Alzheimer's Disease-Related Proteins Targeted by Secondary Metabolite Compounds from Streptomyces: A Scoping Review.

Background: Alzheimer's disease (AD) is a neurodegenerative disease that is characterized as rapid and progressive cognitive decline affecting 26 million people worldwide. Although immunotherapies are ideal, its clinical safety and effectiveness are controversial, hence, treatments are still reliant on symptomatic medications. Concurrently, the Streptomyces genus has attracted attention given its pharmaceutically beneficial secondary metabolites to treat neurodegenerative diseases. Objective: To present secondary metabolites from Streptomyces sp. with regulatory effects on proteins and identified prospective target proteins for AD treatment. Methods: Research articles published between 2010 and 2021 were collected from five databases and 83 relevant research articles were identified. Post-screening, only 12 research articles on AD-related proteins were selected for further review. Bioinformatics analyses were performed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network, PANTHER Go-Slim classification system (PANTHER17.0), and Kyoto Encyclopedia of Genes and Genomes (KEGG) Mapper. Results: A total of 20 target proteins were identified from the 12 shortlisted articles. Amyloid-ß, BACE1, Nrf-2, Beclin-1, and ATG5 were identified as the potential target proteins, given their role in initiating AD, mitigating neuroinflammation, and autophagy. Besides, 10 compounds from Streptomyces sp., including rapamycin, alborixin, enterocin, bonnevillamides D and E, caniferolide A, anhydroexfoliamycin, rhizolutin, streptocyclinone A and B, were identified to exhibit considerable regulatory effects on these target proteins. Conclusions: The review highlights several prospective target proteins that can be regulated through treatments with Streptomyces sp. compounds to prevent AD's early stages and progression. Further identification of Streptomyces sp. compounds with potential anti-AD properties is recommended.

Protease-targeting peptide-functionalized porous silicon nanoparticles for cancer fluorescence imaging.

Background: Porous silicon (pSi) nanoparticles (NPs) functionalized with suitable targeting ligands are now established cancer bioimaging agents and drug-delivery platforms. With growing interest in peptides as tumor-targeting ligands, much work has focused on the use of various peptides in combination with pSi NPs for cancer theranostics. Here, the authors investigated the targeting potential of pSi NPs functionalized with two types of peptide, a linear 10-mer peptide and its branched (Y-shaped) equivalent, that respond to legumain activity in tumor cells. Results: In vitro experiments established that the linear peptide-pSi NP conjugate had better aqueous stability under tumor conditions and higher binding efficiency (p < 0.001) toward legumain-expressing cells such as RAW 264.7 cells compared with that of its branched equivalent. In vivo studies (analyzed using ex vivo fluorescence) with the linear peptide-pSi NP formulation using a syngeneic mouse model of breast cancer showed a higher accumulation (p > 0.05) of linear peptide-conjugated pSi NPs in the tumor site within 4 h compared with nonconjugated pSi NPs. These results suggest that the linear peptide-pSi NP formulation is a nontoxic, stable and efficient fluorescence bioimaging agent and potential drug-delivery platform.

Clinical characteristics, cytokine profiles and plasma IgE in adults with asthma.

Asthma is a disease with complicated network of inflammatory responses of cytokines and ImmunoglobulinE (IgE). The aim of this study was to explore the clinical characteristics, cytokine profile and plasma IgE in the Malaysian population. This is a cross-sectional study involving physician-diagnosed asthma patients (n = 287) recruited from the Chest Clinic, University of Malaya Medical Centre (UMMC). Blood (8 mL) was taken after consent was obtained. The peripheral blood leucocytes (PBL) were cultured in presence of a mitogen for 72 h to quantify cytokines [Interleukin-5(IL-5), Interleukin-9 (IL-9), Interleukin-12 Beta (IL-12ꞵ) and granulocyte-macrophage colony-stimulating factor (GM-CSF)] and plasma was used to quantify IgE levels with commercial ELISA kits. Results were compared against the same biomarkers in healthy subjects (n = 203). In addition, the amount of the biomarkers in the asthma patients were compared with their disease severity and clinical characteristics. Statistical tests in the SPSS software (Mann-Whitney U test and the Kruskal Wallis) were used to compare cytokine production and plasma IgE levels. The mean plasma IgE level was markedly higher (p < 0.0001) in asthmatics compared to controls. There were higher levels of IL-5, IL-9, IL-12ꞵ and GM-CSF (p < 0.0001) produced by cultured PBL from asthma patients compared to controls. However, our results did not expose a significant association between these cytokine levels and severity and clinical symptoms of asthma. However, there was a marked association between asthma severity and blood lymphocyte count [ꭓ2(2) = 6.745, p < 0.05]. These findings support the roles played by cytokines and IgE in the airway inflammation in asthma. The findings of this study provide new information about inflammatory cytokines in Malaysian asthma patients.

Transitioning pre-clinical glioblastoma models to clinical settings with biomarkers identified in 3D cell-based models: A systematic scoping review.

Glioblastoma (GBM) remains incurable despite the overwhelming discovery of 2-dimensional (2D) cell-based potential therapeutics since the majority of them have met unsatisfactory results in animal and clinical settings. Incremental empirical evidence has laid the widespread need of transitioning 2D to 3-dimensional (3D) cultures that better mimic GBM's complex and heterogenic nature to allow better translation of pre-clinical results. This systematic scoping review analyses the transcriptomic data involving 3D models of GBM against 2D models from 22 studies identified from four databases (PubMed, ScienceDirect, Medline, and Embase). From a total of 499 genes reported in these studies, 313 (63%) genes were upregulated across 3D models cultured using different scaffolds. Our analysis showed that 4 of the replicable upregulated genes are associated with GBM stemness, epithelial to mesenchymal transition (EMT), hypoxia, and migration-related genes regardless of the type of scaffolds, displaying close resemblances to primitive undifferentiated tumour phenotypes that are associated with decreased overall survival and increased hazard ratio in GBM patients. The upregulation of drug response and drug efflux genes (e.g. cytochrome P450s and ABC transporters) mirrors the GBM genetic landscape that contributes to in vivo and clinical treatment resistance. These upregulated genes displayed strong protein-protein interactions when analysed using an online bioinformatics software (STRING). These findings reinforce the need for widespread transition to 3D GBM models as a relatively inexpensive humanised pre-clinical tool with suitable genetic biomarkers to bridge clinical gaps in potential therapeutic evaluations.

Development, Characterization, and Evaluation of α-Mangostin-Loaded Polymeric Nanoparticle Gel for Topical Therapy in Skin Cancer.

The aim of this study was to prepare and evaluate α-mangostin-loaded polymeric nanoparticle gel (α-MNG-PLGA) formulation to enhance α-mangostin delivery in an epidermal carcinoma. The poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed using the emulsion-diffusion-evaporation technique with a 3-level 3-factor Box-Behnken design. The NPs were characterized and evaluated for particle size distribution, zeta potential (mV), drug release, and skin permeation. The formulated PLGA NPs were converted into a preformed carbopol gel base and were further evaluated for texture analysis, the cytotoxic effect of PLGA NPs against B16-F10 melanoma cells, and in vitro radical scavenging activity. The nanoscale particles were spherical, consistent, and average in size (168.06 ± 17.02 nm), with an entrapment efficiency (EE) of 84.26 ± 8.23% and a zeta potential of -25.3 ± 7.1 mV. Their drug release percentages in phosphate-buffered solution (PBS) at pH 7.4 and pH 6.5 were 87.07 ± 6.95% and 89.50 ± 9.50%, respectively. The release of α-MNG from NPs in vitro demonstrated that the biphasic release system, namely, immediate release in the initial phase, was accompanied by sustained drug release. The texture study of the developed α-MNG-PLGA NPs gel revealed its characteristics, including viscosity, hardness, consistency, and cohesiveness. The drug flux from α-MNG-PLGA NPs gel and α-MNG gel was 79.32 ± 7.91 and 16.88 ± 7.18 µg/cm2/h in 24 h, respectively. The confocal study showed that α-MNG-PLGA NPs penetrated up to 230.02 µm deep into the skin layer compared to 15.21 µm by dye solution. MTT assay and radical scavenging potential indicated that α-MNG-PLGA NPs gel had a significant cytotoxic effect and antioxidant effect compared to α-MNG gel (p < 0.05). Thus, using the developed α-MNG-PLGA in treating skin cancer could be a promising approach.

Effects of Probiotics on Anxiety, Stress, Mood and Fitness of Badminton Players.

BACKGROUND: Reports of probiotic consumption on athletes' performance are debatable due to their equivocal results. There is a need for more evidence on the effects of probiotic intake on psychological state and fitness level. Thus, this study determined the effects of daily probiotic consumption on competitive anxiety, perceived stress and mood among university badminton players, besides their fitness like aerobic capacity, strength, speed, leg power and agility. METHODS: Thirty university badminton players aged from 19 to 22 years old were randomly divided equally into two groups, where the probiotic group (PG; n = 15) received a drink that contained Lactobacillus casei Shirota (3 × 1010 CFU) and placebo group (CG; n = 15) a placebo drink for six weeks. Anxiety, stress and mood levels were determined using the CSAI-2R, PSS and BRUMS questionnaires, respectively. Fitness levels were measured using by subjecting the players to 20-m shuttle runs (aerobic capacity), handgrips (muscular strength), vertical jumps (leg power), 40-m dash (speed) and T-test (agility). The Student's t-test (p < 0.05) was used to determine the differences between PG and CG players. RESULTS: After six weeks, the anxiety and stress levels of PG players significantly decreased by 16% (p < 0.001) and 20% (p < 0.001), respectively, but there were no significant changes detected in CG players. Supplementation of probiotics also improved aerobic capacity in PG players by 5.9% (p < 0.001) but did not influence the speed, strength, leg power and agility. CONCLUSIONS: Probiotics supplementation showed improved aerobic capacity and relieve anxiety and stress. However, further studies need to be carried out to determine the mechanisms through which probiotic intake produces these effects.

Gamma-tocotrienol modifies methylation of HOXA10, IRF4 and RORα genes in CD4+ T-lymphocytes: Evidence from a syngeneic mouse model of breast cancer.

DNA methylation plays a crucial role in polarising naïve lymphocytes towards their various sub-populations to fight against many immune challenges including establishment of tumour. Gamma-tocotrienol (γT3) is a natural form of vitamin E, reported to possess anticancer and immunomodulatory effects. This study reports the anticancer effects of γT3 through modulation of DNA methylation in several genes in CD4+ T-lymphocytes using a syngeneic mouse model of breast cancer. Female BALB/c mice were fed with γT3 or vehicle (soy oil) for two-weeks via oral gavage before they were inoculated with 4T1 mouse mammary cancer cells. Supplementation continued until the mice were sacrificed. At autopsy, blood was collected via cardiac puncture and CD4+ T-cells were isolated for DNA extraction. The DNA was analysed using the EpiTech Methyl II mouse T-helper cell differentiation PCR array. γT3 supplementation reduced tumour growth in the tumour-induced animals and modulated host immune system by inducing changes in DNA methylation patterns of the HOXA10, IRF4 and RORα genes, which are involved in differentiation and clonal expansion of CD4+ T-cells. Results suggest that γT3 may enhance cell-mediated immune response in mice with breast cancer by inducing changes in DNA methylation pattern.

Ratite oils for local transdermal therapy of 4-OH tamoxifen: development, characterization, and ex vivo evaluation.

The anti-inflammatory property of ratite oils as well as its ability to act as a penetration enhancer makes it an ideal agent to be used in transdermal formulations. The present study aims to develop an effective transfersomal delivery of 4-hydroxytamoxifen (4-OHT), an anti-cancer drug, using ratite oil as a carrier agent for the treatment of breast cancer (BC). The 4-OHT transfersomes were prepared with and without ratite oils using soy phosphatidylcholine and three different edge activators (EAs) in five different molar ratios using the rotary evaporation-ultrasonication method. Optimal transfersome formulations were selected using physical-chemical characterization and ex vivo studies. Results from physical-chemical characterization of the developed formulations found sodium taurocholate to be the most suitable EA, which recorded highest entrapment efficiency of 95.1 ± 2.70% with 85:15, (w/w) and lowest vesicle size of 82.3 ± 0.02 nm with 75:25, (w/w) molar ratios. TEM and DSC studies showed that the vesicles were readily identified and present in a nearly perfect spherical shape. In addition, formulations with emu oil had better stability than formulations with ostrich oil. Physical stability studies at 4 °C showed that ratite oil transfersomes were stable up to 4 weeks, while transfersomes without ratite oils were stable for 8 weeks. Ex vivo permeability studies using porcine skin concluded that 4-OHT transfersomal formulations with (85:15, w/w) without emu oil have the potential to be used in transdermal delivery approach to enhance permeation of 4-OHT, which may be beneficial in the treatment of BC.

Nose to brain delivery of rotigotine loaded chitosan nanoparticles in human SH-SY5Y neuroblastoma cells and animal model of Parkinson's disease.

Rotigotine, a non-ergoline dopamine agonist, has been shown to be highly effective for the treatment of Parkinson's disease (PD). However, despite its therapeutic potential, its' clinical applications were hindered due to low aqueous solubility, first-pass metabolism and low bioavailability. Therefore, we developed rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery and evaluated its neuronal uptake, antioxidant and neuroprotective effects using cell-based studies. The pharmacological effects of nose-to-brain delivery of the RNPs were also evaluated in an animal model of PD. The average particle size, particle size distribution and entrapment efficiency of the RNPs were found to be satisfactory. Exposure of RNPs for 24 h did not show any cytotoxicity towards SH-SY5Y human neuroblastoma cells. Furthermore, the RNPs caused a decrease in alpha-synuclein (SNCA) and an increase in tyrosine hydroxylase (TH) expression in these cells, suggestion that the exposure alleviated some of the direct neurotoxic effects of 6-OHDA. Behavioral and biochemical testing of RNPs in haloperidol-induced PD rats showed a reversal of catalepsy, akinesia and restoration of swimming ability. A decrease in lactate dehydrogenase (LDH) and an increase in catalase activities were also observed in the brain tissues. The results from the animal model of PD show that intranasally-administered RNPs enhanced brain targeting efficiency and drug bioavailability. Thus, RNPs for nose-to-brain delivery has significant potential to be developed as a treatment approach for PD.

Relationship between various cytokines implicated in asthma.

Asthma is a complex disorder involving immunologic, environmental, genetic and other factors. Today, asthma is the most common disease encountered in clinical medicine in both children and adults worldwide. Asthma is characterized by increased responsiveness of the tracheobronchial tree resulting in chronic swelling and inflammation of the airways recognized to be controlled by the T-helper 2 (Th2) lymphocytes, which secrete cytokines to increase the production of IgE by B cells. There are many cytokines implicated in the development of the chronic inflammatory processes that are often observed in asthma. Ultimately, these cytokines cause the release of mediators such as histamine and leukotrienes (LT), which in turn promote airway remodeling, bronchial hyperresponsiveness and bronchoconstriction. The CD4+ T-lymphocytes from the airways of asthmatics express a panel of cytokines that represent the Th2 cells. The knowledge derived from numerous experimental and clinical studies have allowed physicians and scientists to understand the normal functions of these cytokines and their roles in the pathogenesis of asthma. The main focus of this review is to accentuate the relationship between various cytokines implicated in human asthma. However, some key findings from animal models will be highlighted to support the discoveries from clinical studies.

Fabrication, Optimization, and Evaluation of Rotigotine-Loaded Chitosan Nanoparticles for Nose-To-Brain Delivery.

The objective of the present study was to develop, optimize, and evaluate rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery. Rotigotine-loaded chitosan nanoparticles were prepared by the ionic gelation method and optimized for various parameters such as the effect of chitosan, sodium tripolyphosphate, rotigotine concentration on particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency. The prepared nanoparticles were characterized using photon correlation spectroscopy, transmission electron microscopy, scanning electron microscopy, atomic force microscopy, fourier-transform infrared spectroscopy, and X-ray diffraction. The developed RNPs showed a small hydrodynamic particle size (75.37 ± 3.37 nm), small PDI (0.368 ± 0.02), satisfactory zeta potential (25.53 ± 0.45 mV), and very high entrapment efficiency (96.08 ± 0.01). The 24-h in vitro release and ex vivo nasal permeation of rotigotine from the nanoparticles were 49.45 ± 2.09% and 92.15 ± 4.74% while rotigotine solution showed corresponding values of 95.96 ± 1.79%and 58.22 ± 1.75%, respectively. The overall improvement ratio for flux and permeability coefficient were found to be 4.88 and 2.67 when compared with rotigotine solution. A histopathological study showed that the nanoparticulate formulation produced no toxicity or structural damage to nasal mucosa. Our results indicated that rotigotine-loaded chitosan nanoparticles provide an efficient carrier for nose-to-brain delivery.

Red palm olein supplementation on cytokines, endothelial function and lipid profile in centrally overweight individuals: a randomised controlled trial.

BACKGROUND/OBJECTIVES: The consumption of antioxidant-rich cooking oil such as red palm olein may be cardioprotective from the perspective of subclinical inflammation and endothelial function. SUBJECTS/METHODS: Using a crossover design, we conducted a randomised controlled trial in 53 free-living high-risk abdominally overweight subjects, comparing the effects of incorporating red palm olein (with palm olein as control) in a supervised isocaloric 2100 kcal diet of 30% en fat, two-thirds (45 g/day) of which were derived from the test oil for a period of 6 weeks each. RESULTS: We did not observe a significant change in interleukin-6 (IL-6), in parallel with other pro-inflammatory (tumour necrosis factor-ß, interleukin-1ß, IL-1ß, high sensitivity C-reactive protein, hsCRP) and endothelial function (soluble intercellular adhesion molecules, sICAM, soluble intravascular adhesion molecules, sVCAM) parameters. Interestingly, we observed a significant reduction in oxidised LDL levels (P < 0.0386) while on the red palm olein diet, together with the increase in plasma alpha tocopherol (P < 0.0002), alpha carotene (P < 0.0001) and beta carotene (P < 0.0001) concentrations compared with palm olein diet. CONCLUSION: Red palm olein did not improve subclinical inflammation and endothelial function despite profound increase in antioxidant levels. The positive improvement in oxidised LDL merits further attention in this group of subjects at risk of developing cardiovascular disease.

Effects of 25-hydroxyvitamin D and vitamin D-binding protein on bone mineral density and disease activity in Malaysian patients with rheumatoid arthritis.

AIM: Vitamin D3 [25(OH)D] has been shown to be important in bone health and can influence rheumatoid arthritis (RA) disease activity. Vitamin D-binding protein (VDBP) levels vary with race and may modulate 'bioavailable' levels of 25(OH)D. The aim of this study was to explore the relationships between 25(OH)D, VDBP and clinical factors on bone mineral density (BMD) in a group of multi-ethnic Malaysian RA patients and healthy controls. METHODS: A cross-sectional study of 77 female RA patients and 29 controls was performed. Serum 25(OH)D was measured using the Elecsys® Vitamin D total assay. Serum VDBP was measured using a Quantikine® enzyme-linked immunosorbent assay kit. BMD was assessed using dual-energy X-ray absorptiometry (DXA). RESULTS: Overall, mean 25(OH)D levels were 42.66 ± 21.75 nmol/L with no significant difference between RA patients and controls. 25(OH)D levels were significantly higher in Chinese, compared to Malay/Indian subjects. In RA patients, menopausal status and body mass index (BMI) were significantly associated with BMD but not 25(OH)D or RA Disease Activity Score of 28 joints (DAS28). There was no significant correlation between 25(OH)D and DAS28, even after correction for menopausal status and BMI. VDBP levels were not significantly different between the races and did not significantly correlate with BMD, 25(OH)D overall, or DAS28 in RA patients. CONCLUSIONS: In Malaysian RA patients, menopausal status and BMI were more important influences on BMD than 25(OH)D or RA disease activity. The utility of measuring VDBP levels in this population remains uncertain.

Lipid based nanocarriers system for topical delivery of photosensitizers.

Topical photodynamic therapy (PDT) is a non-invasive technique used in the treatment of malignant and non-malignant skin diseases. It offers great promise because of its simplicity, enhanced patient compliance, localisation of the photosensitizer, as well as the use of light and oxygen to achieve photocytotoxicity. Despite progress in photosensitizer-mediated topical PDT, its clinical application is limited by poor penetration of photosensitizers through the skin. Therefore, much effort has been made to develop nanocarriers that can tackle the challenges of conventional photosensitizer-mediated PDT for topical delivery. This review discusses recent data on the use of different types of lipid-based nanocarriers in delivering photosensitizer for topical PDT.

Health-promoting effects of red palm oil: evidence from animal and human studies.

The fruit of the oil palm tree (Elaeis guineesis) is the source of antioxidant-rich red palm oil. Red palm oil is a rich source of phytonutrients such as tocotrienols, tocopherols, carotenoids, phytosterols, squalene, and coenzyme Q10, all of which exhibit nutritional properties and oxidative stability. Mutagenic, nutritional, and toxicological studies have shown that red palm oil contains highly bioavailable ß-carotene and vitamin A and is reasonably stable to heat without any adverse effects. This review provides a comprehensive overview of the nutritional properties of red palm oil. The possible antiatherogenic, antihemorrhagic, antihypertensive, anticancer, and anti-infective properties of red palm oil are examined. Moreover, evidence supporting the potential effectiveness of red palm oil to overcome vitamin A deficiency in children and pregnant women, to improve ocular complications of vitamin A deficiency, to protect against ischemic heart disease, to promote normal reproduction in males and females, to aid in the management of diabetes, to ameliorate the adverse effects of chemotherapy, and to aid in managing hypobaric conditions is presented.

Anti-inflammatory effects of Polygonum minus (Huds) extract (Lineminus™) in in-vitro enzyme assays and carrageenan induced paw edema.

BACKGROUND: The study was aimed to evaluate the anti-inflammatory activity of ethanolic and aqueous extracts of Polygonum minus (Huds) using in vitro and in vivo approaches. METHODS: The in vitro tests used to evaluate ethanolic extract are cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), lipooxygenase (5-LOX), secretory phospholipase-A2 (sPLA2) inhibition assay whilst the in-vivo effect was measured by the ability of aqueous extracts to reduce paw edema induced by λ-carrageenan, in rats. RESULTS: The ethanolic extract inhibited the activities of 5-LOX and COX-1(p < 0.05) whilst the inhibitory effect on COX-2 was only moderate. A marked inhibition of 5-LOX was observed at 30 µg/ ml. The extract did not inhibit the activity of sPLA2. The ability of the ethanolic extracts of Polygonum minus to inhibit both 5-LOX and COX, prompted a study to evaluate the effects of using an aqueous extract of Polygonum minus(LineminusTM); as this would be more suitable for future clinical testing. The anti-inhibitory activity of the aqueous extract from this plant was evaluated using a rat model where inflammation was induced in the paws by injection of λ-carrageenan. The aqueous extracts from Polygonum minus administered at doses of 100 and 300 mg/kg body weight (b.w.), significantly (p < 0.01) reduced paw edema induced by λ-carrageenan in the experimental model, at 4 h compared to the vehicle control. Furthermore, administration of 100 mg/kg b.w. or 300 mg/kg b.w. completely reduced inflammation of the paw 4 h after injection. CONCLUSION: These findings suggest that aqueous extract of Polygonum minus possesses potent anti-inflammatory activities.

Ethnic differences in the prognostic utility of rheumatoid factor isotypes and anticyclic citrullinated peptides in rheumatoid arthritis patients: a cross-sectional study.

OBJECTIVES: The prognostic significance of rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) in rheumatoid arthritis (RA) remains contentious due to the conflicting lines of evidence. This study aims to determine the association between RF isotypes and anti-CCP with disease severity in RA patients from three ethnic groups. METHODS: A total of 147 RA patients from three different ethnic groups (Malays, Chinese, and Indians) who fulfilled the 1987 American College of Rheumatology (ACR) revised criteria for RA were recruited into this study. The seroprevalence of RF isotypes immunoglobulin (Ig)A, IgG, and IgM, as well as anti-CCP was determined using commercial enzyme-linked immunosorbent assay (ELISA) kits. Multinomial regression analysis was performed to assess the independent effects of autoantibody status on the development of deforming and erosive RA and the presence of extra-articular manifestations (EAM). RESULTS: In Chinese patients, we found a significant association (p < 0.05) between IgG RF and anti-CCP and the presence of erosive disease, as well as IgM RF and IgG RF with the presence of joint deformities. In Indian patients, IgM RF was associated with deforming disease, whereas none of the antibodies were associated with disease severity in Malay patients. Multinomial regression analysis revealed that IgG RF was the most important predictor variable for erosive disease in Chinese patients, and IgM RF the only predictor variable associated with deforming disease in both Chinese and Indian RA patients. CONCLUSIONS: There is variability in the phenotypic association of RF isotypes and anti-CCP in relation to disease severity of RA in the three ethnic groups. RF, in particular, IgG and IgM, may be better prognosticators of severe disease in Chinese and Indian patients.

Tocotrienol research: past into present.

The vitamin E family consists of eight isomers known as alpha-, beta-, gamma-, and delta-tocopherols and alpha-, beta-, gamma-, and delta-tocotrienols. Numerous studies focused on the health benefits of these isomers have been performed since the discovery of vitamin E in 1922. Recent discoveries on the potential therapeutic applications of tocotrienols have revolutionized vitamin E research. Nevertheless, despite the abundance of literature, only 1% of vitamin E research has been conducted on tocotrienols. Many new advances suggest that the use of tocotrienols for health improvement or therapeutic purposes is promising. Although the mechanisms of action of tocotrienols in certain disease conditions have been explored, more detailed investigations into the fundamentals of the health-promoting effects of these molecules must be elucidated before they can be recommended for health improvement or for the treatment or prevention of disease. Furthermore, many of the studies on the effects of tocotrienols have been carried out using cell lines and animal models. The effects in humans must be well established before tocotrienols are used as therapeutic agents in various disease conditions, hence the need for more evidence-based human clinical trials.

δ- and γ-tocotrienols induce classical ultrastructural apoptotic changes in human T lymphoblastic leukemic cells.

Tocotrienols are isomers of the vitamin E family, which have been reported to exert cytotoxic effects in various cancer cells. Although there have been some reports on the effects of tocotrienols in leukemic cells, ultrastructural evidence of tocotrienol-induced apoptotic cell death in leukemic cells is lacking. The present study investigated the effects of three isomers of tocotrienols (alpha, delta, and gamma) on a human T lymphoblastic leukemic cell line (CEM-SS). Cell viability assays showed that all three isomers had cytotoxic effects (p < 0.05) on CEM-SS cells with delta-tocotrienol being the most potent. Transmission electron microscopy showed that the cytotoxic effects by delta- and gamma-tocotrienols were through the induction of an apoptotic pathway as demonstrated by the classical ultrastructural apoptotic changes characterized by peripheral nuclear chromatin condensation and nuclear fragmentation. These findings were confirmed biochemically by the demonstration of phosphatidylserine externalization via flow cytometry analysis. This is the first study showing classical ultrastructural apoptotic changes induced by delta- and gamma-tocotrienols in human T lymphoblastic leukemic cells.

Palm tocotrienols decrease levels of pro-angiogenic markers in human umbilical vein endothelial cells (HUVEC) and murine mammary cancer cells.

Anti-angiogenic therapy is widely being used to halt tumour angiogenesis. In this study, the anti-angiogenic activity of palm tocotrienol-rich fraction (TRF) and its individual components (γ- and δ-tocotrienol) were first investigated in vitro in human umbilical vein endothelial cells (HUVEC) and 4T1 mouse mammary cancer cells. Results showed reduced levels of Interkeukin (IL)-8 and IL-6, two pro-angiogenic cytokines in HUVEC treated with palm tocotrienols compared with α-tocopherol (α-T) and control cells (P < 0.05). The production of IL-8 and IL-6 was lowest in δ-tocotrienol (δ-T3)-treated cells followed by γ-tocotrienol (γ-T3) and TRF. There was significant (P < 0.05) reduction in IL-8 and vascular endothelial growth factor (VEGF) production in 4T1 cells treated with TRF or δ-T3. There was decreased expression of VEGF and its receptors; VEGF-R1 (fms-like tyrosine kinase, Flt-1) and VEGF-R2 (Kinase-insert-domain-containing receptor, KDR/Flk-2) in tumour tissues excised from mice supplemented with TRF were observed. There was also decreased expression of VEGF-R2 in lung tissues of mice supplemented with TRF. These observations correlate with the smaller tumour size recorded in the tocotrienol-treated mice. This study confirms previous observations that palm tocotrienols exhibit anti-angiogenic properties that may inhibit tumour progression.