More on Vitamin D, Ergosterol and Cholesterol

Do Vitamin D Levels Affect Cholesterol?

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Higher vitamin D levels appear to be associated with higher total cholesterol levels and higher HDL cholesterol levels, according to a new study presented at the American College of Cardiology’s (ACC) 65th Annual Scientific Sessions.1 

Investigators looked 13 039 adults and found that higher 25-hydroxyvitamin D (25[OH]D) was cross-sectionally and prospectively associated with higher total cholesterol and HDL cholesterol levels and lower total cholesterol-to-HDL cholesterol ratio after considering factors such as diabetes and adiposity.

“We wanted to see the association of low vitamin D with low HDL cholesterol and high total cholesterol-to-HDL cholesterol ratio, but I think we were most surprised to not find an association of vitamin D deficiency with elevated triglycerides, as has been noted in other studies. This may be in part that we carefully adjusted for other confounding lifestyle variables such as physical activity and 2 measures of adiposity (BMI and waist circumference),” said senior study author Erin Michos, MD, MHS, associate professor of medicine and epidemiology and associate director of preventive cardiology at Johns Hopkins School of Medicine in Baltimore.

“We also were surprised that we did not see any association of low vitamin D with elevated LDL cholesterol in our overall sample. However, when we performed a sensitivity analysis looking at individuals who were not taking lipid-lowering therapy at the baseline exam or at any of the follow-up visits, we did see the association of low vitamin D with elevated LDL cholesterol.”

Dr Michos and her colleagues measured lipids at baseline (1990-1992), in 1993-1994, and in 1996-1998. The mean follow-up was 5.2 years.

The investigators used linear and mixed model regression methods to assess associations of 25(OH) D with cross-sectional and lipid trends. They also adjusted for clinical characteristics. The mean age at baseline was 57.6 years, 57% were women, and 24% were black.

Among those individuals without baseline dyslipidemia, participants with low 25(OH) D (<20 ng/mL) compared with optimal levels (≥30 ng/mL) had increased risk for incident dyslipidemia in demographic-adjusted models (hazard ratio [HR]=1.19; 95% CI, 1.02-1.39). Nevertheless, this finding was attenuated in fully-adjusted models (HR=1.12; 95% CI, 0.95-1.32).1

Dr Michos said low concentrations of vitamin D, defined as serum 25(OH)D below 30 ng/mL, are present in more than two-thirds of the US adult population and in an estimated 1 billion individuals worldwide. 

“So, this is a major relevant public health issue. Vitamin D deficiency has been associated with a number of non-bone-related adverse health outcomes, including increased risk for cardiovascular diseases (CVDs). One of the mechanisms by which vitamin D may influence CVD risk is through an effect on lipids,” Dr Michos told Endocrinology Advisor. “The potential link between vitamin D deficiency and adverse lipid profile should be of great interest to a large number of practitioners who treat both vitamin D and lipid disorders, including endocrinologists, internists, lipidologists, and cardiologists.”

Previous studies, including one study conducted by her team and recently published in the Journal of Clinical Lipidology, suggested that low levels of vitamin D were associated with an atherogenic lipid profile consisting of elevated LDL cholesterol, elevated triglycerides, and lower HDL cholesterol, noted Dr Michos.2 However, most of the evidence supporting this association was obtained in cross-sectional analyses. 

For this current investigation, the researchers analyzed the association between vitamin D status and the lipid profile prospectively using data from the Atherosclerosis Risk in Communities (ARIC) study. This large study of a US community-based sample of blacks and whites collected data on numerous demographic, lifestyle, and clinical variables spanning multiple clinic visits. Unlike prior investigations, ARIC allowed for extensive adjustment of possible confounders over time, according to Dr Michos. It also contained information regarding initiation of lipid-lowering medication use during follow-up. 

Dr Michos said further research is warranted, including randomized, controlled trials, to assess whether treating vitamin D deficiency can impact lipids and thereby influence CVD risk.

References

  1. Faridi K, Zhao D, Martin SS, et al. Vitamin D and Change in Lipids Over 5 Years: The Atherosclerosis Risk in Communities (ARIC) Study. Presented at: ACC 65th Annual Scientific Session & Expo; April 2-4, 2016; Chicago, IL.
  2. Lupton JR, Faridi KF, Martin SS, et al. Deficient serum 25-hydroxyvitamin D is associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-3) study. J Clin Lipidol. 2016;10(1):72-81. doi:10.1016/j.jacl.2015.09.006.

Study Finds New Iodine Mouthwash May Impact LDL Cholesterol

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SAN ANTONIO–(BUSINESS WIRE)–Cleaning your mouth and cleaning your arteries could be as simple as a once-a-day oral rinse if additional studies confirm preliminary findings about a new product.

“We didn’t expect to see any difference in LDL cholesterol”

Biomedical Development Corporation (BDC) on April 23 will present data to the American Academy of Oral Medicine showing that its oral rinse was safe and effective at fighting gingivitis in a recent clinical trial.  But the most surprising finding of the study was that users of the oral rinse showed significantly lower LDL cholesterol levels than the placebo group.

“We didn’t expect to see any difference in LDL cholesterol,” said Dr. Charles Gauntt, the study’s principal investigator. “We expected to see improvements in oral health, and we did.  But we also monitored a number of biological markers for inflammation. The results showed the oral rinse had no adverse effects and users exhibited lower levels of LDL, or what many people know as bad cholesterol.  This definitely merits further study.”

The three-month, phase II trial was funded by the National Heart, Lung and Blood Institute (NHLBI).  The trial was preceded by a phase I clinical trial for safety and a phase II pilot efficacy clinical trial.  Another, longer phase II trial is now under way and will evaluate gingivitis patients over a six-month period.  This new trial, conducted by the Center for Oral Health Research at the University of Kentucky, will monitor gingivitis and LDL cholesterol levels as the previous trial did.  The NHLBI is funding the research, which is also supported by the Kentucky SBIR/STTR Matching Funds Program.

BDC’s product is designed as a once-daily, 30-second oral rinse.  The active ingredient is a proprietary formula based on iodine.  The National Institutes of Health Office of Dietary Supplements fact sheet on iodine addresses a variety of important roles for iodine in the human body, from helping the thyroid function properly to appearing to play a part in the body’s immune response system.  About 40 percent of the world’s population is thought to be at risk of iodine deficiency.

Gauntt also notes that iodine is known to be effective in inactivating viruses, bacteria and funguses. He is intrigued by recent clinical studies showing what appears to be a closer link between oral health and cardiovascular health. Although scientists cannot yet fully explain how the two are connected, there is ample statistical evidence to suggest that gum disease and heart disease are closely related.  According to the American Academy of Periodontology, people with periodontal disease (gum disease) are almost twice as likely to have coronary artery disease.  The academy also notes that one study showed stroke victims were more likely than the general population to also have oral infections.

Gauntt believes that future research might make it much clearer that a healthy mouth, free of gum disease and its associated toxins and bacteria, is critical to a healthy cardiovascular system.  Although further study is required, he adds, he believes BDC’s oral rinse may eventually prove to be an important tool in keeping both mouths and cardiovascular systems healthy, in addition to proper nutrition and exercise.

Phyllis Siegel, CEO of BDC, said that while results of its ongoing clinical trials are pending, a specific formulation of the product called iCLEAN®, designed for general mouth cleaning, will soon be available. For more information, visit www.iCLEANmouths.com.

Properties and Therapeutic Application of Bromelain(Pineapple):A Review

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Abstract

Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple. Fruit bromelain and stem bromelainare prepared differently and they contain different enzymatic composition. “Bromelain” refers usually to the “stem bromelain.” Bromelain is a mixture of different thiol endopeptidases and other components like phosphatase, glucosidase, peroxidase, cellulase, escharase, and several protease inhibitors. In vitro and in vivo studies demonstrate that bromelain exhibits various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities. Bromelain is considerably absorbable in the body without losing its proteolytic activity and without producing any major side effects. Bromelain accounts for many therapeutic benefits like the treatment of angina pectoris, bronchitis, sinusitis, surgical trauma, and thrombophlebitis, debridement of wounds, and enhanced absorption of drugs, particularly antibiotics. It also relieves osteoarthritis, diarrhea, and various cardiovascular disorders. Bromelain also possesses some anticancerous activities and promotes apoptotic cell death. This paper reviews the important properties and therapeutic applications of bromelain, along with the possible mode of action.

1. Introduction

Pineapple is the common name of Ananas comosus (syns. A. sativus, Ananassa sativa, Bromelia ananas, B. comosa). Pineapple is the leading edible member of the family Bromeliaceae, grown in several tropical and subtropical countries including Philippines, Thailand, Indonesia, Malaysia, Kenya, India, and China. It has been used as a medicinal plant in several native cultures [] and these medicinal qualities of pineapple are attributed to bromelain (EC 3.4.22.32), which is a crude extract from pineapple that contains, among other compounds, various closely related proteinases, exhibiting various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities in vitro and in vivo. Bromelain has been chemically known since 1875 and is used as a phytomedical compound []. Bromelain concentration is high in pineapple stem, thus necessitating its extraction because, unlike the pineapple fruit which is normally used as food, the stem is a waste byproduct and thus inexpensive []. A wide range of therapeutic benefits have been claimed for bromelain, such as reversible inhibition of platelet aggregation, sinusitis, surgical traumas [], thrombophlebitis, pyelonephriti angina pectoris, bronchitis [], and enhanced absorption of drugs, particularly of antibiotics []. Several studies have been carried out indicating that bromelain has useful phytomedical application. However, these results are yet to be amalgamated and critically compared so as to make out whether bromelain will gain wide acceptance as a phytomedical supplement []. Bromelain acts on fibrinogen giving products that are similar, at least in effect, to those formed by plasmin []. Experiment in mice showed that antacids such as sodium bicarbonate preserve the proteolytic activity of bromelain in the gastrointestinal tract []. Bromelain is considered as a food supplement and is freely available to the general public in health food stores and pharmacies in the USA and Europe []. Existing evidence indicates that bromelain can be a promising candidate for the development of future oral enzyme therapies for oncology patients []. Bromelain can be absorbed in human intestines without degradation and without losing its biological activity [].

2. Biochemical Properties

The crude aqueous extract from stem and fruit of pineapple is known as bromelain. It is a mixture of different thiol endopeptidases and other components like phosphatases, glucosidase, peroxidases, cellulases, glycoproteins, carbohydrates, and several protease inhibitors []. Stem bromelain (EC.3.4.22.32) is different from fruit bromelain (EC.3.4.22.33) []. The enzymatic activities of bromelain comprise a wide spectrum with pH range of 5.5 to 8.0 []. Different protein fractions were obtained by mean of various “biochemical techniques as sodium dodecyl sulphate polyacrylamide gel electrophoresis” (SDS-PAGE), isoelectric focusing (IEF), and multicathodal-PAGE []. Nowadays, bromelain is prepared from cooled pineapple juice by centrifugation, ultrafiltration, and lyophilization. The process yields a yellowish powder, the enzyme activity of which is determined with different substrates such as casein (FIP unit), gelatin (gelatin digestion units), or chromogenic tripeptides [].

3. Absorption and Bioavailability

The body can absorb significant amount of bromelain; about 12 gm/day of bromelain can be consumed without any major side effects []. Bromelain is absorbed from the gastrointestinal tract in a functionally intact form; approximately 40% of labeled bromelain is absorbed from intestine in high molecular form []. In a study carried out by Castell et al. [] bromelain was detected to retain its proteolytic activity in plasma and was also found linked with alpha 2-macroglobulin and alpha1-antichymotrypsin, the two antiproteinases of blood. In a recent study, it was demonstrated that 3.66 mg/mL of bromelain was stable in artificial stomach juice after 4 hrs of reaction and also 2.44 mg/mL of bromelain remained in artificial blood after 4 hrs of reaction [].

4. Medicinal Uses

Clinical studies have shown that bromelain may help in the treatment of several disorders.

4.1. Effects of Bromelain on Cardiovascular and Circulation

Bromelain prevents or minimizes the severity of angina pectoris and transient ischemic attack (TIA). It is useful in the prevention and treatment of thrombophlebitis. It may also break down cholesterol plaques and exerts a potent fibrinolytic activity. A combination of bromelain and other nutrients protect against ischemia/reperfusion injury in skeletal muscle []. Cardiovascular diseases (CVDs) include disorders of the blood vessels and heart, coronary heart disease (heart attacks), cerebrovascular disease (stroke), raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, heart failure, and congenital heart disease []. Stroke and heart disease are the main cause of death, about 65% of people with diabetes die from stroke or heart disease. Bromelain has been effective in the treatment of CVDs as it is an inhibitor of blood platelet aggregation, thus minimizing the risk of arterial thrombosis and embolism []. King et al. [] reported that administration of medication use to control the symptoms of diabetes, hypertension, and hypercholesteromia increased by 121% from 1988–1994 to 2001–2006 (P < 0.05) and was greater for patients with fewer healthy lifestyle habits. Bromelain supplement could reduce any of risk factors that contribute to the development of cardiovascular disease. In a recent research, Bromelain was found to attenuate development of allergic airway disease (AAD), while altering CD4+ to CD8+T lymphocyte populations. From this reduction in AAD outcomes it was suggested that bromelain may have similar effects in the treatment of human asthma and hypersensitivity disorders []. In another study, carried out by Juhasz et al., Bromelain was proved to exhibit the ability of inducing cardioprotection against ischemia-reperfusion injury through Akt/Foxo pathway in rat myocardium [].

4.2. Bromelain Relieves Osteoarthritis

Osteoarthritis is the most common form of arthritis in Western countries; in USA prevalence of osteoarthritis ranges from 3.2 to 33% dependent on the joint []. A combination of bromelain, trypsin, and rutin was compared to diclofenac in 103 patients with osteoarthritis of the knee. After six weeks, both treatments resulted in significant and similar reduction in the pain and inflammation []. Bromelain is a food supplement that may provide an alternative treatment to nonsteroidal anti-inflammatory drug (NSAIDs) []. It plays an important role in the pathogenesis of arthritis []. Bromelain has analgesic properties which are thought to be the result of its direct influence on pain mediators such as bradykinin []. The earliest reported studies investigating bromelain were a series of case reports on 28 patients, with moderate or severe rheumatoid or osteoarthritis [].

4.3. Effect of Bromelain on Immunogenicity

Bromelain has been recommended as an adjuvant therapeutic approach in the treatment of chronic inflammatory, malignant, and autoimmune diseases []. In vitro experiments have shown that Bromelain has the ability to modulate surface adhesion molecules on T cells, macrophages, and natural killer cells and also induce the secretion of IL-1β, IL-6, and tumour necrosis factor α (TNFα) by peripheral blood mononuclear cells (PBMCs) []. Bromelain can block the Raf-1/extracellular-regulated-kinase- (ERK-) 2 pathways by inhibiting the T cell signal transduction []. Treatment of cells with bromelain decreases the activation of CD4 (+) T cells and reduce the expression of CD25 []. Moreover, there is evidence that oral therapy with bromelain produces certain analgesic and anti-inflammatory effects in patients with rheumatoid arthritis, which is one of the most common autoimmune diseases [].

4.4. Effect of Bromelain on Blood Coagulation and Fibrinolysis

Bromelain influences blood coagulation by increasing the serum fibrinolytic ability and by inhibiting the synthesis of fibrin, a protein involved in blood clotting []. In rats, the reduction of serum fibrinogen level by bromelain is dose dependent. At a higher concentration of bromelain, both prothrombin time (PT) and activated partial thromboplastin time (APTT) are markedly prolonged []. In vitro and in vivostudies have suggested that bromelain is an effective fibrinolytic agent as it stimulates the conversion of plasminogen to plasmin, resulting in increased fibrinolysis by degrading fibrin [].

4.5. Effects of Bromelain on Diarrhea

Evidence has suggested that bromelain counteracts some of the effects of certain intestinal pathogens like Vibrio cholera and Escherichia coli, whose enterotoxin causes diarrhoea in animals. Bromelain appears to exhibit this effect by interacting with intestinal secretory signaling pathways, including adenosine 3′ : 5′-cyclic monophosphatase, guanosine 3′ : 5′-cyclic monophosphatase, and calcium-dependent signaling cascades []. Other studies suggest a different mechanism of action. In E. coli infection, an active supplementation with bromelain leads to some antiadhesion effects which prevent the bacteria from attaching to specific glycoprotein receptors located on the intestinal mucosa by proteolytically modifying the receptor attachment sites [].

4.6. Effect of Bromelain on Cancer Cells

Recent studies have shown that bromelain has the capacity to modify key pathways that support malignancy. Presumably, the anticancerous activity of bromelain is due to its direct impact on cancer cells and their microenvironment, as well as on the modulation of immune, inflammatory, and haemostatic systems []. Most of the in vitro and in vivo studies on anticancer activity of bromelain are concentrated on mouse and human cells, both cancerous and normal, treated with bromelain preparations. In an experiment conducted by Beez et al chemically induced mouse skin papillomas were treated with bromelain and they observed that it reduced tumor formation, tumor volume and caused apoptotic cell death []. In one study related to bromelain treatment of gastric carcinoma Kato III cell lines, significant reduction of cell growth was observed [] while in another study bromelain reduced the invasive capacity of glioblastoma cells and reduced de novo protein synthesis []. Bromelain is found to increase the expression of p53 and Bax in mouse skin, the well-known activators of apoptosis []. Bromelain also decreases the activity of cell survival regulators such as Akt and Erk, thus promoting apoptotic cell death in tumours. Different studies have demonstrated the role of NF-κB, Cox-2, and PGE2 as promoters of cancer progression. Evidence shows that the signaling and overexpression of NF-κB plays an important part in many types of cancers []. Cox-2, a multiple target gene of NF-κB, facilitates the conversion of arachidonic acid into PGE2 and thus promotes tumour angiogenesis and progression []. It is considered that inhibiting NF-κB, Cox-2, and PGE2 activity has potential as a treatment of cancer. Bromelain was found to downregulate NF-κB and Cox-2 expression in mouse papillomas [] and in models of skin tumourigenesis []. Bromelain was also shown to inhibit bacterial endotoxin (LPS)-induced NF-κB activity as well as the expression of PGE2 and Cox-2 in human monocytic leukemia and murine microglial cell lines []. Bromelain markedly has in vivo antitumoural activity for the following cell lines: P-388 leukemia, sarcoma (S-37), Ehrlich ascetic tumour, Lewis lung carcinoma, and ADC-755 mammary adenocarcinoma. In these studies, intraperitoneal administration of bromelain after 24 hours of tumour cell inoculation resulted in tumour regression [].

4.7. Role of Bromelain in Surgery

Administration of bromelain before a surgery can reduce the average number of days for complete disappearance of pain and postsurgery inflammation []. Trials indicate that bromelain might be effective in reducing swelling, bruising, and pain in women having episiotomy []. Nowadays, bromelain is used for treating acute inflammation and sports injuries [].

4.8. Role of Bromelain in Debridement Burns

The removal of damaged tissue from wounds or second/third degree burns is termed as debridement. Bromelain applied as a cream (35% bromelain in a lipid base) can be beneficial for debridement of necrotic tissue and acceleration of healing. Bromelain contains escharase which is responsible for this effect. Escharase is nonproteolytic and has no hydrolytic enzyme activity against normal protein substrate or various glycosaminoglycan substrates. Its activity varies greatly with different preparations []. In two different enzymatic debridement studies carried out in porcine model, using different bromelain-based agents, namely, Debriding Gel Dressing (DGD) and Debrase Gel Dressing showed rapid removal of the necrotic layer of the dermis with preservation of the unburned tissues []. In another study on Chinese landrace pigs, enzymatic debridement using topical bromelain in incised wound tracks accelerated the recovery of blood perfusion, pO2in wound tissue, controlled the expression of TNF-α, and raised the expression of TGT-β []. Enzymatic debridement using bromelain is better than surgical debridement as surgical incision is painful, nonselective and exposes the patients to the risk of repeated anaesthesia and significant bleeding [].

4.9. Toxicity of Bromelain

According to Taussig et al. [] bromelain has very low toxicity with an LD50(lethal doses) greater than 10 g/kg in mice, rates, and rabbits. Toxicity tests on dogs, with increasing level of bromelain up to 750 mg/kg administered daily, showed no toxic effects after six months. Dosages of 1500 mg/kg per day when administered to rats showed no carcinogenic or teratogenic effects and did not provoke any alteration in food intake, histology of heart, growth, spleen, kidney, or hematological parameters []. Eckert et al. [] after giving bromelain (3000 FIP unit/day) to human over a period of ten days found no significant changes in blood coagulation parameters.

5. Conclusion

Bromelain has a wide range of therapeutic benefits, but the mode of its action is not properly understood. It is proved that bromelain is well absorbed in body after oral administration and it has no major side effects, even after prolonged use. All the evidences reviewed in this paper suggest that bromelain can be used as an effective health supplement to prevent cancer, diabetes, and various cardiovascular diseases in the long run.

6. Future Trends and Perspectives

Bromelain can be a promising candidate for the development of oral enzyme therapies for oncology patients. It is clear from this paper that bromelain is a multiaction enzyme; however, more research is required to understand the proper mechanism of action of bromelain so that the multiaction activities of bromelain can be harnessed efficiently.

Acknowledgments

The authors are grateful to DEAN, Department of Biotechnology, IBMER, Mangalayatan University, Aligarh, India, for providing necessary facilities and encouragement. They are also thankful to all faculty members of the Institute of Biomedical Education and Research, Mangalayatan University, Aligarh, India, for their generous help and suggestions during the paper preparation.

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Statin Therapy and Decreased Incidence of Positive Candida Cultures Among Patients With Type 2 Diabetes Mellitus Undergoing Gastrointestinal Surgery

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OBJECTIVE

To assess whether statin therapy decreases the incidence of cultures positive for Candida species among high-risk hospitalized patients with type 2 diabetes mellitus (DM).

PATIENTS AND METHODS

We performed a retrospective cohort study analyzing the records of all patients with type 2 DM who were admitted to Massachusetts General Hospital for lower gastrointestinal tract surgery between January 1, 2001, and May 1, 2008. We defined statin exposure as the filling of at least 1 prescription of statins during the 6 months before hospitalization or during the current hospital stay. The primary outcome was a culture positive for Candida species during hospitalization. Clinical information on a wide range of covariates was collected. Logistic regression analysis was used to adjust for possible confounders.

RESULTS

Of the 1019 patients who were eligible for the study, 493 (48%) were receiving statins. A total of 139 patients (14%) had at least 1 culture positive for Candida species during hospitalization. An adjusted multivariate model based on a backward stepwise elimination procedure showed that statin therapy significantly decreased the incidence of cultures positive for Candida species (odds ratio, 0.60; 95% confidence interval [CI], 0.38-0.96; P=.03) with a statistically significant prolonged time to event compared with no statin therapy (adjusted hazard ratio, 0.62; 95% CI, 0.44-0.88; P=.01). The benefit of statins was more prominent in patients with type 2 DM who had greater comorbidities (Charlson Comorbidity Index ≥2) (adjusted odds ratio, 0.47; 95% CI, 0.27-0.79; P=.01).

CONCLUSION

Among patients with type 2 DM who underwent gastrointestinal surgery, use of statins correlated with a decreased incidence of cultures positive for Candida species.