Effect of Calorie Restriction and Intermittent Fasting Regimens on Brain-Derived Neurotrophic Factor Levels and Cognitive Function in Humans: A Systematic Review.

Background: The potential positive interaction between intermittent fasting (IF) and brain-derived neurotrophic factor (BDNF) on cognitive function has been widely discussed. This systematic review tried to assess the efficacy of interventions with different IF regimens on BDNF levels and their association with cognitive functions in humans. Interventions with different forms of IF such as caloric restriction (CR), alternate-day fasting (ADF), time-restricted eating (TRE), and the Ramadan model of intermittent fasting (RIF) were targeted. Methods: A systematic review was conducted for experimental and observational studies on healthy people and patients with diseases published in EMBASE, Scopus, PubMed, and Google Scholar databases from January 2000 to December 2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statements (PRISMA) for writing this review. Results: Sixteen research works conducted on healthy people and patients with metabolic disorders met the inclusion criteria for this systematic review. Five studies showed a significant increase in BDNF after the intervention, while five studies reported a significant decrease in BDNF levels, and the other six studies showed no significant changes in BDNF levels due to IF regimens. Moreover, five studies examined the RIF protocol, of which, three studies showed a significant reduction, while two showed a significant increase in BDNF levels, along with an improvement in cognitive function after RIF. Conclusions: The current findings suggest that IF has varying effects on BDNF levels and cognitive functions in healthy, overweight/obese individuals and patients with metabolic conditions. However, few human studies have shown that IF increases BDNF levels, with controversial results. In humans, IF has yet to be fully investigated in terms of its long-term effect on BDNF and cognitive functions. Large-scale, well-controlled studies with high-quality data are warranted to elucidate the impact of the IF regimens on BDNF levels and cognitive functions.

Reflection on Ramadan Fasting Research Related to Sustainable Development Goal 3 (Good Health and Well-Being): A Bibliometric Analysis.

There is a large body of research on Ramadan intermittent fasting (RIF) and health in Muslim communities, that can offer insights to promote the achievement of Sustainable Development Goal 3 (SDG 3), which encompasses good health and well-being. Based on recent bibliometric evidence, we hypothesized that RIF research is highly relevant to SDG 3, particularly Targets 3.1, 3.2, 3.4, and 3.5. Therefore, this bibliometric study quantified RIF literature supporting SDG 3 and associated targets over the past seven decades and explored themes and trends. All types of research articles were extracted from the Scopus database from inception to March 2022. Microsoft Excel, Biblioshiny, and VOSviewer were used to qualitatively and quantitatively examine RIF research trends supporting SDG 3 and associated targets. We identified 1729 relevant articles. The number of publications notably increased since 1986, with a dramatic increase in 2019-2020. RIF research predominantly supported Target 3.4 (reducing risk for non-communicable diseases), with research hotspots being diabetes, diabetes medications, pregnancy, physiology, metabolic diseases, and obesity and metabolism. This target was also the most commonly supported by dedicated authors and institutions publishing on RIF, whereas other SDG 3 targets were negligibly addressed in comparison. Our comprehensive bibliometric analysis of RIF literature showed growing support for SDG 3 through positive contributions to half of the SDG 3 targets, although Target 3.4 received the most attention. We also identified knowledge gaps that may shape further research directions on RIF and promote the achievement of SDG 3 in Muslim communities.

Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: effects of in vivo statin treatment.

OBJECTIVE: Statins may have beneficial vascular effects in systemic lupus erythematosus (SLE) beyond their cholesterol-lowering action, although the mechanisms involved are not completely understood. We investigated potential mechanisms involved in the efficacy of fluvastatin in preventing atherothrombosis in SLE. METHODS: Eighty-five patients with SLE and 62 healthy donors were included in the study. Selected patients (n=27) received 20 mg/day fluvastatin for 1 month. Blood samples were obtained before the start and at the end of treatment. Monocytes from five patients were treated in vitro with fluvastatin. RESULTS: Increased prothrombotic and inflammatory variables were found in patients with SLE. SLE monocytes displayed altered mitochondrial membrane potential and increased oxidative stress. Correlation and association analyses demonstrated a complex interplay among autoimmunity, oxidative stress, inflammation and increased risk of atherothrombosis in SLE. Fluvastatin treatment of patients for 1 month reduced the SLE Disease Activity Index and lipid levels, oxidative status and vascular inflammation. Array studies on monocytes demonstrated differential expression in 799 genes after fluvastatin treatment. Novel target genes and pathways modulated by fluvastatin were uncovered, including gene networks involved in cholesterol and lipid metabolism, inflammation, oxidative stress and mitochondrial activity. Electron microscopy analysis showed increased density volume of mitochondria in monocytes from fluvastatin-treated patients, who also displayed higher expression of genes involved in mitochondrial biogenesis. In vitro treatment of SLE monocytes confirmed the results obtained in the in vivo study. CONCLUSIONS: Our overall data suggest that fluvastatin improves the impairment of a redox-sensitive pathway involved in processes that collectively orchestrate the pathophysiology of atherothrombosis in SLE.

The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice.

The Membrane Theory of Aging proposes that lifespan is inversely related to the level of unsaturation in membrane phospholipids. Calorie restriction (CR) without malnutrition extends lifespan in many model organisms, which may be related to alterations in membrane phospholipids fatty acids. During the last few years our research focused on studying how altering the predominant fat source affects the outcome of CR in mice. We have established four dietary groups: one control group fed 95 % of a pre-determined ad libitum intake (in order to prevent obesity), and three CR groups fed 40 % less than ad libitum intake. Lipid source for the control and one of the CR groups was soybean oil (high in n-6 PUFA) whereas the two remaining CR groups were fed diets containing fish oil (high in n-3 PUFA), or lard (high in saturated and monounsaturated fatty acids). Dietary intervention periods ranged from 1 to 18 months. We performed a longitudinal lifespan study and a cross-sectional study set up to evaluate several mitochondrial parameters which included fatty acid composition, H(+) leak, activities of electron transport chain enzymes, ROS generation, lipid peroxidation, mitochondrial ultrastructure, and mitochondrial apoptotic signaling in liver and skeletal muscle. These approaches applied to different cohorts of mice have independently indicated that lard as a fat source often maximizes the effects of 40 % CR on mice. These effects could be due to significant increases of monounsaturated fatty acids levels, in accordance with the Membrane Theory of Aging.

Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q(10) treatment.

The exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q(10) (CoQ(10)). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors. Increased peroxide production, nuclear abundance of Nrf2, antioxidant enzymatic activity, decreased intracellular glutathione, and altered mitochondrial membrane potential were found in monocytes and neutrophils from APS patients. Accelerated atherosclerosis in APS patients was found associated with their inflammatory or oxidative status. CoQ(10) preincubation of healthy monocytes before IgG-antiphospholipid antibody treatment decreased oxidative stress, the percentage of cells with altered mitochondrial membrane potential, and the induced expression of tissue factor, VEGF, and Flt1. In addition, CoQ(10) significantly improved the ultrastructural preservation of mitochondria and prevented IgG-APS-induced fission mediated by Drp-1 and Fis-1 proteins. In conclusion, the oxidative perturbation in APS patient leukocytes, which is directly related to an inflammatory and pro-atherothrombotic status, relies on alterations in mitochondrial dynamics and metabolism that may be prevented, reverted, or both by treatment with CoQ(10).

Knowledge, Awareness, and Practices toward Colorectal Cancer and Its Dietary and Lifestyle-Related Risk Factors among Jordanian University Students: A Cross-Sectional Study.

Background: Globally, colorectal cancer (CRC) incidence is rising, and it is a leading cause of mortality, with greater death rates pronounced in developing countries, including Jordan. Understanding knowledge and awareness of etiologic factors, unhealthy lifestyles, and dietary patterns is crucial for combating ailments. Hence, this study is aimed at investigating the level of knowledge and awareness of CRC-related risk factors, practices, and possible associations of studied variables among young Jordanians. Methodology. A cross-sectional, observational study was conducted using an online self-reported assessment of anthropometrics, knowledge, awareness, and dietary and lifestyle practices toward CRC and its related risk factors. Results: A study of 795 Jordanian university students found that 93.8% were Jordanians, 73.0% were female, aged 18-24, and single. Most participants were from medical and science schools (69.4%). The vast majority (about 84%) were found to have good knowledge and awareness of CRC and its risk factors, but this was not reflected in their dietary practices. There are significant differences in physical activity, smoking, vegetable consumption, and serving sizes of red meat and processed meats between the sexes. Academic study specialties significantly impact knowledge and awareness. Conclusion: The study reveals that while young Jordanian university students have good knowledge and awareness about CRC and its risk factors, these levels are not reflected in their dietary behaviors and food choices for CRC prevention, highlighting the need for national programs to improve these practices, particularly in the younger population.

Comprehensive review of melatonin as a promising nutritional and nutraceutical supplement.

Background: Melatonin is an indoleamine hormone secreted by the pineal gland at night and has an essential role in regulating human circadian rhythms (the internal 24-h clock) and sleep-wake patterns. However, it has recently gained considerable attention for its demonstrated ability in disease management. This review discusses the major biological activities of melatonin, its metabolites as nutritional supplements, and its bioavailability in food sources. Methods: The information acquisition process involved conducting a comprehensive search across academic databases including PubMed, Scopus, Wiley, Embase, and Springer using relevant keywords. Only the most recent, peer-reviewed articles published in the English language were considered for inclusion. Results: The molecular mechanisms by which melatonin induces its therapeutic effects have been the subject of various studies. Conclusion: While melatonin was initially understood to only regulate circadian rhythms, recent studies indicate that it has a far-reaching effect on various organs and physiological systems, such as immunity, cardiovascular function, antioxidant defense, and lipid hemostasis. As a potent antioxidant, anti-cancer, anti-inflammatory, and immunoregulatory agent, multiple therapeutic applications have been proposed for melatonin.

Effect of camel milk on lipid profile among patients with diabetes: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.

The effects of camel milk (CM) intake on lipid profile among patients with diabetes remain controversial. This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to calculate the effect size of CM intake on blood lipids among patients with type 1 (T1D) and type 2 (T2D) diabetes. We searched nine databases from inception until December 31, 2022, to identify relevant RCTs. Effect sizes for total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) were calculated and expressed using mean differences (MD) and confidence intervals (CI). Of 4,054 retrieved articles, 10 RCTs (a total of 347 participants aged 8-70 years, 60.5% male) were eligible for inclusion. The pooled results from a random-effects model showed statistically significant decreases in TC (MD - 21.69, 95% CI: 41.05, - 2.33; p = 0.03; I2=99%), TG (MD - 19.79, 95% CI: -36.16, - 3.42; p=0.02, I2=99%), and LDL (MD -11.92, CI: -20.57, -3.26; p = 0.007, I2=88%), and a significant increase in HDL (MD 10.37, 95% CI, 1.90, 18.84; p=0.02, I2=95%) in patients with diabetes supplemented with CM compared with usual care alone. Subgroup analysis revealed that only long-term interventions (> 6 months) elicited a significant reduction in TC levels and TG levels. Consumption of fresh CM by patients with diabetes resulted in significant reductions in TC, TG, and LDL levels, while showing a significant increase in HDL levels. Patients with T1D elicited a more beneficial effect in lowering TC, LDL, and TG levels and in increasing HDL levels than their corresponding partners with T2D. In conclusion, long-term consumption of CM for patients with diabetes, especially those with T1D, could be a useful adjuvant therapy to improve lipid profile alongside prescribed medications. However, the high heterogeneity in the included studies suggests that more RCTs with larger sample sizes and longer intervention durations are required to improve the robustness of the available evidence.

Ramadan intermittent fasting is associated with ameliorated inflammatory markers and improved plasma sphingolipids/ceramides in subjects with obesity: lipidomics analysis.

Intermittent fasting (IF) is associated with enormous metabolic alterations that underpin its diverse health effects. Changes in lipid metabolism, particularly ceramides, and other sphingolipids, are among the most notable of these alterations. This study investigated the lipidomic alterations associated with 29-30 days of Ramadan diurnal intermittent fasting (RIF) in metabolically healthy overweight and obese subjects. A prospective cohort of 57 overweight and obese adults (70% males, 38.4 ± 11.2 years), with an age range of 18-58 years was observed prior to and at the conclusion of Ramadan. At both time points, anthropometric, biochemical (lipid profile, glycemic, and inflammatory markers), and dietary intake measurements were taken. Using liquid chromatography-mass spectrometry, a lipidomic analysis of ceramides and other sphingolipids was conducted. Using paired sample t-tests, pre- and post-Ramadan anthropometric, biochemical, and dietary values were compared. RIF was associated with improved levels of lipid profile compartments and inflammatory markers. In addition, RIF was associated with a decrease in plasma sphingosine and sphinganine, which was accompanied by a decrease in sphingosine 1-phosphate and sphinganine 1-phosphate. In addition, RIF was associated with decreased C17, C22, and C24 sphingomyelin, but not C14, C16, C18, C20, and C24:1 sphingomyelin, as well as C20, C22, C24, and C24:1 dihydrosphingomyelin, but not C16 and C18 dihydrosphingomyelin. This study demonstrates that RIF is associated with improvements in plasma sphingosine, sphinganine sphingomyelin, and dihydrosphingomyelin lipid species, as well as improved lipid profile and inflammatory markers, which may confer short-term protection against cardiometabolic problems in patients with overweight/obesity.

The Impact of Aging, Calorie Restriction and Dietary Fat on Autophagy Markers and Mitochondrial Ultrastructure and Dynamics in Mouse Skeletal Muscle.

Loss of skeletal muscle mass and function is a hallmark of aging. This phenomenon has been related to a dysregulation of mitochondrial function and proteostasis. Calorie restriction (CR) has been demonstrated to delay aging and preserve function until late in life, particularly in muscle. Recently, we reported the type of dietary fat plays an important role in determining life span extension with 40% CR in male mice. In these conditions, lard fed mice showed an increased longevity compared to mice fed soybean or fish oils. In this article, we analyze the effect of 40% CR on muscle mitochondrial mass, autophagy, and mitochondrial dynamics markers in mice fed these diets. In CR fed animals, lard preserved muscle fibers structure, mitochondrial ultrastructure, and fission/fusion dynamics and autophagy, not only compared to control animals, but also compared with CR mice fed soybean and fish oils as dietary fat. We focus our discussion on dietary fatty acid saturation degree as an essential predictor of life span extension in CR mice.

Conserved and species-specific molecular denominators in mammalian skeletal muscle aging.

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process.

Dietary fat and aging modulate apoptotic signaling in liver of calorie-restricted mice.

Imbalance between proliferation and cell death accounts for several age-linked diseases. Aging, calorie restriction (CR), and fat source are all factors that may influence apoptotic signaling in liver, an organ that plays a central metabolic role in the organism. Here, we have studied the combined effect of these factors on a number of apoptosis regulators and effectors. For this purpose, animals were fed diets containing different fat sources (lard, soybean oil, or fish oil) under CR for 6 or 18 months. An age-linked increase in the mitochondrial apoptotic pathway was detected with CR, including a decrease in Bcl-2/Bax ratio, an enhanced release of cytochrome c to the cytosol and higher caspase-9 activity. However, these changes were not fully transmitted to the effectors apoptosis-inducing factor and caspase-3. CR (which abated aging-related inflammatory responses) and dietary fat altered the activities of caspases-8, -9, and -3. Apoptotic index (DNA fragmentation) and mean nuclear area were increased in aged animals with the exception of calorie-restricted mice fed a lard-based fat source. These results suggest possible protective changes in hepatic homeostasis with aging in the calorie-restricted lard group.

Mitochondrial ultrastructure and markers of dynamics in hepatocytes from aged, calorie restricted mice fed with different dietary fats.

In this paper we analyzed changes in hepatocyte mitochondrial mass and ultrastructure as well as in mitochondrial markers of fission/fusion and biogenesis in mice subjected to 40% calorie restriction (CR) for 18 months versus ad libitum-fed controls. Animals subjected to CR were separated into three groups with different dietary fats: soybean oil (also in controls), fish oil and lard. Therefore, the effect of the dietary fat under CR was studied as well. Our results show that CR induced changes in hepatocyte and mitochondrial size, in the volume fraction occupied by mitochondria, and in the number of mitochondria per hepatocyte. Also, mean number of mitochondrial cristae and lengths were significantly higher in all CR groups compared with controls. Finally, CR had no remarkable effects on the expression levels of fission and fusion protein markers. However, considerable differences in many of these parameters were found when comparing the CR groups, supporting the idea that dietary fat plays a relevant role in the modulation of CR effects in aged mice.

SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass.

Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans.

The Fusarium oxysporum gnt2, encoding a putative N-acetylglucosamine transferase, is involved in cell wall architecture and virulence.

With the aim to decipher the molecular dialogue and cross talk between Fusarium oxysporum f.sp. lycopersci and its host during infection and to understand the molecular bases that govern fungal pathogenicity, we analysed genes presumably encoding N-acetylglucosaminyl transferases, involved in glycosylation of glycoproteins, glycolipids, proteoglycans or small molecule acceptors in other microorganisms. In silico analysis revealed the existence of seven putative N-glycosyl transferase encoding genes (named gnt) in F. oxysporum f.sp. lycopersici genome. gnt2 deletion mutants showed a dramatic reduction in virulence on both plant and animal hosts. Δgnt2 mutants had αalterations in cell wall properties related to terminal αor ß-linked N-acetyl glucosamine. Mutant conidia and germlings also showed differences in structure and physicochemical surface properties. Conidial and hyphal aggregation differed between the mutant and wild type strains, in a pH independent manner. Transmission electron micrographs of germlings showed strong cell-to-cell adherence and the presence of an extracellular chemical matrix. Δgnt2 cell walls presented a significant reduction in N-linked oligosaccharides, suggesting the involvement of Gnt2 in N-glycosylation of cell wall proteins. Gnt2 was localized in Golgi-like sub-cellular compartments as determined by fluorescence microscopy of GFP::Gnt2 fusion protein after treatment with the antibiotic brefeldin A or by staining with fluorescent sphingolipid BODIPY-TR ceramide. Furthermore, density gradient ultracentrifugation allowed co-localization of GFP::Gnt2 fusion protein and Vps10p in subcellular fractions enriched in Golgi specific enzymatic activities. Our results suggest that N-acetylglucosaminyl transferases are key components for cell wall structure and influence interactions of F. oxysporum with both plant and animal hosts during pathogenicity.

Alterations of ultrastructural and fission/fusion markers in hepatocyte mitochondria from mice following calorie restriction with different dietary fats.

We analyzed ultrastructural changes and markers of fission/fusion in hepatocyte mitochondria from mice submitted to 40% calorie restriction (CR) for 6 months versus ad-libitum-fed controls. To study the effects of dietary fat under CR, animals were separated into three CR groups with soybean oil (also in controls), fish oil, and lard. CR induced differential changes in hepatocyte and mitochondrial size, in the volume fraction occupied by mitochondria, and in the number of mitochondria per hepatocyte. The number of cristae per mitochondrion was significantly higher in all CR groups compared with controls. Proteins related to mitochondrial fission (Fis1 and Drp1) increased with CR, but no changes were detected in proteins involved in mitochondrial fusion (Mfn1, Mfn2, and OPA1). Although many of these changes could be attributed to CR regardless of dietary fat, changing membrane lipid composition by different fat sources did modulate the effects of CR on hepatocyte mitochondria.

Dietary fat modifies mitochondrial and plasma membrane apoptotic signaling in skeletal muscle of calorie-restricted mice.

Calorie restriction decreases skeletal muscle apoptosis, and this phenomenon has been mechanistically linked to its protective action against sarcopenia of aging. Alterations in lipid composition of membranes have been related with the beneficial effects of calorie restriction. However, no study has been designed to date to elucidate if different dietary fat sources with calorie restriction modify apoptotic signaling in skeletal muscle. We show that a 6-month calorie restriction decreased the activity of the plasma membrane neutral sphingomyelinase, although caspase-8/10 activity was not altered, in young adult mice. Lipid hydroperoxides, Bax levels, and cytochrome c and AIF release/accumulation into the cytosol were also decreased, although caspase-9 activity was unchanged. No alterations in caspase-3 and apoptotic index (DNA fragmentation) were observed, but calorie restriction improved structural features of gastrocnemius fibers by increasing cross-sectional area and decreasing circularity of fibers in cross sections. Changing dietary fat with calorie restriction produced substantial alterations of apoptotic signaling. Fish oil augmented the protective effect of calorie restriction decreasing plasma membrane neutral sphingomyelinase, Bax levels, caspase-8/10, and -9 activities, while increasing levels of the antioxidant coenzyme Q at the plasma membrane, and potentiating the increase of cross-sectional area and the decrease of fiber circularity in cross sections. Many of these changes were not found when we used lard. Our data support that dietary fish oil with calorie restriction produces a cellular anti-apoptotic environment in skeletal muscle with a downregulation of components involved in the initial stages of apoptosis engagement, both at the plasma membrane and the mitochondria.