Interactive Nutrient Process (INP) in a Generative AI of a New Drug-6-Shogaol as a Potential Case.

The dynamically evolving science of pharmacology requires AI technology to advance a new path for drug development. The author proposes generative AI for future drugs, identifying suitable drug molecules, uncharacteristically to previous generations of medicines, incorporating the wisdom, experience, and intuit of traditional materia medica and the respective traditional medicine practitioners. This paper describes the guiding principles of the new drug development, springing from the tradition and practice of Tibetan medicine, defined as the Interactive Nutrient Process (INP). The INP provides traditional knowledge and practitioner's experience, contextualizing and teaching the new drug therapy. An illustrative example of the outcome of the INP is a potential small molecule drug, 6-Shogaol and related shogaol derivatives, from ginger roots (Zingiber officinalis fam. Zingiberaceae) evaluated clinically for 12 months for biological markers of iron homeostasis in patients with the myelodysplastic syndromes (MDS). The study's preliminary results indicate that 6-Shogaol and related shogaols may improve iron homeostasis in low-risk/intermediate-1 MDS patients without objective or subjective side effects.

Vitamin K Insufficiency in the Indian Population: Pilot Observational Epidemiology Study.

BACKGROUND: The fat-soluble K vitamins K1 and K2 play an essential role in the blood coagulation cascade and are made available predominantly through selective dietary intakes. They are less known for their nonessential roles in a family of vitamin K-dependent proteins that promote various functions of organs and systems in the body. A lack of vitamin K can characterize vitamin and nutritional element insufficiency, which is different from a clinically apparent vitamin deficiency. OBJECTIVE: This epidemiological study evaluated the nutritional status of vitamin K in a sample of the Indian population and vitamin K content in staple Indian foods. METHODS: Serum levels of vitamin K1 and vitamin K2 in the form of menaquinone-7 (MK-7) were assessed via high-performance liquid chromatography coupled with fluorescence detection in 209 patients with type 2 diabetes, 50 healthy volunteers, and common staple foods in India. RESULTS: After comparing populations with high and low serum vitamin K levels from various geographical regions, our results indicated that the sample of healthy Indian individuals and the sample of Indian patients with type 2 diabetes had low (insufficient) levels of vitamin K2 (MK-7; range 0.3-0.4 ng/mL). No significant differences existed in vitamin K1-related and MK-7-related values between healthy male and female subjects, between male and female subjects with diabetes, and between the healthy sample and the sample of patients with diabetes. The staple, commonly consumed Indian foods that were tested in this study had undetectable levels of vitamin K2, while levels of vitamin K1 varied widely (range 0-37 µg/100 g). CONCLUSIONS: Based on our sample's low serum levels of vitamin K2 (MK-7) as well as the low levels of vitamin K2 in their typical diet, we propose that the general Indian population could benefit from the consumption of vitamin K2 in the form of MK-7 supplements. TRIAL REGISTRATION: Clinical Trials Registry - India CTRI/2019/05/014246; http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=21660&EncHid=&userName=014246; Clinical Trials Registry - India CTRI/2019/03/018278; http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=32349&EncHid=&userName=018278.

Is 6-Shogaol an Effective Phytochemical for Patients With Lower-risk Myelodysplastic Syndrome? A Narrative Review.

Myelodysplastic syndrome (MDS) evolves due to genomic instability, dysregulated signaling pathways, and overproduction of inflammatory markers. Reactive oxygen species contribute to the inflammatory response, which causes gene damage, cellular remodeling, and fibrosis. MDS can be a debilitating condition, and management options in patients with MDS aim to improve cytopenias, delay disease progression, and enhance quality of life. High serum ferritin levels, a source of iron for reactive oxygen species production, correlate with a higher risk of progression to acute myeloid leukemia, and iron overload is compounded by blood transfusions given to improve anemia. 6-shogaol is a natural phenolic compound formed when ginger is exposed to heat and/or acidic conditions, and it has been shown to possess anti-tumor activity against leukemia cell lines and antioxidant effects. This narrative review assessed the potential benefits of this phytochemical in lower-risk MDS patients through examining the current evidence on the pharmacological and therapeutic properties of ginger and 6-shogaol.

Phytoecdysteroids Do Not Have Anabolic Effects in Skeletal Muscle in Sedentary Aging Mice.

Skeletal muscle mass and strength are lost with aging. Phytoecdysteroids, in particular 20-hydroxyecdysone (20E), increase protein synthesis in C2C12 skeletal muscle cells and muscle strength in young rats. The objective of this study was to determine whether an extract from Ajuga turkestanica (ATE), enriched in phytoecdysteroids, and 20E affect skeletal muscle mass and fiber size, fiber type, activation of the PI3K-Akt signaling pathway, and the mRNA levels of MAFbx, MuRF-1, and myostatin in sedentary aging mice. Aging male C57BL/6 mice (20 months old) received ATE, 20E, or vehicle (CT) once per day for 28 days or a single acute dose. Treatment did not alter body, muscle, or organ mass; fiber cross-sectional area; or fiber type in the triceps brachii or plantaris muscles. Likewise, protein synthesis signaling markers (i.e., phosphorylation of AktSer473 and p70S6kThr389) measured after either 28 days or acutely were unchanged. Neither ATE nor 20E treatment for 28 days affected the mRNA levels of MAFbx, MuRF-1, and myostatin. In conclusion, these data indicate that phytoecdysteroid treatment does not alter muscle mass or fiber type, nor does it activate protein synthesis signaling in the skeletal muscle of sedentary aging mice.

Sceletium tortuosum (Zembrin® ) ameliorates experimentally induced anxiety in healthy volunteers.

OBJECTIVE: To investigate the anxiolytic properties of a standardized extract of Sceletium tortuosum (trademarked-Zembrin® ). METHODS: Two studies utilized a placebo-controlled, double-blind, between-subject experimental design to investigate the effects of a single dose of Sceletium tortuosum (25 mg, Zembrin® ) on laboratory stress/anxiety responding in 20 young healthy volunteers. To elicit feelings of stress/anxiety, participants completed 20 min of the multitasking framework in study 1 and a 5-min simulated public speaking task in study 2. Study 1 measured subjective experiences of mood at baseline, prestress induction, and poststress induction. Study 2 measured subjective experiences of anxiety and physiological indicators of stress (heart rate [HR] and galvanic skin response) at baseline, prestress induction, during stress induction, and poststress induction. RESULTS: A series of analysis of covariances (baseline entered as the covariate) revealed no treatment effect in study 1; however, study 2 revealed subjective anxiety levels to be significantly lower in the Zembrin® group at the prestress induction point and a significant interaction between treatment and time on HR. Taken together, results indicate that a single dose of Zembrin® can ameliorate laboratory stress/anxiety responding in healthy volunteers. CONCLUSION: We provide the first tentative behavioral evidence to support the anxiolytic properties of Sceletium tortuosum (25 mg Zembrin® ).

A mixture of citrus polymethoxyflavones, green tea polyphenols and lychee extracts attenuates adipogenesis in 3T3-L1 adipocytes and obesity-induced adipose inflammation in mice.

Adipocyte-macrophage interaction in obesity can cause adipose tissue inflammation and contribute to insulin resistance. Here, we investigated the effect of SlimTrym®-a formulated product containing citrus polymethoxyflavones (PMFs), green tea extract, and lychee polyphenols-on 3T3-L1 adipocyte differentiation and obesity-induced inflammation. SlimTrym® inhibited mitotic clonal expansion (MCE) of 3T3-L1 adipocytes by inducing G1 cell cycle arrest via upregulation of p21 and p53. SlimTrym® attenuated adipogenic differentiation by downregulating adipogenic factors, such as CCAAT-enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ), and upregulating AMP-activated protein kinase (AMPK). Pretreatment with compound C significantly reduced SlimTrym®-mediated suppression of lipid accumulation. SlimTrym® reduced the expression of pro-inflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1ß and IL-6, in co-cultured 3T3-L1 adipocytes and RAW264.7 macrophages. C57BL/6 mice administered with SlimTrym® for 16 weeks showed markedly reduced high-fat diet (HFD)-induced infiltration of monocytes/macrophages in adipose tissue; however, the level of M2 macrophage markers (CD163 and IL-10) was increased. Taken together, these findings indicate that SlimTrym® exerts both anti-adipogenic and anti-inflammatory effects, and can potentially treat obesity and adipose tissue inflammation.

Role of Vitamin D and Its Receptors in the Pathophysiology of Chronic Rhinosinusitis.

OBJECTIVES: Chronic rhinosinusitis (CRS) is a disease that represents a challenging therapeutic problem. Vitamin D and its receptors (VDR) are involved in the regulation of the immune system and may play role in CRS. Objectives of this study were to assess the relationships between the total concentration of vitamin D (25VD3) in sera, vitamin D receptor (VDR) expression, 1α-hydroxylase expression, and clinical data, including age, gender, Sino-Nasal Outcome Test (SNOT-22), computerized tomography (CT) scan, allergy status, and vitamin D supplementation in CRS patients with (CRSwNP) and without nasal polyps (CRSsNP), and in a control group. METHODS: The studied group comprised 52 patients with CRS without nasal polyps (sNP), 55 with CRS with nasal polyps (wNP), and 59 in the control group. The endpoints were determined by appropriate methods. We conducted immunohistochemical staining of gathered tissue from the ostiomeatal complex for determination of VDR and 1α-hydroxylase. Analytical results were compared with clinical data as already noted. RESULTS: A decrease in VDR nuclear staining occurred in CRS patients as compared to controls. Insignificant differences were observed in 1α-hydroxylase, expression in all studied groups, while VDR and cytochrome CYP27B1 protein expression (1α-hydroxylase) correlated with clinical data. CONCLUSIONS: The data provide evidence that indicates that vitamin D and its receptor and enzymes may play a role in CRS.

Decreased Levels of Circulating Carboxylated Osteocalcin in Children with Low Energy Fractures: A Pilot Study.

OBJECTIVE: In the past decades, an increased interest in the roles of vitamin D and K has become evident, in particular in relation to bone health and prevention of bone fractures. The aim of the current study was to evaluate vitamin D and K status in children with low-energy fractures and in children without fractures. METHODS: The study group of 20 children (14 boys, 6 girls) aged 5 to 15 years old, with radiologically confirmed low-energy fractures was compared with the control group of 19 healthy children (9 boys, 10 girls), aged 7 to 17 years old, without fractures. Total vitamin D (25(OH)D3 plus 25(OH)D2), calcium, BALP (bone alkaline phosphatase), NTx (N-terminal telopeptide), and uncarboxylated (ucOC) and carboxylated osteocalcin (cOC) serum concentrations were evaluated. Ratio of serum uncarboxylated osteocalcin to serum carboxylated osteocalcin ucOC:cOC (UCR) was used as an indicator of bone vitamin K status. Logistic regression models were created to establish UCR influence for odds ratio of low-energy fractures in both groups. RESULTS: There were no statistically significant differences in the serum calcium, NTx, BALP, or total vitamin D levels between the two groups. There was, however, a statistically significant difference in the UCR ratio. The median UCR in the fracture group was 0.471 compared with the control group value of 0.245 (p < 0.0001). In the logistic regression analysis, odds ratio of low-energy fractures for UCR was calculated, with an increased risk of fractures by some 78.3 times. CONCLUSIONS: In this pilot study, better vitamin K status expressed as the ratio of ucOC:cOC-UCR—is positively and statistically significantly correlated with lower rate of low-energy fracture incidence.

Effect of the Ginger Derivative, 6-Shogaol, on Ferritin Levels in Patients With Low to Intermediate-1-Risk Myelodysplastic Syndrome-A Small, Investigative Study.

BACKGROUND: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal stem cell disorders characterized by dysplastic and ineffective hematopoiesis and peripheral cytopenias. Elevated serum ferritin (SF) is often observed in nontransfused, lower risk MDS. It has been reported that ineffective erythropoiesis enhances iron absorption in MDS through downregulation of hepcidin and its prohormones such that SF rises. AIM: To determine the effect of 6-shogaol, a dehydration derivative of ginger, known to have hepatoprotective and chemotherapeutic activity, on 6 early-stage, transfusion-independent patients with MDS, 3 of whom had raised levels of SF. METHOD: Six patients with MDS with low or intermediate-1 subtypes, as defined by the International Prognostic Scoring System (IPSS), were recruited into the study and were administered 1 gel capsule daily containing 20 mg ginger extract standardized for 20% 6-shogaol. Blood and urine samples were collected and various markers monitored at regular intervals. RESULTS: 6-shogaol caused a decrease in SF levels in 3 of 6 patients with early MDS (50%) whose SF levels were elevated at the start of the study. Our findings suggest upregulation of hepcidin and its prohormones, possibly through an improvement in liver function. DISCUSSION: In light of the encouraging results in this small, investigative study, we are planning a larger study to confirm the beneficial effect of 6-shogaol in patients with raised ferritin levels due to ineffective erythropoiesis.

Effects of water extract of Curcuma longa (L.) roots on immunity and telomerase function.

Background Immunity and Longevity Methods A water extract of Curcuma longa (L.) [vern. Turmeric] roots (TurmericImmune™) standardized for a minimum 20 % of turmeric polysaccharides ukonan A, B, C and D was evaluated for its biological properties in in vitro tissue culture studies. Results The water extract of turmeric (TurP) exhibited induced-nitric oxide (NO) production in RAW264.7 macrophages. These results suggested the immunomodulatory effects of TurP. In addition, the polysaccharides up-regulated function of telomerase reverse transcriptase (TERT) equally to the phenolic compound from turmeric, curcumin. Conclusions The ukonan family of polysaccharides may assist in promoting cellular immune responses, tissue repair and lifespan by enhancing immune response and telomere function.

Roles of Vitamins D and K, Nutrition, and Lifestyle in Low-Energy Bone Fractures in Children and Young Adults.

The research on skeletal system health in children and young adults, while recognizing the important role of calcium and vitamin D, goes beyond these nutritional standards. This review focuses on the role of vitamin K in combination with vitamin D and other factors in bone health. The current understanding is that maintaining bone health and prevention of low-energy fractures in any pediatric population includes nutritional factors combined with an active lifestyle. Calcium, vitamin D, and vitamin K supplementation contribute independently and collectively to bone health. The beneficial role of vitamin K, particularly vitamin K2 as menaquinone-7 (MK-7), in bone and cardiovascular health is reasonably well supported scientifically, with several preclinical, epidemiological, and clinical studies published over the last decade. Osteocalcin and matrix-Gla (glutamate-containing) protein (MGP) exemplify vitamin K-dependent proteins involved in building bone matrix and keeping calcium from accumulating in the arterial walls, respectively. An important part of the mechanism of vitamin K involves carboxylation and posttranslational activation of the family of vitamin K-dependent proteins, which prevent expression of pro-inflammatory factors and support improvement in bone mineral concentration, bone mineral density, and the quality of bone matrix. Understanding the combined approach to a healthy skeletal system in children and young adults, including the roles of vitamins D and K, calcium, healthy diet, and exercise, is particularly important in view of reports of subclinical insufficiency of vitamins D and K in otherwise healthy pediatric populations with low-energy bone fractures.

Combination of citrus polymethoxyflavones, green tea polyphenols, and Lychee extracts suppresses obesity and hepatic steatosis in high-fat diet induced obese mice.

SCOPE: SlimTrym® is a formulated product composed of citrus polymethoxyflavones (PMFs), green tea extract, and lychee extract. We investigated the effect of dietary SlimTrym® on diet-induced obesity and associated non-alcoholic fatty liver disease (NAFLD) in mice. METHODS AND RESULTS: Male C57BL/6 mice were fed a normal diet (ND), high fat diet (HFD) or HFD containing 0.1% or 0.5% SlimTrym® for 16 weeks. Dietary SlimTrym® significantly reduced weight gain and relative perigonadal, retroperitoneal, mesenteric fat weight as well as the size of adipocyte in HFD-fed mice. SlimTrym® supplementation also effectively diminished hepatic steatosis and the serum levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), triacylglycerol (TG), and total cholesterol (TCHO). Down-regulation of peroxisome proliferator-activated receptor (PPAR)γ, sterol regulatory element-binding protein (SREBP)-1, and the activation of AMP-activated protein kinase (AMPK) signaling by SlimTrym® in both adipose tissue and liver may be responsible for the observed anti-obesity effects. CONCLUSION: SlimTrym® supplementation potentially diminished diet-induced obesity and hepatic steatosis via regulating AMPK signaling and molecules involved in lipid metabolism.

Boswellia serrata resin extract alleviates azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis.

SCOPE: Boswellia serrata (BS) resin is a popular dietary supplement for joint nourishment. In this study, we investigated the chemopreventive effects of dietary BS extract and its impact of gut microbiota on azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated colon cancer in mice. METHODS AND RESULTS: Male ICR mice were injected with AOM and 2% DSS via drinking water. The mice were fed with 0.25 or 0.5% BS extract, and colonic tissue were collected at 15 weeks. The main effective components of BS supercritical CO2 extraction were analyzed by LC-MS/MS are boswellic acids. We found that treatment with BS extract significantly reduce the colonic tumor formation. Western blot and histological analysis revealed that dietary BS extract could markedly reduce the inflammation associated protein levels expression. Furthermore, BS extract reduced cell proliferation via inhibiting phosphorylation level of protein kinase B (Akt), glycogen synthase kinase 3ß (GSK3ß), and downregulation of cyclin D1. In addition, BS extract also altered the composition of gut microbiota by enhancing the proportion of Clostridiales and reducing the percentage of Bacteroidales. CONCLUSION: In summary, BS extract decreased the protein levels of inflammative enzymes such as inducible nitric oxide synthase and cyclooxygenase-2 in colonic mucosa. It also mediated Akt/GSK3ß/cyclin D1 signaling pathway and altered the composition of gut microbiota to alleviate tumor growth. Taken together, this study suggests that BS extract has great potential to suppress colon tumorigenesis.

Association between Vitamin D Receptor Polymorphism and Serum Vitamin D Levels in Children with Low-Energy Fractures.

OBJECTIVE: Fractures of bones, especially forearm fractures, are very common in children and their number is increasing. This study was designed to determine the impact of vitamin D serum levels and vitamin D receptor (VDR) polymorphisms on the occurrence of low-energy fractures in children. METHODS: The study group consisted of 100 children with clinically relevant bone fractures and a control group consisted of 127 children without fractures. Total vitamin D [25(OH)D3 plus 25(OH)D2] serum concentrations were evaluated in every patient. Genotypes for 4 restriction fragment length polymorphisms of the vitamin D receptor gene (FokI, ApaI, TaqI, and BsmI) were determined by standard polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques. RESULTS: Differences in concentrations of vitamin D were observed between the group with bone fractures (median = 12 ng/ml) and the control group (median = 16 ng/ml; p = 0.000044). Higher levels of vitamin D reduced the risk of fracture by 1.06 times (p = 0.0005). No impact of particular VDR polymorphism on the occurrence of low-energy fractures in children was detected. However, there were significant differences in the prevalence of FokI polymorphism genotypes between the fracture and control groups (p = 0.05). Furthermore, the recessive "aa" genotype of ApaI polymorphism and the dominant "TT" genotype of TaqI polymorphism were associated with higher levels of vitamin D (p = 0.005 and p = 0.036, respectively). CONCLUSIONS: Vitamin D deficiency is an independent risk factor for fractures in children. ApaI polymorphism recessive "aa" and TaqI polymorphism dominant "TT" genotypes are associated with higher levels of vitamin D in serum.

Inhibition of TNF-α, IL-1α, and IL-1ß by Pretreatment of Human Monocyte-Derived Macrophages with Menaquinone-7 and Cell Activation with TLR Agonists In Vitro.

Circulatory markers of low-grade inflammation such as tumor necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-1α), and interleukin-1 beta (IL-1ß) positively correlate with endothelial damage, atheroma formation, cardiovascular disease, and aging. The natural vitamin K2-menaquinone-7 (MK-7) added to the cell culture of human monocyte-derived macrophages (hMDMs) at the same time as toll-like receptor (TLR) agonists did not influence the production of TNF-α. When the cells were pretreated up to 6 h with MK-7 before treatment with TLR agonists, MK-7 did not inhibit significantly the production of TNF-α after the TLR activation. However, 30 h pretreatment of hMDMs with at least 10 µM of MK-7 effectively and dose dependently inhibited the proinflammatory function of hMDMs. Pretreatment of hMDMs with 10 µM of MK-7 for 30 h resulted in 20% inhibition of TNF-α production after lipopolysaccharide (LPS) activation (P < .05) and 43% inhibition after macrophage-activating lipopeptide (MALP) activation (P < .001). Pathogen-associated molecular pattern (PMPP) activation was inhibited by 20% with MK-7 pretreatment; however, this inhibition was not statistically significant. The 30 h pretreatment of a THP-1-differentiated monocyte cell line with MK-7 resulted in a dose-dependent downregulation of TNFα, IL-1α, and IL-1ß gene expression as evaluated by RNA semiquantitative reverse transcription polymerase chain reaction (RT-PCR). MK-7 is able to modulate immune and inflammatory reactions in the dose-response inhibition of TNF-α, IL-1α, and IL-1ß gene expression and protein production by the healthy hMDMs in vitro.

A Review of Natural Stimulant and Non-stimulant Thermogenic Agents.

Obesity and overweight are major health issues. Exercise and calorie intake control are recognized as the primary mechanisms for addressing excess body weight. Naturally occurring thermogenic plant constituents offer adjunct means for assisting in weight management. The controlling mechanisms for thermogenesis offer many intervention points. Thermogenic agents can act through stimulation of the central nervous system with associated adverse cardiovascular effects and through metabolic mechanisms that are non-stimulatory or a combination thereof. Examples of stimulatory thermogenic agents that will be discussed include ephedrine and caffeine. Examples of non-stimulatory thermogenic agents include p-synephrine (bitter orange extract), capsaicin, forskolin (Coleus root extract), and chlorogenic acid (green coffee bean extract). Green tea is an example of a thermogenic with the potential to produce mild but clinically insignificant undesirable stimulatory effects. The use of the aforementioned thermogenic agents in combination with other extracts such as those derived from Salacia reticulata, Sesamum indicum, Lagerstroemia speciosa, Cissus quadrangularis, and Moringa olifera, as well as the use of the carotenoids as lutein and fucoxanthin, and flavonoids as naringin and hesperidin can further facilitate energy metabolism and weight management as well as sports performance without adverse side effects. © 2016 The Authors Phytotherapy Research published by John Wiley & Sons Ltd.

Se-Allylselenocysteine induces autophagy by modulating the AMPK/mTOR signaling pathway and epigenetic regulation of PCDH17 in human colorectal adenocarcinoma cells.

SCOPE: Selenium (Se)-conjugated compounds have been established as anti-carcinogenic compounds. The use of chemicals as cancer chemotherapeutic agents to induce programmed cell death (PCD) involves genetic and epigenetic modifications. In this study, we investigated the underlying molecular mechanisms of Se-allylselenocysteine (ASC)-induced PCD and protocadherin 17 (PCDH17) expression in HT-29 cells. METHODS AND RESULTS: Cell viability analysis indicated that the ability of ASC to induce cancer cell death was greater than that of Se-methylselenocysteine in colorectal cancer cells. ASC also decreased global DNA methylation levels via downregulation of DNA methyltransferase 1 expression. The autophagic cell death is the cause in ASC-induced cytotoxicity that was inhibited by pretreatment with autophagy inhibitor. At the molecular level, ASC induced PCDH17 expression through decreased PCDH17 promoter hypermethylation. PCDH17 is also an important role in ASC-induced autophagy by HT-29 transfected with PCDH17 shRNA or expression plasmid. Our western blot analysis showed that ASC significantly induced autophagy via the AMPK/mTOR pathway that was also regulated PCDH17 expression. Additionally, we used the HT-29 tumor xenograft models to confirm the ability of ASC inhibited tumor growth. CONCLUSION: These results reveal that ASC is an effective inducer of autophagy through regulating the AMPK/mTOR and PCDH17 expression via epigenetic modification.

Se-Methyl-L-selenocysteine Induces Apoptosis via Endoplasmic Reticulum Stress and the Death Receptor Pathway in Human Colon Adenocarcinoma COLO 205 Cells.

Selenomethionine (SeMet) and Se-methyl-L-selenocysteine (MSeC) are natural organoselenium compounds found in garlic, onion, and broccoli. In addition, these compounds have lower toxicity and better anticancer activities than inorganic Se. This study investigated the effects of MSeC treatment on the growth of COLO 205 human colorectal adenocarcinoma cells and evaluated the mechanisms related to the MSeC-induced effects. When COLO 205 cells were treated with 200 µM MSeC for 24 h, MSeC caused 80% apoptosis in cells. MSeC increased the expression of Fas and FasL, followed by the cleavage of caspase-3, caspase-8, DNA fragmentation factor (DFF45), and poly(ADP-ribose) polymerase (PARP). MSeC also increased the levels of Bax protein and decreased the levels of Bid and Bcl-2 proteins. However, MSeC did not cause apoptosis through reactive oxygen species (ROS) stress but instead through endoplasmic reticulum (ER) stress. The cleavage of caspase-12 and caspase-9 was shown to increase the growth arrest and protein levels of DNA-damage inducible genes (GADD) 153 and 45. MSeC also downregulated the ERK1/2 and PI3K/AKT protein levels and upregulated the p38 and JNK protein levels in COLO 205 cells. These results showed that the mechanism by which MSeC induced apoptosis in COLO 205 cells involved caspase activation, the extrinsic apoptotic pathway, and the regulation of ER-stress-induced apoptosis.

Safety assessment of menaquinone-7 for use in human nutrition.

Vitamin K occurs widely in foods and has been shown to have a beneficial effect on the cardiovascular system, as well as anticancer, anti-inflammatory, and antiosteoporosis properties. A previous study indicates that long-chain menaquinone-7 may be more bioavailable than vitamin K and short-chain menaquinones. In the present study, acute, subacute toxicity and genotoxicity assays were carried out to evaluate the safety of oral menaquinone-7 in albino Wistar rats. Oral administration of menaquinone-7, at a concentration of 2000 mg/kg, did not cause toxic symptoms in either male or female rats. A subacute toxicity study also proved the safety and tolerance of prolonged treatment (for 90 days) with menaquinone-7 in rats, as evidenced by biochemical, hematological, and urine parameters as well as by histopathological analysis. Genotoxicity and mutagenicity studies were performed by comet, micronucleus, and Ames tests on Salmonella typhimurium strains, which showed cellular safety and nonmutagenicity of menaquinone-7. The results indicate the safety of menaquinone-7 for human consumption.

Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia.

Introduction. Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB). Objective. The primary endpoint was to examine the neurocognitive effects of extract Sceletium tortuosum (Zembrin) and to assess the safety and tolerability of Zembrin in cognitively healthy control subjects. Method. We chose the randomized double-blind placebo-controlled cross-over design in our study. We randomized normal healthy subjects (total n = 21) to receive either 25 mg capsule Zembrin or placebo capsule once daily for 3 weeks, in a randomized placebo-controlled 3-week cross-over design. We administered battery of neuropsychological tests: CNS Vital Signs and Hamilton depression rating scale (HAM-D) at baseline and regular intervals and monitored side effects with treatment emergent adverse events scale. Results. 21 subjects (mean age: 54.6 years ± 6.0 yrs; male/female ratio: 9/12) entered the study. Zembrin at 25 mg daily dosage significantly improved cognitive set flexibility (P < 0.032) and executive function (P < 0.022), compared with the placebo group. Positive changes in mood and sleep were found. Zembrin was well tolerated. Conclusion. The promising cognitive enhancing effects of Zembrin likely implicate the PDE-4-cAMP-CREB cascade, a novel drug target in the potential treatment of early Alzheimer's dementia. This trial is registered with ClinicalTrials.gov NCT01805518.