Targeting Drug Chemo-Resistance in Cancer Using Natural Products.

Cancer is one of the leading causes of death globally. The development of drug resistance is the main contributor to cancer-related mortality. Cancer cells exploit multiple mechanisms to reduce the therapeutic effects of anticancer drugs, thereby causing chemotherapy failure. Natural products are accessible, inexpensive, and less toxic sources of chemotherapeutic agents. Additionally, they have multiple mechanisms of action to inhibit various targets involved in the development of drug resistance. In this review, we have summarized the basic research and clinical applications of natural products as possible inhibitors for drug resistance in cancer. The molecular targets and the mechanisms of action of each natural product are also explained. Diverse drug resistance biomarkers were sensitive to natural products. P-glycoprotein and breast cancer resistance protein can be targeted by a large number of natural products. On the other hand, protein kinase C and topoisomerases were less sensitive to most of the studied natural products. The studies discussed in this review will provide a solid ground for scientists to explore the possible use of natural products in combination anticancer therapies to overcome drug resistance by targeting multiple drug resistance mechanisms.

A Cross-Sectional Study on the Combined Effect of Body Weight and Coffee Consumption on Serum Levels of Leptin, Vitamin B12, and Folic Acid in Healthy Young Adult Males.

PURPOSE: Studies on the effect of body weight and coffee consumption on leptin, vitamin B12, and folic acid are scarce and conflicting. This study investigates the effect of body weight and/or coffee consumption rate on the serum levels of these molecules in healthy young adult males. PATIENTS AND METHODS: This observational cross-sectional study was carried out at the faculty of pharmacy, Applied Science Private University (ASU), Amman, Jordan, from July to September 2020. Young healthy males were invited to participate in the study and fill a questionnaire regarding lifestyle habits including coffee consumption during the last 3 months, medical history, and anthropometric measurements. Depending on BMI and extent of coffee consumption, participants were divided into 4 groups; normal body weight and moderate coffee consumption (NW/MCC) group; normal body weight and heavy coffee consumption (NW/HCC) group; overweight and moderate coffee consumption (OW/MCC) group; overweight and heavy coffee consumption (OW/HCC) group. Serum samples were taken to measure leptin, vitamin B12, and folic acid levels in addition to morning and midnight salivary cortisol and dehydroepiandrosterone (DHEA) samples. RESULTS: Healthy males (n = 122) aged 18 to 26 years continued participation in this study. Serum levels of leptin in NW/MCC, NW/HCC, OW/MCC, OW/HCC groups were 5.93, 5.75, 14.86, 16.79 ng/mL, respectively. Serum levels of vitamin B12 in these groups were 356.09, 402.71, 334.25, 331.05 pg/mL, respectively. While, the serum levels of folic acid were 8.92, 10.27, 10.12, 10.47 ng/mL, respectively. Body weight was positively associated with leptin (p = 0.00), negatively associated with vitamin B12 (p = 0.047), and not associated with folic acid (p = 0.235). Coffee consumption rate had no significant effect on leptin, vitamin B12, or folic acid. Finally, the combination of body weight and coffee consumption had no significant effect on leptin, vitamin B12, or folic acid. CONCLUSION: There was no possible synergistic effect between body weight and coffee consumption rate on leptin, vitamin B12, or folic acid levels. However, overweight was associated with higher leptin, lower vitamin B12, and no change in folic acid levels. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT04488731.

Evaluation of women knowledge and perception about polycystic ovary syndrome and its management in Jordan: A survey-based study.

OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder in females in their reproductive-age and is associated with clinical complications. The aim of this study was to evaluate the knowledge and perception of women in Jordan about PCOS, its symptoms, diagnosis and treatment. METHODS: A descriptive, cross-sectional study that was designed in order to assess female knowledge, and perceptions about PCOS in Jordan. The study was carried out through a validated questionnaire and 227 was the number of recruited female participants. RESULTS: The result showed that the participants had inadequate knowledge about PCOS. The major sources of information were physician and family (n = 77, 34%), 205 participants were aware that irregular or absence of menstrual cycle is a symptom of PCOS (90.3%). More than half of participants (55.9%) believe that PCOS patients have low body image. The educational level and marital status factors were significantly associated with participants' knowledge about PCOS (P-value = .008 and .004, respectively). CONCLUSION: The result of this study concluded that women have insufficient knowledge about PCOS and its complication. There is a need to enhance the knowledge and perception in female population in Jordan by developing education using different sources.

Combined Effect Of Coffee Consumption And Cigarette Smoking On Serum Levels Of Vitamin B12, Folic Acid, And Lipid Profile In Young Male: A Cross-Sectional Study.

OBJECTIVE: To investigate the associations of coffee consumption and/or smoking on certain clinical outcomes including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), vitamin B12, and folic acid in a population of young healthy men. METHOD: This cross-sectional study was conducted in Amman, Jordan, over 4 months. Participants were approached for study participation and asked to fill a questionnaire about their anthropometric information, habitual smoking, and coffee consumption during the last 3 months. Their fasting blood samples were taken to measure TC and LDL-C. RESULTS: Healthy male participants (n=117) in the age range of 18 to 26 years were recruited. Mean serum TC was higher in heavy coffee consumers (C++) group (≥3 cups/day) with or without smoking (M= 179.9±34.59 mg/dL and 195.94±23.69 mg/dL) in comparison with moderate coffee consumers (C+) group (1-2 cups/day) (M= 158.1±24.82 mg/dL and 177.23±34.17 mg/dL), and the mean level was higher in subjects who were coffee consumers only than smokers who were coffee consumers. LDL-C levels were higher in participants who were coffee consumers (M= 103.06±34.82mg/dL and 118.06±19.31 mg/dL) than smokers who were coffee consumers (M= 88.6±22.40 mg/dL and 108.26±37.57 mg/dL). No significant difference was noted regarding HDL-C, vitamin B12, and folic acid. CONCLUSION: Our findings showed that heavy coffee consumption was more associated with hyperlipidemia than cigarette smoking. Accordingly, we conclude that moderate coffee consumption may reduce the risk of cardiovascular diseases or their consequences in male.

Associations Between Sleep Deprivation and Salivary Testosterone Levels in Male University Students: A Prospective Cohort Study.

Sleep deprivation is a common health problem that is growing rapidly worldwide and it is associated with short- and long-term impacts on health. The aim of this study was to detect potential predictors of salivary testosterone (sT) association with sleep deprivation in Arab male university students. In this prospective cohort study, 77 university male students in the age range of 18 to 26 years were divided into two groups, sleep-deprived (SD) participants and non-sleep-deprived (NSD) participants. Sleep deprivation was defined as sleeping less than 5 hr per night. Blood samples and sT were collected from fasting participants to measure serum levels of glucose, lipid profile, leptin, serotonin, sT, and body mass index (BMI) values. The multiple linear correlation model of high-density lipoprotein cholesterol (HDL-C), BMI, and serotonin was positively correlated with sT ( r = .977, p < .05) in the SD group. No correlations were identified with sT in the NSD group. In the SD study group, the multiple linear regression model of HDL-C, BMI, and serotonin was significantly influenced by sT ( R² = .955, p < .05). These predictors together explained approximately 96% of the variance in sT levels in the SD study group. No predictive variables for sT were reported in the NSD group. Results indirectly confirmed the presence of a positive association between sT and sleep deprivation in young men. This association is mediated by three factors, HDL-C, BMI, and serum serotonin, which are collectively considered as part of a significant physiological adaptation to sleep deprivation in young men.

Trans- but not cis-resveratrol impairs angiotensin-II-mediated vascular inflammation through inhibition of NF-κB activation and peroxisome proliferator-activated receptor-gamma upregulation.

Angiotensin II (Ang-II) displays inflammatory activity and is implicated in several cardiovascular disorders. This study evaluates the effect of cis- and trans (t)-resveratrol (RESV) in two in vivo models of vascular inflammation and identifies the cardioprotective mechanisms that underlie them. In vivo, Ang-II-induced arteriolar leukocyte adhesion was inhibited by 71% by t-RESV (2.1 mg/kg, i.v.), but was not affected by cis-RESV. Because estrogens influence the rennin-angiotensin system, chronic treatment with t-RESV (15 mg/kg/day, orally) inhibited ovariectomy-induced arteriolar leukocyte adhesion by 81%, partly through a reduction of cell adhesion molecule (CAM) expression and circulating levels of cytokine-induced neutrophil chemoattractant, MCP-1, and MIP-1alpha. In an in vitro flow chamber system, t-RESV (1-10 microM) undermined the adhesion of human leukocytes under physiological flow to Ang-II-activated human endothelial cells. These effects were accompanied by reductions in monocyte and endothelial CAM expression, chemokine release, phosphorylation of p38 MAPK, and phosphorylation of the p65 subunit of NF-kappaB. Interestingly, t-RESV increased the expression of peroxisome proliferator-activated receptor-gamma in human endothelial and mononuclear cells. These results demonstrate for the first time that the in vivo anti-inflammatory activity of RESV is produced by its t-RESV, which possibly interferes with signaling pathways that cause the upregulation of CAMs and chemokine release. Upregulation of proliferator-activated receptor-gamma also appears to be involved in the cardioprotective effects of t-RESV. In this way, chronic administration of t-RESV may reduce the systemic inflammatory response associated with the activation of the rennin-angiotensin system, thereby decreasing the risk of further cardiovascular disease.

Inflammation determines the pro-adhesive properties of high extracellular d-glucose in human endothelial cells in vitro and rat microvessels in vivo.

BACKGROUND: Hyperglycemia is acknowledged as an independent risk factor for developing diabetes-associated atherosclerosis. At present, most therapeutic approaches are targeted at a tight glycemic control in diabetic patients, although this fails to prevent macrovascular complications of the disease. Indeed, it remains highly controversial whether or not the mere elevation of extracellular D-glucose can directly promote vascular inflammation, which favors early pro-atherosclerotic events. METHODS AND FINDINGS: In the present work, increasing extracellular D-glucose from 5.5 to 22 mmol/L was neither sufficient to induce intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression, analyzed by flow cytometry, nor to promote leukocyte adhesion to human umbilical vein endothelial cells (HUVEC) in vitro, measured by flow chamber assays. Interestingly, the elevation of D-glucose levels potentiated ICAM-1 and VCAM-1 expression and leukocyte adhesion induced by a pro-inflammatory stimulus, such as interleukin (IL)-1beta (5 ng/mL). In HUVEC, high D-glucose augmented the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and nuclear transcription factor-kappaB (NF-kappaB) elicited by IL-1beta, measured by Western blot and electromobility shift assay (EMSA), respectively, but had no effect by itself. Both ERK 1/2 and NF-kappaB were necessary for VCAM-1 expression, but not for ICAM-1 expression. In vivo, leukocyte trafficking was evaluated in the rat mesenteric microcirculation by intravital microscopy. In accordance with the in vitro data, the acute intraperitoneal injection of D-glucose increased leukocyte rolling flux, adhesion and migration, but only when IL-1beta was co-administered. CONCLUSIONS: These results indicate that the elevation of extracellular D-glucose levels is not sufficient to promote vascular inflammation, and they highlight the pivotal role of a pro-inflammatory environment in diabetes, as a critical factor conditioning the early pro-atherosclerotic actions of hyperglycemia.

Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan.

The incidence of cardiovascular diseases in premenopausal women is lower than in men or postmenopausal women. This study reports the discovery of a low grade of systemic inflammation, including monocyte adhesion to arterial endothelium, elicited by menopause or estrogen depletion. Chronic treatment with low dose of 17-beta-estradiol or inhibition of the renin-angiotensin system reduced this inflammation. Using an in vitro flow chamber system with human arterial and venous endothelial cells, we found that leukocytes from healthy postmenopausal women were more adhesive to the arterial endothelium than those from premenopausal women regardless of the stimulus used on endothelial cells. Increased circulating levels of IL-8, MCP-1, RANTES, and MIP-1alpha and monocyte CD11b expression were also encountered in postmenopausal vs premenopausal subjects. This translational data led us to investigate the mechanisms in Sprague-Dawley rats. Using intravital microscopy, we imaged mesenteric arterioles and found significant increases in arteriolar leukocyte adhesion, cell adhesion molecule expression, and plasma levels of cytokine-induced neutrophil chemoattractant (CINC/KC), MCP-1, and MIP-1alpha in 1-mo ovariectomized rats. Chronic treatment of ovariectomized rats with low dose of 17-beta-estradiol, losartan, both, or benazepril inhibited ovariectomy-induced arteriolar mononuclear leukocyte adhesion by 77%, 58%, 92%, and 65% respectively, partly by inhibition of cell adhesion molecule up-regulation and the increase in circulating chemokines. These results demonstrate that menopause and ovariectomy generate a low grade of systemic inflammation. Therefore, administration of low doses of estrogens or inhibition of the renin-angiotensin system, at early stages of estrogen deficiency, might prevent the systemic inflammation associated with menopause and decrease the risk of suffering further cardiovascular diseases.

Angiotensin II-induced mononuclear leukocyte interactions with arteriolar and venular endothelium are mediated by the release of different CC chemokines.

Angiotensin II (Ang-II) is associated with atherogenesis and arterial subendothelial mononuclear leukocyte infiltration. We have demonstrated that Ang-II causes the initial attachment of mononuclear cells to the arteriolar endothelium. We now report on the contribution of CC chemokines to this response. Intraperitoneal administration of 1 nM Ang-II induced MCP-1, RANTES, and MIP-1alpha generation, maximal at 4 h, followed by mononuclear leukocyte recruitment at 8 and 24 h. Using intravital microscopy within the rat mesenteric microcirculation 4 h after exposure to 1 nM Ang-II, arteriolar mononuclear cell adhesion was 80-90% inhibited by pretreatment with Met-RANTES, a CCR1 and CCR5 antagonist, or an anti-MCP-1 antiserum, without affecting the increased endothelial expression of P-selectin and VCAM-1. Conversely, leukocyte interactions with the venular endothelium, although inhibited by Met-RANTES, were little affected by the anti-MCP-1. Using rat whole blood in vitro, Ang-II (100 nM) induced the expression of monocyte CD11b that was inhibited by Met-RANTES but not by anti-MCP-1. Stimulation of human endothelial cells (human umbilical arterial endothelial cells and HUVECs) with 1-1000 nM Ang-II, predominantly acting at its AT(1) receptor, induced the release of MCP-1 within 1 h, RANTES within 4 h, and MCP-3 within 24 h. Eotaxin-3, a natural CCR2 antagonist, was released within 1 h and may delay mononuclear cell responses to MCP-1. Therefore, Ang-II-induced mononuclear leukocyte recruitment at arterioles and venules is mediated by the production of different CC chemokines. Thus, Ang-II may be a key molecule in the initial attachment of mononuclear cells to the arterial endothelium in cardiovascular disease states where this event is a characteristic feature.