Cymbopogon citratus and Citral Overcome Doxorubicin Resistance in Cancer Cells via Modulating the Drug's Metabolism, Toxicity, and Multidrug Transporters.

Multidrug resistance (MDR) is the major complex mechanism that causes the failure of chemotherapy, especially with drugs of natural origin such as doxorubicin (DOX). Intracellular drug accumulation and detoxification are also involved in cancer resistance by reducing the susceptibility of cancer cells to death. This research aims to identify the volatile composition of Cymbopogon citratus (lemon grass; LG) essential oil and compare the ability of LG and its major compound, citral, to modulate MDR in resistant cell lines. The composition of LG essential oil was identified using gas chromatography mass spectrometry (GC-MS). In addition, a comparison of the modulatory effects of LG and citral, performed on breast (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) MDR cell lines, were compared to their parent sensitive cells using the MTT assay, ABC transporter function assays, and RT-PCR. Oxygenated monoterpenes (53.69%), sesquiterpene hydrocarbons (19.19%), and oxygenated sesquiterpenes (13.79%) made up the yield of LG essential oil. α-citral (18.50%), ß-citral (10.15%), geranyl acetate (9.65%), ylangene (5.70), δ-elemene (5.38%), and eugenol (4.77) represent the major constituents of LG oil. LG and citral (20 µg/mL) synergistically increased DOX cytotoxicity and lowered DOX dosage by >3-fold and >1.5-fold, respectively. These combinations showed synergism in the isobologram and CI < 1. DOX accumulation or reversal experiment confirmed that LG and citral modulated the efflux pump function. Both substances significantly increased DOX accumulation in resistant cells compared to untreated cells and verapamil (the positive control). RT-PCR confirmed that LG and citral targeted metabolic molecules in resistant cells and significantly downregulated PXR, CYP3A4, GST, MDR1, MRP1, and PCRP genes. Our results suggest a novel dietary and therapeutic strategy combining LG and citral with DOX to overcome multidrug resistance in cancer cells. However, these results should be confirmed by additional animal experiments before being used in human clinical trials.

The Association between Vitamin D Hypovitaminosis and Cardiovascular Disease Risk in Saudi Diabetic Patients Type II.

We evaluated the prevalence and association of Vitamin D deficiency with glycemic control and CVD risk in T2DM patients. Serum 25 (OH)D3, lipid profile, glucose panel, HbA1c, serum insulin, and HOMA-IR were assessed in 93 T2DM patients and 69 controls. 10 years and lifetime ASCVD risk scores were calculated. The levels of 25(OH)D3 were significantly low in T2DM patients compared to the control. T2DM patients with hypovitaminosis D displayed significantly increased FBG, insulin, and HOMA-IR compared to normovitaminosis. Their lifetime and 10-year ASCVD risk scores were significantly higher regardless of vitamin D deficiency levels (P=0.006; P=0.023) in comparison to patients with sufficient levels of vitamin D. Among patients, the lifetime and 10 years of ASCVD risk showed a significant negative correlation with serum 25(OH)D3 and HDLc (P=0.037; 0.018) (P=0.0001), respectively, and significant positive correlation with T2DM duration, serum insulin, and HOMA-IR (P=0.018; 0.0001) (P=0.002; 0.001) (P=0.005; 0.001), respectively. The 10-year ASCVD risk exhibited a significant positive correlation with FBG (P=0.003) and HbA1c (P=0.009). T2DM duration was a predictor of vitamin D deficiency among T2DM patients (ß = 0.22; CI = 0.002-0.04). There is a considerable association between lifetime and 10 years of ASCVD risk with hypovitaminosis D in T2DM, regardless of the deficiency levels which could be predicted by the diabetes duration.

Serum Ferritin and its Importance for SARS-CoV-2-Infected Patients.

BACKGROUND: Serum ferritin is an acute-phase protein whose level is increased in several inflammatory diseases. This review describes the structure and function of ferritin as well as its association with the prognosis of patients with COVID-19. METHODS: We searched MEDLINE/PubMed databases, Scopus, and Web of Science for prospective and review articles that examined ferritin and its association with COVID-19 severity. Based on all these articles and clinical experience, a review was constructed and full texts of the articles that were retrieved were accessed. RESULTS: All COVID-19 related studies conducted in 2020, which performed serum ferritin testing, clearly showed ferritin as a biomarker of COVID-19 severity in hospitalized patients. Ferritin levels in severe patients were significantly increased relative to those in non-severe patients (p < 0.001). Non-survivors had significantly higher ferritin levels than the survivors (p < 0.001). CONCLUSIONS: Determination of ferritin levels was specific and sensitive for early disease severity prediction in patients with COVID-19. Serum ferritin can also be used for predicting the response to COVID-19 vaccines.

Association of TNF-α-308 (G >A) (rs1800629) Gene Polymorphism with Adverse Outcomes of Sepsis in Critically Ill Patients.

Sepsis-related mortality and morbidity are major health care problems worldwide. More effort is required to identify factors associated with adverse outcome. Evaluate the prognostic capacity of tumor necrosis factor (TNF), kidney injury molecule (KIM), and lactate and TNF-α-308 G > A gene polymorphism for prediction of 28 days-intensive care unit (ICU) mortality. TNF-α-308 G > A single nucleotide polymorphisms was detected by real-time-PCR on 112 had septic shock and 88 were septic. Serum TNF-α and urinary KIM were assessed by enzyme-linked immunosorbent assay. This study included 200 critically ill patients, 125 (62.5%) of them died within 28 days in ICU (nonsurvivors). Frequencies of TNF-308 G > A was (70.7) GG, (28) GA and (1.3) AA in survivors versus (85.6) GG, (12) GA and (2.4) AA for nonsurvivors, revealed significant association with ICU mortality but not sepsis severity (p = 0.15) or sepsis-induced acute kidney injury (AKI). In contrast, urinary KIM-1 revealed significant association with sepsis severity (p = 0.036) and AKI (p = 0.0001), but not 28-days ICU mortality. The relative risk of death in patients with GG genotype was 2.5 mainly in ICU younger male patients (odds ratios 24 and 4.9, p = 0.001). The genotype GG and GA were significantly associated with [increased urinary KIM-1 (0.29 ± 0.1) (p = 0.0001), terminal creatinine (1.67 ± 0.8) (p = 0.0001)] and [increased terminal urea (109 ± 0.001) (p = 0.001) and basal serum TNF (60 ± 0.001) (p = 0.0001)], respectively. In linear regression analysis, AKI 0.0001 (0.4-0.67), basal serum TNF 0.04 (0.0001-0.04), and TNF-308 GG 0.007 (0.05-0.33) were associated with 28 days ICU mortality [p value (95% confidence interval)]. The same results were observed for initial urea 0.024 (0.0001-0.003) and lack of diuretic usage 0.0001 (0.35-0.7) mainly in septic patients. Major frequency of TNF-308 G > A polymorphism (mainly in young age male patients), AKI and serum TNF were associated with increased risk for 28 days-ICU mortality. Furthermore, sepsis severity was influenced by TNF and urinary KIM-1, which reflects in AKI.

Correction to: Assessment of tumor necrosis factor alpha polymorphism TNF-α-238 (rs 361525) as a risk factor for development of acute kidney injury in critically ill patients.

The title of the original article has been corrected to: Assessment of tumor necrosis factor alpha polymorphism TNF-α-238 (rs 361525) as a risk factor for development of acute kidney injury in critically ill patients. The original article has been corrected to reflect the correct title.

Assessment of tumor necrosis factor alpha polymorphism TNF-α-238 (rs 361525) as a risk factor for development of acute kidney injury in critically ill patients.

Critically ill patients revealed significant adverse outcomes (sepsis, septic shock, organ dysfunction/failure, and mortality) despite variable effort. AIM: this study evaluated the association of TNF-a-238 (rs 361525) with adverse outcomes in critically ill patients. TNF-α-238 (rs 361525) SNP was performed by RT-PCR on 200 critically-ill patients (112 had severe sepsis and septic shock and 88 were septic), 127 of them had AKI. Urinary N-acetyl-ß-(D)-glucosaminidase and serum creatinine were assessed by modified Jaffé and ELISA respectively. These results revealed that heterozygous genotype GA of TNF-α-238 (rs 361525) SNP significantly increased the risk of adverse-outcome (mortality rate) (P = 0.0001; OR 8.9), regardless of organ dysfunction (P = 0.09) or severity of sepsis (P = 0.6). Moreover, heterozygous genotype GA of TNF-α-238 (rs 361525) SNP was significantly associated with inflammatory marker (sTNF-α) (P = 0.014) and tubular injury marker (uNAG) (P = 0.001) that displayed a significant association with severity of sepsis (0.001, 0.035) and organ dysfunction (0.012, 0.0001) respectively. In critically ill patients with sepsis induced AKI, serum TNF-α and uNAG measured at admission can predict severity of sepsis and AKI (defined by REFILE) occurrence along with pre-existing CKD and DM. However, TNF-238 yielded additional prognostic information on ICU mortality irrelevant to AKI in septic patients.

Testosterone, obesity, and waist circumference as determinants of metabolic syndrome in Saudi women.

BACKGROUND: High serum total testosterone is associated with metabolic syndrome (MS). This study aimed to identify possible alterations in total testosterone and their relationship with plasma glucose, blood pressure, and serum lipid profile. METHODS: One hundred forty-two female subjects were selected to participate in this study, and they were recruited by consultant physicians from the Clinic and Medical Out-Patient, King Abdulaziz Hospital, Kingdom of Saudi Arabia. The anthropometric characteristics were obtained from questionnaires by using standard methods. Blood samples were obtained for the determination of glucose, triglycerides, total cholesterol, low-density lipoprotein, and high-density lipoprotein by using enzymatic methods. Total testosterone was determined by enzyme-linked immunosorbent assay for the quantitative measurement of testosterone in human serum. RESULTS: Significantly higher concentrations of total testosterone, low-density lipoprotein, and glucose, but lower concentrations of high-density lipoprotein, were observed in subjects with MS compared with women without MS (P<0.05). CONCLUSION: This study suggests that high levels of total testosterone and disturbance in lipid profile were associated with MS in Saudi women.

Potential Cardiovascular and Renal Protective Effects of Vitamin D and Coenzyme Q10 in l-NAME-Induced Hypertensive Rats.

BACKGROUND: Hypertension is one of the primary modifiable risk factors for cardiovascular disease. Adequate vitamin D (vit D) levels have been shown to reduce vascular smooth muscle contraction and to increase arterial compliance, which may be beneficial in hypertension. Further, coenzyme Q10 (COQ10) through its action to lower oxidative stress has been reported to have beneficial effects on hypertension and heart failure. This study examined the possible cardiac and renal protective effects of vit D and COQ10 both separately and in combination with an angiotensin II receptor blocker, valsartan (vals) in l-NAME hypertensive rats. MATERIALS AND METHODS: Hypertension was induced in rats by l-NAME administration. Following induction of hypertension, the rats were assigned into the following 6 subgroups: an l-NAME alone group and treated groups receiving the following drugs intraperitoneally for 6 weeks; vals, vit D, COQ10 and combination of vals with either vit D or COQ10. A group of normotensive rats were used as negative controls. At the end of the treatment period, blood pressure, serum creatinine, blood urea nitrogen, lipids and serum, cardiac and renal parameters of oxidative stress were measured. RESULTS: Compared to the l-NAME only group, all treatments lowered systolic, diastolic, mean arterial pressure, total cholesterol, low-density lipoprotein cholesterol, and creatinine levels as well as TNF-α and malondialdehyde. Further, the agents increased serum, cardiac and renal total antioxidant capacity. Interestingly, the combination of agents had further effects on all the parameters compared to treatment with each single agent. CONCLUSIONS: The study suggests that the additive protective effects of vit D and COQ10 when used alone or concurrent with vals treatment in hypertensive rats may be due to their effects as antioxidants, anticytokines and blood pressure conservers.

Effect of variable antidiabetic treatments strategy on oxidative stress markers in obese patients with T2DM.

AIM: To evaluate the effect of different anti-diabetic treatment strategy on oxidative stress markers in patients with type 2 diabetes mellitus (T2DM). SUBJECT AND METHODS: A total of 93 patients with T2DM treated with metformin (G1 = 25), OHA (G2 = 22), OA and insulin (G3 = 26) and insulin alone (G4 = 20). In all patients, lipid profile and glycemic indices were assessed using routine laboratory tests. MDA and Oxidized LDL were assessed using commercially available ELISA kits. Laboratory tests were performed at baseline and at a control visit after 24 weeks of treatment. RESULTS: A significant decrease in the levels of MDA with improvement of glycemic control was observed in the group receiving OHA in combination with insulin therapy. A similar decrease of oxLDL was observed in all diabetic subgroups with borderline significance in those receiving metformin alone. The remaining clinical and biochemical parameters were not changed during follow-up in any of the involved groups. CONCLUSION: A combination therapy with insulin was more effective in glycemic control and MDA reduction in T2DM. Whereas, a significant oxLDLc reduction was observed in T2DM irrespective of categories of antidiabetic treatment or glycemic control.

Trace Element Alterations in the Hair of Diabetic and Obese Women.

Alterations in the trace element content can induce metabolic disorders as these elements are involved in the regulation of metabolism. Obesity increases the likelihood of various diseases, particularly cardiovascular disease and type 2 diabetes, and is more prevalent in Saudi Arabia, especially in women. This study explored the potential of alterations in hair trace elements as long-term markers in diabetic and/or obese Saudi females. In total, 65 diabetic obese women, 47 non-diabetic obese women, and 70 normal-weight women were recruited. Clinical and familial history and anthropometric variables were recorded. Hair Se, Zn, Cu, Mn, and Fe levels were analyzed. Fasting blood sugar (FBS), glycated hemoglobin (HbA1c), and lipid profile were analyzed. Our findings revealed a marked decrease of hair Zn, Mn, and Fe and elevated Se and Cu levels in obese women. In addition, Zn and Fe levels were decreased in diabetic women. Thus, the metabolic distress occurring in obesity and hyperglycemia may affect trace element status by increasing the excretion and decreasing the bioavailability of trace elements or redistributing them among various pools. Hair trace elements can serve as important long-term markers for metabolic disorders; however, larger prospective studies are warranted to validate their diagnostic and follow-up utilities.