The Gary Null Show - 03.01.21

Curcumin for amyloidosis and lipid metabolism -- a novel insight

Shinshu University (Japan), February 26, 2021

Curcumin is a polyphenol compound produced by plants of the Curcuma longa species and has been reported to have many physiological activities, which include anti-oxidation, anti-inflammatory, anti-cancer, and anti-amyloid properties. However, the mechanism and network of action are not completely clear. Amyloidosis is a group of diseases characterized by abnormal aggregates of proteins, known as amyloid fibrils, and subsequent deposition in various tissues and organs, such as Alzheimer's disease, immunoglobulin light chain amyloidosis.

In previous studies, curcumin has been shown to suppress the aggregation and cytotoxicity of many amyloid proteins in vitro, such as amyloid ß (Aß), α-synuclein, transthyretin, and prion protein, and has also been reported to inhibit the deposition of Aß fibrils in a mouse model of Alzheimer's disease. The group investigated amyloid deposition and molecular changes in a mouse model of amyloid apolipoprotein A-II (AApoAII) amyloidosis, in which mice were fed a curcumin-supplemented diet. In this research, it was found that curcumin intake elevated ApoA-II and HDL-cholesterol concentration in plasma by activating the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway, resulting in increased AApoAII amyloid deposition and peroxisome proliferation. These findings demonstrate the novel agonistic effect of curcumin on PPARα, which is an important transcription factor for lipid metabolism, and may have far-reaching significance for the treatment of amyloidosis and other metabolic disorders.

It was reported that high-fat diet supplement aggravates a variety of amyloid deposition including Aß in Alzheimer's disease model mice, but a link between lipid metabolism and the development of amyloidosis has not been completely established. These results provide a promising molecular target to understand the molecular mechanism of amyloidogenesis, which the activation state of PPARα pathway may be a bridge to connect the change of lipid metabolism level and the degree of amyloid deposition. In addition, it has been regarded that curcumin, as an agonist of PPARγ, exerts anti-inflammatory, anti-cancer and antioxidant activities in the past. However, this study demonstrates that curcumin is a PPARα/γ dual activator and may affect expression levels of proteins involved in amyloid deposition and other metabolism functions in a complex manner. By focusing on the PPARα pathway, the group hope to provide an opportunity to reconsider the mechanism of the physiological effects of curcumin.

In the next stage, the group would like to clarify how curcumin activates the PPARα signaling pathway in vitro and confirm whether the activation of PPARα can affect amyloid deposition on other types of amyloidosis in vivo (Alzheimer's disease, ATTR amyloidosis etc.). The goal in this research is to elucidate the molecular pathways involved in the pathogenesis of amyloidosis in vivo and to develop effective therapeutic or preventive methods against the development of amyloidosis. As a future study, the group hopes to fully understand the molecular fluctuations of PPARα-activated cells and verify the effectiveness of interventions in these pathways for various metabolic diseases.

 

 

Older women who ate more plant protein had lower risk of premature, dementia-related death

University of Iowa, February 24, 2021 

Postmenopausal women who ate high levels of plant protein had lower risks of premature death, cardiovascular disease and dementia-related death compared with women who ate less plant proteins, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association.

Previous research has shown an association between diets high in red meat and cardiovascular disease risk, yet the data is sparse and inconclusive about specific types of proteins, the study authors say.

In this study, researchers analyzed data from more than 100,000 postmenopausal women (ages 50 to 79) who participated in the national Women's Health Initiative study between 1993 and 1998; they were followed through February 2017. At the time they enrolled in the study, participants completed questionnaires about their diet detailing how often they ate eggs, dairy, poultry, red meat, fish/shellfish and plant proteins such as tofu, nuts, beans and peas. During the study period, a total of 25,976 deaths occurred (6,993 deaths from cardiovascular disease; 7,516 deaths from cancer; and 2,734 deaths from dementia).

Researchers noted the levels and types of protein women reported consuming, divided them into groups to compare who ate the least and who ate the most of each protein. The median percent intake of total energy from animal protein in this population was 7.5% in the lowest quintile and 16.0% in the highest quintile. The median percent intake of total energy from plant protein in this population was 3.5% in the lowest quintile and 6.8% in the highest quintile.

Among the key findings:

• Compared to postmenopausal women who had the least amount of plant protein intake, those with the highest amount of plant protein intake had a 9% lower risk of death from all causes, a 12% lower risk of death from cardiovascular disease and a 21% lower risk of dementia-related death.
• Higher consumption of processed red meat was associated with a 20% higher risk of dying from dementia.
• Higher consumption of unprocessed meat, eggs and dairy products was associated with a 12%, 24% and 11% higher risk of dying from cardiovascular disease, respectively.
• Higher consumption of eggs was associated with a 10% higher risk of death due to cancer.
• However, higher consumption of eggs was associated with a 14% lower risk of dying from dementia, while higher poultry consumption was associated with a 15% lower risk.

"It is unclear in our study why eggs were associated with a higher risk of cardiovascular and cancer death," said lead study author Wei Bao, M.D., Ph.D., an assistant professor of epidemiology at the University of Iowa in Iowa City. "It might be related to the way people cook and eat eggs. Eggs can be boiled, scrambled, poached, baked, basted, fried, shirred, coddled or pickled or in combinations with other foods. In the United States, people usually eat eggs in the form of fried eggs and often with other foods such as bacon. Although we have carefully accounted for many potential confounding factors in the analysis, it is still difficult to completely tease out whether eggs, other foods usually consumed with eggs, or even non-dietary factors related to egg consumption, may lead to the increased risk of cardiovascular and cancer death."

Researchers noted that substitution of total red meat, eggs or dairy products with nuts was associated with a 12% to 47% lower risk of death from all causes depending on the type of protein replaced with nuts.

"It is important to note that dietary proteins are not consumed in isolation, so the interpretation of these findings could be challenging and should be based on consideration of the overall diet including different cooking methods," said Yangbo Sun, M.D., Ph.D., co-author of the study, a postdoctoral research scholar at the University of Iowa in Iowa City and currently an assistant professor of epidemiology at the University of Tennessee Health Science Center.

The analysis also revealed that women who ate the highest amount of animal protein such as meat and dairy were more likely to be white and have a higher education and income, and they were more likely to be past smokers, drink more alcohol and be less physically active. Moreover, these women were more likely to have Type 2 diabetes at the start of the study, a family history of heart attacks and a higher body mass index -- all risk factors for cardiovascular disease.

"Our findings support the need to consider dietary protein sources in future dietary guidelines," said Bao. "Current dietary guidelines mainly focus on the total amount of protein, and our findings show that there may be different health influences associated with different types of protein foods."

2020-2025 Dietary Guidelines for Americans, jointly published by the U.S. Departments of Agriculture (USDA) and Health and Human Services (HHS), recommend eating a variety of protein foods: low-fat meat, low-fat poultry, eggs, seafood, beans, peas, lentils, nuts, seeds and soy products including at least 8 ounces of cooked seafood per week.

The AHA's 2020 Dietary Cholesterol and Cardiovascular Risk advisory notes that given the relatively high content of cholesterol in egg yolks, it remains advisable to limit intake. Healthy individuals can include up to one whole egg or the equivalent daily.

The study had several limitations including that it was observational, based on self-reported data at the beginning of the study and lacked data on how the proteins were cooked. In addition, the findings may not apply to younger women or men.

 

 

Citrus Flavonoid May Help to Improve Metabolic and Inflammatory Markers

Sao Paulo State University (Brazil), February 20, 2021

The researchers from Sao Paulo State University and the US Horticultural Research Laboratory associated the citrus flavonoid with a significant reduction in levels of cholesterols and triglycerides which are markers of insulin resistance at low (10 and 25 mg/kg BW) and high ( 100 mg/kg BW) doses, with the best results being observed at 25 mg per kg of body weight. 

The study authors wrote, “Therefore, our results showed that low doses of dietary eriocitrin are able to counteract the deleterious effects of high-fat diet and prevent risk factors of metabolic syndrome and chronic disease related to obesity.” 

“Further, the use of lower doses may help to prevent unintended complications possibly occurring at much higher doses of potent antioxidant supplements such as eriocitrin.”

“As a leading supplier of citrus flavonoids, we put great importance into the continual development of research into these powerful ingredients,” said Rob Brewster who is the President of Ingredients by Nature (IBN). “Eriocitrin is not as commonly recognized as other fruit-derived flavonoids, but the science shows that it is a potent source of health support for a variety of health complications. We look forward to seeing what future research will continue to reveal about it.”

During this study 40 male mice were fed a high-fat diet for 4 weeks to induce obesity, then they were divided at random into four different groups for an additional 4 weeks and given doses of eriocitrin at 0, 10, 25, or 100 mg per kg of body weight, while a control group was fed a standard diet for the 8 weeks. 

The researchers reported the best results being observed in the eriocitrin group taking 25 mg/kg with reductions in triglycerides of 31%, total cholesterol of 6%, and liver triacylglycerols of 28% compared to the control group. Eriocitrin at 25 mg/kg was associated with a reduction in lipid peroxidation of 19%, and markers of insulin resistance including resistin and the insulin resistance index also significantly decreased. Additionally, serum glucose levels also significantly decreased by 25%, insulin levels by 35% in this same group. 

“Most studies on eriocitrin haven’t explored its effect on obesity induces metabolic disturbances and, because the global rate of obesity continues to increase, we felt that it was important to examine the topic further,” said the corresponding author Dr. Thais Cesar who is also an associate professor of nutrition at Sao Paulo State University. “Eriocitrin significantly improved metabolic, inflammatory, and oxidative stress parameters across multiple biomarkers, showing potential to delay the development of inflammatory complications. We look forward to performing additional research on eriocitrin in the future.”

This study was sponsored by IBM, and also showed that eriocitrin was effective in terms of glucose and lipid metabolism, especially with blood glucose reduction, along with delivering a strong antioxidant defense by directly helping the uptake of oxygen radicals and promoting the activation of endogenous defense mechanisms. This effect has been reported in previous studies including with the lemon flavonoid blend Eriomin, which is made up primarily of eriocitrin. Last year, the company also received patent approval from the USPTO for IBN’s use of eriocitrin as a method of reducing blood glucose levels

 

Resveratrol may be an effective intervention for lung aging

The Saban Research Institute (Los Angeles), February 22, 2021

 

In a study led by Barbara Driscoll, PhD, of The Saban Research Institute of Children's Hospital Los Angeles, researchers demonstrate, for the first time that inhaled resveratrol treatments slow aging-related degenerative changes in mouse lung. Lung aging, characterized by airspace enlargement and decreasing lung function, is a significant risk factor for chronic human lung diseases. The study is published online in the journal Thorax.

 

"We believe that ours is the first study to demonstrate a beneficial effect of lung-directed resveratrol treatments on aging lung function," said Driscoll.

 

Resveratrol (RSL), a chemical found in red wine, is an antimicrobial chemical substance produced by plants to protect against infection and stress-related changes. It has previously been shown to support muscle metabolism when delivered orally.

 

RSL prophylaxis by inhalation was a novel measure taken by the research team as a potential approach for slowing age-related deterioration of lung function and structure by preserving alveolar epithelial type 2 cells (AEC2) which line alveoli (the tiny air sacs in the lungs through which the exchange of oxygen and carbon dioxide takes place) and produce surfactant which is vital for efficient breathing.

 

In healthy young adults, breathing is an essential, efficient process, but natural aging of the lung occurs at a steady and irreversible rate, as measured by a decline in lung function. This natural deterioration leads to a significantly reduced quality of life, over a time frame dependent on genetic and environmental factors. Although some available therapies can ameliorate symptoms, aging-related lung failure is generally irreversible and is accompanied by high rates of morbidity and mortality due to increased disease risk, including development of COPD, with accompanying emphysema and chronic bronchitis.

 

Using a rapidly aging mouse model, the research team investigated whether the accumulation of age-related degenerative changes in the lung could be slowed by inhaled RSL. Treatment cohorts received either RSL or vehicle by intratracheal (IT) instillation monthly for three months. One month following the final treatment, whole lung function and injury-related gene expression in AEC2 were assessed.

 

The research team found that inhaled, prophylactic resveratrol treatments can slow the rate of lung function decline, alveolar enlargement and alveolar epithelial type 2 cell DNA damage that occurs in the early stages of lung aging. They concluded that administration of resveratrol directly to the lungs may be an effective intervention for lung aging, which is a significant risk factor for development of chronic lung disease.

 

"While the natural deterioration of the human lung generally occurs over decades, the injury to lung cells is analogous to the lung cell damage that occurs in premature infants who experience respiratory distress before their lungs have fully developed," added Driscoll. "Identifying a way to protect and strengthen young lungs before significant damage occurs is the goal of our research."

 

 

Deficient magnesium levels prevalent in an older population

Kathmandu Medical College (Nepal), February 19, 2021

According to news reporting out of Kathmandu Medical College research stated, “Magnesium deficiency is common in the elderly and critically ill population and has been associated with a prolonged ICU stay. The knowledge of hypomagnesemia is essential as it could have prognostic and therapeutic implications in the elderly population.”

The news correspondents obtained a quote from the research from Kathmandu Medical College: “This study aimed to estimate the prevalence of hypomagnesemic in the elderly population visiting a tertiary care center. This descriptive cross-sectional study was conducted in a tertiary care hospital from March 21, 2020 to September 21, 2020. After obtaining ethical clearance from the institutional review committee (Ref. 2003202008), convenience sampling was done. Data were collected and entered in Microsoft Excel version 2007. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data. Out of 384 participants, 174 (45%) participants were found to have deranged magnesium levels, in which 111 (29%) (31.3-26.7 at 95% Confidence Interval) were found to be hypomagnesemia. Among them, 62 (29.4%) males and 49 (28.5%) females were hypomagnesemia. The average level of serum magnesium was 2.02±0.76 mg/dl ranging from 0.03 to 4.71. The mean age of participants was 70.31±8.13 years, among which the participants between the age group of 71-80 years presented with a maximum percentage of hypomagnesemia.”

According to the news reporters, the research concluded: “The present study has shown that an apparently-healthy elderly population may have a magnesium deficiency that may need to be identified and treated for optimizing clinical care. Further multicentric studies with a greater sample size should be done in this field, which will benefit the elderly population.”

 

 

Researchers identify mechanism by which exercise strengthens bones and immunity

University of Texas Medical Center, February 24, 2021

Scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) have identified the specialized environment, known as a niche, in the bone marrow where new bone and immune cells are produced. The study, published in Nature, also shows that movement-induced stimulation is required for the maintenance of this niche, as well as the bone and immune-forming cells that it contains. Together, these findings identify a new way that exercise strengthens bones and immune function.

Researchers from the Morrison laboratorydiscovered that forces created from walking or running are transmitted from bone surfaces along arteriolar blood vessels into the marrow inside bones. Bone-forming cells that line the outside of the arterioles sense these forces and are induced to proliferate. This not only allows the formation of new bone cells, which helps to thicken bones, but the bone-forming cells also secrete a growth factor that increases the frequency of cells that form lymphocytes around the arterioles. Lymphocytes are the B and T cells that allow the immune system to fight infections.

When the ability of the bone-forming cells to sense pressure caused by movement, also known as mechanical forces, was inactivated, it reduced the formation of new bone cells and lymphocytes, causing bones to become thinner and reducing the ability of mice to clear a bacterial infection. 

"As we age, the environment in our bone marrow changes and the cells responsible for maintaining skeletal bone mass and immune function become depleted. We know very little about how this environment changes or why these cells decrease with age," says Sean Morrison, Ph.D., the director of CRI and a Howard Hughes Medical Institute Investigator. "Past research has shown exercise can improve bone strength and immune function, and our study discovered a new mechanism by which this occurs."

Previous work from the Morrison laboratory discovered the skeletal stem cells that give rise to most of the new bone cells that form during adulthood in the bone marrow. They are Leptin Receptor+ (LepR+) cells. They line the outside of blood vessels in the bone marrow and form critical growth factors for the maintenance of blood-forming cells. The Morrison lab also found that a subset of LepR+ cells synthesize a previously undiscovered bone-forming growth factor called Osteolectin. Osteolectin promotes the maintenance of the adult skeleton by causing LepR+ to form new bone cells.

In the current study, Bo Shen, Ph.D., a postdoctoral fellow in the Morrison laboratory, looked more carefully at the subset of LepR+ cells that make Osteolectin. He discovered that these cells reside exclusively around arteriolar blood vessels in the bone marrow and that they maintain nearby lymphoid progenitors by synthesizing stem cell factor (SCF) - a growth factor on which those cells depend. Deleting SCF from Osteolectin-positive cells depleted lymphoid progenitors and undermined the ability of mice to mount an immune response to bacterial infection.

"Together with our previous work, the findings in this study show Osteolectin-positive cells create a specialized niche for bone-forming and lymphoid progenitors around the arterioles. Therapeutic interventions that expand the number of Osteolectin-positive cells could increase bone formation and immune responses, particularly in the elderly," says Shen.

Shen found that the number of Osteolectin-positive cells and lymphoid progenitors decreased with age. Curious if he could reverse this trend, Shen put running wheels in the cages so that the mice could exercise. He found the bones of these mice became stronger with exercise, while the number of Osteolectin-positive cells and lymphoid progenitors around the arterioles increased. This was the first indication that mechanical stimulation regulates a niche in the bone marrow. 

Shen found that Osteolectin-positive cells expressed a receptor on their surfaces - known as Piezo1 - that signals inside the cell in response to mechanical forces. When Piezo1 was deleted from Osteolectin-positive cells of mice, these cells and the lymphoid progenitors they support became depleted, weakening bones and impairing immune responses.

"We think we've found an important mechanism by which exercise promotes immunity and strengthens bones, on top of other mechanisms previously identified by others," says Morrison.

 

Long-term iodine nutrition associated with longevity in older adults: a 20 year follow-up of the Randers-Skagen Study

Aalborg University (Denmark), February 23, 2021

According to news reporting originating in Aalborg, Denmark, research stated, “Iodine intake affects the occurrence of thyroid disorders. However, the association of iodine intake with longevity remains to be described.”

The news reporters obtained a quote from the research from Aalborg University Hospital, “This led us to perform a 20 years’ follow-up on participants from the Randers-Skagen (RaSk) study. Residents in Randers born in 1920 (n 210) and Skagen born in 1918-1923 (n 218) were included in a clinical study in 1997-1998. Mean iodine content in drinking water was 2 mu g/l in Randers and 139 mu g/l in Skagen. We collected baseline data through questionnaires, performed physical examinations and measured iodine concentrations in spot urine samples. Income data were retrieved from Danish registries. We performed follow-up on mortality until 31 December 2017 using Danish registries. Complete follow-up data were available on 428 out of 430 of participants (99 center dot 5 %). At baseline, the median urinary iodine concentration was 55 mu g/l in Randers and 160 mu g/l in Skagen residents. Participants were long-term residents with 72.8 and 92.7 % residing for more than 25 years in Randers and Skagen, respectively. Cox regression showed that living in Skagen compared with Randers was associated with a lower hazard ratio (HR) of death in both age- and sex-adjusted analyses (HR 0.60, 95 % CI 0.41, 0.87, P = 0.006), but also after adjustment for age, sex, number of drugs, Charlson co-morbidity index, smoking, alcohol and income (HR 0.60, 95 % CI 0.41, 0.87, P = 0.008). Residing in iodine-replete Skagen was associated with increased longevity.”

According to the news reporters, the research concluded: “This indicates that long-term residency in an iodine-replete environment may be associated with increased longevity compared with residency in an iodine-deficient environment.”

This research has been peer-reviewed.