silibinin) can alleviate the ionizing radiation-induced adverse side effects and induce synergies between these therapeutic modalities. In the present review, the potential radiosensitization effects of silymarin/silibinin during cancer radiation exposure/radiotherapy were studied. METHODS: According to the PRISMA guideline, a systematic search was performed for the identification of relevant studies in different electronic databases of Google Scholar, PubMed, Web of Science, and Scopus up to October 2022. We screened 843 articles in accordance with a predefined set of inclusion and exclusion criteria. Seven studies were finally included in this systematic review. RESULTS: Compared to the control group, the cell survival/proliferation of cancer cells treated with ionizing radiation was considerably less, and silymarin/silibinin administration synergistically increased ionizing radiation-induced cytotoxicity. Furthermore, there was a decrease in the tumor volume, weight, and growth of ionizing radiation-treated mice as compared to the untreated groups, and these diminutions were predominant in those treated with radiotherapy plus silymarin/ silibinin. Furthermore, the irradiation led to a set of biochemical and histopathological changes in tumoral cells/tissues, and the ionizing radiation-induced alterations were synergized following silymarin/silibinin administration (in most cases). CONCLUSION: In most cases, silymarin/silibinin administration could sensitize the cancer cells to ionizing radiation through an increase of free radical formation, induction of DNA damage, increase of apoptosis, inhibition of angiogenesis and metastasis, etc. However, suggesting the use of silymarin/silibinin during radiotherapeutic treatment of cancer patients requires further clinical studies.

Melatonin in Chemo/Radiation Therapy; Implications for Normal Tissues Sparing and Tumor Suppression: An Updated Review.

Resistance to therapy and the toxicity of normal tissue are the major problems for efficacy associated with chemotherapy and radiotherapy. Drug resistance is responsible for most cases of mortality associated with cancer. Furthermore, their side effects can decrease the quality of life for surviving patients. An enhancement in the tumor response to therapy and alleviation of toxic effects remain unsolved challenges. One of the interesting topics is the administration of agents with low toxicity to protect normal tissues and/or sensitize cancers to chemo/radiotherapy. Melatonin is a natural body hormone that is known as a multitasking molecule. Although it has antioxidant properties, a large number of experiments have uncovered interesting effects of melatonin that can increase the therapeutic efficacy of chemo/radiation therapy. Melatonin can enhance anticancer therapy efficacy through various mechanisms, cells such as the immune system, and modulation of cell cycle and death pathways, tumor suppressor genes, and also through suppression of some drug resistance mediators. However, melatonin may protect normal tissues through the suppression of inflammation, fibrosis, and massive oxidative stress in normal cells and tissues. In this review, we will discuss the distinct effects of melatonin on both tumors and normal tissues. We review how melatonin may enhance radio/chemosensitivity of tumors while protecting normal tissues such as the lung, heart, gastrointestinal system, reproductive system, brain, liver, and kidney.

The metformin immunoregulatory actions in tumor suppression and normal tissues protection.

The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor-promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.

The key role of microRNA-766 in the cancer development.

Cancer is caused by defects in coding and non-coding RNAs. In addition, duplicated biological pathways diminish the efficacy of mono target cancer drugs. MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that regulate many target genes and play a crucial role in physiological processes such as cell division, differentiation, cell cycle, proliferation, and apoptosis, which are frequently disrupted in diseases such as cancer. MiR-766, one of the most adaptable and highly conserved microRNAs, is notably overexpressed in several diseases, including malignant tumors. Variations in miR-766 expression are linked to various pathological and physiological processes. Additionally, miR-766 promotes therapeutic resistance pathways in various types of tumors. Here, we present and discuss evidence implicating miR-766 in the development of cancer and treatment resistance. In addition, we discuss the potential applications of miR-766 as a therapeutic cancer target, diagnostic biomarker, and prognostic indicator. This may shed light on the development of novel therapeutic strategies for cancer therapy.

A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity.

PURPOSE: Although doxorubicin chemotherapy is commonly applied for treating different malignant tumors, cardiotoxicity induced by this chemotherapeutic agent restricts its clinical use. The use of silymarin/silibinin may mitigate the doxorubicin-induced cardiac adverse effects. For this aim, the potential cardioprotective effects of silymarin/silibinin against the doxorubicin-induced cardiotoxicity were systematically reviewed. METHODS: In this study, we performed a systematic search in accordance with PRISMA guideline for identifying all relevant studies on "the role of silymarin/silibinin against doxorubicin-induced cardiotoxicity" in different electronic databases up to June 2022. Sixty-one articles were obtained and screened based on the predefined inclusion and exclusion criteria. Thirteen eligible papers were finally included in this review. RESULTS: According to the echocardiographic and electrocardiographic findings, the doxorubicin-treated groups presented a significant reduction in ejection fraction, tissue Doppler peak mitral annulus systolic velocity, and fractional shortening as well as bradycardia, prolongation of QT and QRS interval. However, these echocardiographic abnormalities were obviously improved in the silymarin plus doxorubicin groups. As well, the doxorubicin administration led to induce histopathological and biochemical changes in the cardiac cells/tissue; in contrast, the silymarin/silibinin co-administration could mitigate these induced alterations (for most of the cases). CONCLUSION: According to the findings, it was found that the co-administration of silymarin/silibinin alleviates the doxorubicin-induced cardiac adverse effects. Silymarin/silibinin exerts its cardioprotective effects via antioxidant, anti-inflammatory, anti-apoptotic activities, and other mechanisms.

Prostate cancer and microRNAs: New insights into apoptosis.

Prostate cancer (PCa) is known as one of the most prevalent malignancies globally and is not yet curable owing to its progressive nature. It has been well documented that Genetic and epigenetic alterations maintain mandatory roles in PCa development. Apoptosis, a form of programmed cell death, has been shown to be involved in a number of physiological processes. Apoptosis disruption is considered as one of the main mechanism involved in lots of pathological conditions, especially malignancy. There is ample of evidence in support of the fact that microRNAs (miRNAs) have crucial roles in several cellular biological processes, including apoptosis. Escaping from apoptosis is a common event in malignancy progression. Emerging evidence revealed miRNAs capabilities to act as apoptotic or anti-apoptotic factors by altering the expression levels of tumor inhibitor or oncogene genes. In the present narrative review, we described in detail how apoptosis dysfunction could be involved in PCa processes and additionally, the mechanisms behind miRNAs affect the apoptosis pathways in PCa. Identifying the mechanisms behind the effects of miRNAs and their targets on apoptosis can provide scientists new targets for PCa treatment.

Multifaceted role of NF-κB in hepatocellular carcinoma therapy: Molecular landscape, therapeutic compounds and nanomaterial approaches.

The predominant kind of liver cancer is hepatocellular carcinoma (HCC) that its treatment have been troublesome difficulties for physicians due to aggressive behavior of tumor cells in proliferation and metastasis. Moreover, stemness of HCC cells can result in tumor recurrence and angiogenesis occurs. Another problem is development of resistance to chemotherapy and radiotherapy in HCC cells. Genomic mutations participate in malignant behavior of HCC and nuclear factor-kappaB (NF-κB) has been one of the oncogenic factors in different human cancers that after nuclear translocation, it binds to promoter of genes in regulating their expression. Overexpression of NF-κB has been well-documented in increasing proliferation and invasion of tumor cells and notably, when its expression enhances, it induces chemoresistance and radio-resistance. Highlighting function of NF-κB in HCC can shed some light on the pathways regulating progression of tumor cells. The first aspect is proliferation acceleration and apoptosis inhibition in HCC cells mediated by enhancement in expression level of NF-κB. Moreover, NF-κB is able to enhance invasion of HCC cells via upregulation of MMPs and EMT, and it triggers angiogenesis as another step for increasing spread of tumor cells in tissues and organs. When NF-κB expression enhances, it stimulates chemoresistance and radio-resistance in HCC cells and by increasing stemness and population of cancer-stem cells, it can provide the way for recurrence of tumor. Overexpression of NF-κB mediates therapy resistance in HCC cells and it can be regulated by non-coding RNAs in HCC. Moreover, inhibition of NF-κB by anti-cancer and epigenetic drugs suppresses HCC tumorigenesis. More importantly, nanoparticles are considered for suppressing NF-κB axis in cancer and their prospectives and results can also be utilized for treatment of HCC. Nanomaterials are promising factors in treatment of HCC and by delivery of genes and drugs, they suppress HCC progression. Furthermore, nanomaterials provide phototherapy in HCC ablation.

Serum concentrations of persistent organic pollutants and the metabolic syndrome in Akwesasne Mohawks, a Native American community.

The metabolic syndrome (MetS) is a group of diseases that tend to occur together, including diabetes, hypertension, central obesity, cardiovascular disease and hyperlipidemia. Exposure to persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) has been associated with increased risk of development of several of the components of the MetS. The goal of this study is to determine whether the associations with POPs are identical for each of the components and for the MetS. The subject population was 601 Native Americans (Akwesasne Mohawks) ages 18 to 84 who answered a questionnaire, were measured for height and weight and provided blood samples for clinical chemistries (serum lipids and fasting glucose) and analysis of 101 PCB congeners and three OCPs [dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and mirex]. Associations between concentrations of total PCBs and pesticides, as well as various PCB congener groups with each of the different components of the MetS were determine so as to ask whether there were similar risk factors for all components of the MetS. After adjustment for other contaminants, diabetes and hypertension were strongly associated with lower chlorinated and mono-ortho PCBs, but not other PCB groups or pesticides. Obesity was most closely associated with highly chlorinated PCBs and was negatively associated with mirex. High serum lipids were most strongly associated with higher chlorinated PCBs and PCBs with multiple ortho-substituted chlorines, as well as total pesticides, DDE and HCB. Cardiovascular disease was not closely associated with levels of any of the measured POPs. While exposure to POPs is associated with increased risk of most of the various diseases comprising the MetS, the specific contaminants associated with risk of the component diseases are not the same.

Diabetes Prevalence in Relation to Serum Concentrations of Polychlorinated Biphenyl (PCB) Congener Groups and Three Chlorinated Pesticides in a Native American Population.

BACKGROUND: Exposure to persistent organic pollutants (POPs) is known to increase risk of diabetes. OBJECTIVE: To determine which POPs are most associated with prevalence of diabetes in 601 Akwesasne Native Americans. METHODS: Multiple logistic regression analysis was used to assess associations between quartiles of concentrations of 101 polychlorinated biphenyl (PCBs) congeners, congener groups and three chlorinated pesticides [dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and mirex] with diabetes. In Model 1, the relationship between quartiles of exposure and diabetes were adjusted only for sex, age, body mass index (BMI), and total serum lipids. Model 2 included additional adjustment for either total PCBs or total pesticides. RESULTS: Total serum PCB and pesticide concentrations were each significantly associated with prevalence of diabetes when adjusted only for covariates (Model 1), but neither showed a significant OR for highest to lowest quartiles after additional adjustment for the other (Model 2). When applying Model 2 to PCB congener groups and individual pesticides, there were significant omnibus differences between the four quartiles (all ps < 0.042) for most groups, with the exception of penta- and hexachlorobiphenyls, DDE and mirex. However, when comparing highest to lowest quartiles only non- and mono-ortho PCBs [OR = 4.55 (95% CI: 1.48, 13.95)], tri- and tetrachloro PCBs [OR = 3.66 (95% CI: 1.37, -9.78)] and HCB [OR = 2.64 (95% CI: 1.05, 6.61)] showed significant associations with diabetes. Among the non- and mono-ortho congeners, highest to lowest quartile of dioxin TEQs was not significant [OR = 1.82 (95% CI: 0.61, 5.40)] but the OR for the non-dioxin-like congeners was [OR = 5.01 (95% CI: 1.76, 14.24)]. CONCLUSION: The associations with diabetes after adjustment for other POPs were strongest with the more volatile, non-dioxin-like, low-chlorinated PCB congeners and HCB. Because low-chlorinated congeners are more volatile, these observations suggest that inhalation of vapor-phase PCBs is an important route of exposure. CITATION: Aminov Z, Haase R, Rej R, Schymura MJ, Santiago-Rivera A, Morse G, DeCaprio A, Carpenter DO, and the Akwesasne Task Force on the Environment. 2016. Diabetes prevalence in relation to serum concentrations of polychlorinated biphenyl (PCB) congener groups and three chlorinated pesticides in a Native American population. Environ Health Perspect 124:1376-1383; http://dx.doi.org/10.1289/ehp.1509902.

Diabetes in Native Americans: elevated risk as a result of exposure to polychlorinated biphenyls (PCBs).

We have studied rates of diabetes in 601 members of the Mohawk Nation at Akwesasne, ages 18-84 years, in relation to serum concentrations of 101 polychlorinated biphenyl (PCB) congeners and three chlorinated pesticides [dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and mirex]. Diabetes was determined from either a diagnosis by a physician or by having a fasting glucose concentration of >125 mg/dL. Rates of diabetes are high in this community. Three models were used. In the first model rate ratios (RR) were determined for quartiles of total PCBs after adjustment for age, sex, body mass index (BMI) and total serum lipids. For total PCBs RR=2.21 (1.2-4.2), while for total pesticides RR=3.75 (1.3-10.7). When the total PCB results were also adjusted for total pesticides and the total pesticide results were also adjusted for total PCBs (Model 2) the RRs were somewhat reduced. In Model 3 we considered subgroups of PCBs based on numbers of chlorines on the molecule (tri-/tetra, penta-/hexa, hepta plus) and numbers of ortho chlorines (non-/mono; di-, tri-/tetra-), and considered each of the pesticides individually after adjustment for all other contaminants as well as age, sex, BMI and serum lipids. We found a highly significant association between diabetes and PCBs with only three or four chlorines (RR=5.02), but no significant association with those with greater chlorination. When evaluating PCBs based on numbers of ortho chlorines only, those with no or one ortho chlorine showed significant associations. As mono-ortho PCBs include some with dioxin-like activity, we compared those with and without a TEF, and found that the association with diabetes was exclusively with the non-dioxin-like congeners. Of the pesticides only hexachlorobenzene showed a small but significant association with diabetes. Because lower chlorinated PCBs are more volatile and do not greatly accumulate in fish, these results suggest that inhalation is the major route of exposure to those PCBs that increase risk of diabetes.

Racial differences in levels of serum lipids and effects of exposure to persistent organic pollutants on lipid levels in residents of Anniston, Alabama.

Serum lipid levels are major risk factors for cardiovascular disease. In addition to diet, exercise, genetics, age and race, serum concentrations of persistent organic pollutants (POPs) influence concentrations of serum lipids. We investigated associations between fasting concentrations of 35 polychlorinated biphenyl (PCB) congeners and nine organochlorine pesticides in relation to total serum lipids, total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides in 525 Caucasian and African American residents of Anniston, Alabama, who were not on any lipid-lowering medication. In Model 1, data were adjusted for age, age quadratic, gender, BMI, alcohol consumption, smoking and exercise, while in Model 2, additional adjustment was done for other POPs. As compared to Caucasians, African Americans had lower levels of total lipids and triglycerides with higher concentrations of HDL cholesterol, but higher concentrations of PCBs and pesticides. Total pesticides were more strongly associated with elevations in serum lipids than were total PCBs, and the associations were stronger in African Americans. Total DDTs were not associated with serum lipids after adjustment for other POPs in either racial group, while the strongest positive associations were seen for hexachlorobenzene (HCB) in both racial groups. Racial differences in lipid profiles, concentrations of POPs and associations between POP concentrations and serum lipids are relevant to racial differences in rates of cardiovascular disease.

Analysis of the effects of exposure to polychlorinated biphenyls and chlorinated pesticides on serum lipid levels in residents of Anniston, Alabama.

BACKGROUND: Anniston, Alabama, is the site of a former Monsanto plant where polychlorinated biphenyls (PCBs) were manufactured from 1929 until 1971. Residents of Anniston are known to have elevated levels of PCBs. The objective of the study was to test the hypothesis that levels of the various lipid components (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) are differentially associated with concentrations of total PCBs and total pesticides, and further that different congeners, congener groups and different pesticides do not have identical associations in serum samples obtained from Anniston residents in a cross-sectional study. METHODS: Fasting serum samples were obtained from 575 residents of Anniston who were not on any lipid-lowering medication and were analyzed for 35 PCB congeners, nine chlorinated pesticides, total cholesterol, LDL and HDL cholesterol and triglyceride concentrations. Associations between toxicant concentrations and lipid levels were determined using multiple linear regression analysis. RESULTS: We observed that elevated serum concentrations of lipids were associated with elevated serum concentrations of ΣPCBs and summed pesticides in analyses adjusted for age, race, gender, BMI, alcohol consumption, smoking and exercising status. The strongest associations were seen for PCB congeners with three, four, or at least eight substituted chlorines. Mono-ortho substituted congeners 74 and 156, di-ortho congeners 172 and 194, and tri- and tetra-ortho congeners 199, 196-203, 206 and 209 each were significantly associated with total lipids, total cholesterol and triglycerides. Serum concentrations of HCB and chlordane also had strong associations with lipid components. CONCLUSIONS: Increased concentrations of PCBs and organochlorine pesticides are associated with elevations in total serum lipids, total cholesterol and triglycerides, but the patterns are different for different groups of PCBs and different pesticides. These observations show selective effects of different organochlorines on serum concentrations of different groups of lipids. This elevation in concentrations of serum lipids may be the basis for the increased incidence of cardiovascular disease found in persons with elevated exposures to PCBs and chlorinated pesticides.

Mechanisms of cell death of thymocytes induced by polyunsaturated, monounsaturated and trans-fatty acids.

Polyunsaturated fatty acids (PUFAs) are rapidly cytotoxic to isolated murine thymocytes, and the degree of cell death has been correlated with changes in membrane fluidity, elevation of intracellular calcium concentration and generation of reactive oxygen species. We have compared the degree of cell death and increase in membrane fluidity of C-20 and C-22 omega-3 and 6 PUFAs to those induced by monounsaturated and trans-fatty acids, and find that concentrations which induce comparable increases in membrane fluidity do not cause comparable cell death. The C-18 omega-6 causes a decrease in membrane fluidity, yet is the most potent in causing cell death. Omega-6 PUFAs are more cytotoxic than omega-3 PUFAs, while monounsaturated and trans-fats show little cytotoxicity and only at much higher concentrations. Cell death is preceded by reductions of both plasma and mitochondrial membrane potential, and occurs via apoptosis. These results indicate that cell death is due to mechanisms other than changes in membrane fluidity.