Melanoma in the liver: Oxidative stress and the mechanisms of metastatic cell survival.

Metastatic melanoma is a fatal disease with a rapid systemic dissemination. The most frequent target sites are the liver, bone, and brain. Melanoma metastases represent a heterogeneous cell population, which associates with genomic instability and resistance to therapy. Interaction of melanoma cells with the hepatic sinusoidal endothelium initiates a signaling cascade involving cytokines, growth factors, bioactive lipids, and reactive oxygen and nitrogen species produced by the cancer cell, the endothelium, and also by different immune cells. Endothelial cell-derived NO and H2O2 and the action of immune cells cause the death of most melanoma cells that reach the hepatic microvascularization. Surviving melanoma cells attached to the endothelium of pre-capillary arterioles or sinusoids may follow two mechanisms of extravasation: a) migration through vessel fenestrae or b) intravascular proliferation followed by vessel rupture and microinflammation. Invading melanoma cells first form micrometastases within the normal lobular hepatic architecture via a mechanism regulated by cross-talk with the stroma and multiple microenvironment-related molecular signals. In this review special emphasis is placed on neuroendocrine (systemic) mechanisms as potential promoters of liver metastatic growth. Growing metastatic cells undergo functional and metabolic changes that increase their capacity to withstand oxidative/nitrosative stress, which favors their survival. This adaptive process also involves upregulation of Bcl-2-related antideath mechanisms, which seems to lead to the generation of more resistant cell subclones.

Metabolic and Functional Improvements in a Patient with Charcot-Marie-Tooth Disease Type 2 after EGCG Administration: A Case Report.

Background and objectives: The aim of this study was to report a case of a patient with Charcot-Marie-Tooth disease type 2 (CMT2) treated with epigallocatechin gallate (EGCG) for 4 months in order to assess its therapeutic potential in CMT2. Materials and Methods: The study included a brother and a sister who have CMT2. The sister received 800 mg of EGCG for 4 months, while her brother received placebo for the same period of time. Both participants were assessed before and after daily administration by means of anthropometry; analysis of inflammatory and oxidation markers of interleukin-6 (IL-6) and paraoxonase 1 (PON1) in the blood sample; and motor tests: 2-min walk test (2MWT), 10-m walk test (10MWT), nine-hole peg test (9HPT) and handgrip strength measurement using a handheld Jamar dynamometer. Results: Regarding muscular and motor functions associated with higher inflammation and oxidation, improvements only observed in the woman in all analysed parameters (both biochemical and clinical associated with the metabolism and functionality) after 4 months of treatment with EGCG are noteworthy. Thus, this treatment is proposed as a good candidate to treat the disease.

Causes and risk factors for same-day discharge failure after total hip and knee arthroplasty: a meta-analysis.

In recent decades, the trend toward early same-day discharge (SDD) after surgery has dramatically increased. Efforts to develop adequate risk stratification tools to guide decision-making regarding SDD versus prolonged hospitalization after total hip arthroplasty (THA) remain largely incomplete. The purpose of this report is to identify the most frequent causes and risk factors associated with SDD failure in patients undergoing THA and total knee arthroplasty (TKA). A systematic search following PRISMA guidelines of four bibliographic databases was conducted for comparative studies between patients who were successfully discharged on the same day and those who failed. Outcomes of interests were causes and risk factors associated with same-day discharge failure. Odds ratios (OR) were calculated for dichotomous variables, whereas mean differences (MD) were calculated for continuous variables. Meta-analysis was performed using RevMan software. Random effects were used if there was evidence of heterogeneity. Eight studies with 3492 patients were included. The most common cause of SDD failure was orthostatic hypotension, followed by inadequate physical condition, nausea/vomiting, pain, and urinary retention. Female sex was a risk factor for failure (OR 0.77, 95% CI 0.63-0.93), especially in the THA subgroup. ASA score IV (OR 0.33, 95% CI 0.14-0.76) and III (OR 0.72, 95% CI 0.52-0.99) were risk factors, as were having > 2 allergies and smoking patients. General anesthesia increased failure risk (OR 0.58, 95% CI 0.42-0.80), while spinal anesthesia was protective (OR 1.62, 95% CI 1.17-2.24). The direct anterior and posterior approaches showed no significant differences. In conclusion, orthostatic hypotension was the primary cause of SDD failure. Risk factors identified for SDD failure in orthopedic surgery include female sex, ASA III and IV classifications, a higher number of allergies, smoking patients and the use of general anesthesia. These factors can be addressed to enhance SDD outcomes.

Predictive Factors of Functional Outcomes and Quality of Life in Patients with Ankle Fractures: A Systematic Review.

Background: Evaluating the predictors of unfavorable outcomes in patients with ankle fractures is crucial for identifying high-risk patients and implementing personalized treatment strategies. This study aimed to analyze factors that influence quality of life in patients with ankle fractures. Methods: Four databases were consulted. The main outcomes were functionality and quality of life scales combined using the standard mean difference (SMD) (Review Manager 5.4). Results: Eight studies with 2486 patients were included. A significant correlation was found between female sex and worse functionality scores (beta 4.15, 95% CI 1.84-6.46). Additionally, older age was correlated with worse functionality scores (beta -0.24, 95% CI -0.29 to -0.19). Patients with diabetes or metabolic syndrome also had worse outcomes (SMD 0.27, 95% CI 0.18-0.36). High BMI and obesity were also associated with worse quality of life scores (beta 2.62, 95% CI 0.77-4.48). Smokers had greater disability in the analyzed scales (SMD 0.22, 95% CI 0.05-0.39). No significant differences were observed with respect to syndesmotic involvement. Conclusions: Age, sex, diabetes, high BMI, and smoking negatively impact functional outcomes and quality of life in patients with ankle fractures.

Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism.

BACKGROUND: Interleukin (IL)-6 (mainly of tumor origin) activates glutathione (GSH) release from hepatocytes and its interorgan transport to B16-F10 melanoma metastatic foci. We studied if this capacity to overproduce IL-6 is regulated by cancer cell-independent mechanisms. METHODS: Murine B16-F10 melanoma cells were cultured, transfected with red fluorescent protein, injected i.v. into syngenic C57BL/6J mice to generate lung and liver metastases, and isolated from metastatic foci using high-performance cell sorting. Stress hormones and IL-6 levels were measured by ELISA, and CRH expression in the brain by in situ hybridization. DNA binding activity of NF-κB, CREB, AP-1, and NF-IL-6 was measured using specific transcription factor assay kits. IL-6 expression was measured by RT-PCR, and silencing was achieved by transfection of anti-IL-6 small interfering RNA. GSH was determined by HPLC. Cell death analysis was distinguished using fluorescence microscopy, TUNEL labeling, and flow cytometry techniques. Statistical analyses were performed using Student's t test. RESULTS: Plasma levels of stress-related hormones (adrenocorticotropin hormone, corticosterone, and noradrenaline) increased, following a circadian pattern and as compared to non-tumor controls, in mice bearing B16-F10 lung or liver metastases. Corticosterone and noradrenaline, at pathophysiological levels, increased expression and secretion of IL-6 in B16-F10 cells in vitro. Corticosterone- and noradrenaline-induced transcriptional up-regulation of IL-6 gene involves changes in the DNA binding activity of nuclear factor-κB, cAMP response element-binding protein, activator protein-1, and nuclear factor for IL-6. In vivo inoculation of B16-F10 cells transfected with anti-IL-6-siRNA, treatment with a glucocorticoid receptor blocker (RU-486) or with a ß-adrenoceptor blocker (propranolol), increased hepatic GSH whereas decreased plasma IL-6 levels and metastatic growth. Corticosterone, but not NORA, also induced apoptotic cell death in metastatic cells with low GSH content. CONCLUSIONS: Our results describe an interorgan system where stress-related hormones, IL-6, and GSH coordinately regulate metastases growth.

The Confusion Assessment Method Could Be More Accurate than the Memorial Delirium Assessment Scale for Diagnosing Delirium in Older Cancer Patients: An Exploratory Study.

BACKGROUND: Older people with cancer carry a high risk of delirium, an underdiagnosed syndrome due to its diagnostic complexity and often subtle presentation. Tools based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) are available to different health professionals. Our aim is to assess the prevalence of delirium in older people with cancer in an inpatient unit and the accuracy of the Confusion Assessment Method (CAM) and Memorial Delirium Assessment Scale (MDAS). METHODS: This exploratory, cross-sectional study included people aged 65 years or older with a diagnosis of cancer and admitted to the medical oncology unit from June 2021 to December 2022. The diagnostic accuracy of CAM and MDAS was analyzed against the gold standard medical diagnosis based on DSM-5 criteria by two medical oncologists. The cutoff point for the MDAS was determined using a receiver-operating characteristics (ROC) curve. RESULTS: Among the 75 included patients (mean age 71.6 years, standard deviation 4.1; 52% males), the prevalence of delirium was 62.7%. The most prevalent types of cancer in patients with delirium were hematological and lung cancer. The scale with the highest diagnostic accuracy was the CAM, with a sensitivity of 100% and specificity of 86%, followed by the MDAS, with a sensitivity of 88% and specificity of 30%. The presence of cognitive impairment hindered the detection of delirium. CONCLUSIONS: The CAM scale was more accurate than the MDAS pre-existing cognitive impairment in our sample. Further studies are needed to analyze the diagnostic accuracy of delirium tools in older populations with cancer and in the presence of cognitive impairment.

Liposomal Epigallocatechin-3-Gallate for the Treatment of Intestinal Dysbiosis in Children with Autism Spectrum Disorder: A Comprehensive Review.

Autism Spectrum Disorder (ASD) is characterized by varying degrees of difficulty in social interaction and communication. These deficits are often associated with gastrointestinal symptoms, indicating alterations in both intestinal microbiota composition and metabolic activities. The intestinal microbiota influences the function and development of the nervous system. In individuals with ASD, there is an increase in bacterial genera such as Clostridium, as well as species involved in the synthesis of branched-chain amino acids (BCAA) like Prevotella copri. Conversely, decreased amounts of Akkermansia muciniphila and Bifidobacterium spp. are observed. Epigallocatechin-3-gallate (EGCG) is one of the polyphenols with the greatest beneficial activity on microbial growth, and its consumption is associated with reduced psychological distress. Therefore, the objective of this review is to analyze how EGCG and its metabolites can improve the microbial dysbiosis present in ASD and its impact on the pathology. The analysis reveals that EGCG inhibits the growth of pathogenic bacteria like Clostridium perfringens and Clostridium difficile. Moreover, it increases the abundance of Bifidobacterium spp. and Akkermansia spp. As a result, EGCG demonstrates efficacy in increasing the production of metabolites involved in maintaining epithelial integrity and improving brain function. This identifies EGCG as highly promising for complementary treatment in ASD.

Lipid Profile in Multiple Sclerosis: Functional Capacity and Therapeutic Potential of Its Regulation after Intervention with Epigallocatechin Gallate and Coconut Oil.

BACKGROUND: Multiple sclerosis (MS) patients present dyslipidemia and functional disability. Epigallocatechin gallate (EGCG) and coconut oil have been shown to be effective against dyslipidemia. OBJECTIVE: To analyze the relationship between lipid profiles, fat consumption, and functional disability in patients with MS after administering EGCG and coconut oil. METHODS: A four-month pilot study was conducted on 45 MS patients, divided into an intervention group (IG) and a control group (CG). The IG received 800 mg of EGCG and 60 mL of coconut oil. Lipid profiles were measured before and after the intervention, along with other data such as dietary habits, inflammatory markers, and functional capacity. RESULTS: Dyslipidemia did not correlate with the patients' fat consumption. After the intervention, triglycerides (TG) levels were lower in IG compared to CG. This decrease was positively correlated with an improvement in functional disability (determined by the Expanded Disability Status Scale (EDSS)) and negatively with high-density cholesterol (HDL) and apolipoprotein A1. Significant and positive correlations were observed between EDSS and C-reactive protein (CRP) in the IG. These changes in the IG could be related to body fat decrease, whose percentage shows a positive correlation with CRP and TG levels, and a negative correlation with HDL levels. CONCLUSIONS: Patients with MS present a certain type of dyslipemia not associated with their nutritional habits. The administration of EGCG and coconut oil seems to decrease blood TG levels, which could explain the functional improvements.

Intertissue flow of glutathione (GSH) as a tumor growth-promoting mechanism: interleukin 6 induces GSH release from hepatocytes in metastatic B16 melanoma-bearing mice.

B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show high metastatic activity in vivo. An intertissue flow of GSH, where the liver is the main reservoir, can increase GSH content in metastatic cells and promote their growth. We have studied here possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1- and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin in B16-F10-bearing mice) may facilitate GSH release from hepatocytes and its interorgan transport to metastatic growing foci.

Bone Quality in Patients with Parkinson's Disease Determined by Quantitative Ultrasound (QUS) of the Calcaneus: Influence of Sex Differences.

(1) Background: Parkinson's disease (PD) is a relatively common neurodegenerative disease in elderly individuals, with a high risk of falls. There is abundant literature on the relationship between PD and osteoporosis. The aim of this study is to describe the bone quality of a population with PD by calcaneal ultrasound and to compare it with a healthy control, assessing the influence of possible sex differences. (2) Methods: 21 patients diagnosed with PD were recruited. The control group was composed of 30 healthy individuals with similar sociodemographic characteristics. The bone quality of all participants was assessed using calcaneal quantitative ultrasound (QUS). The parameters recorded were broadband ultrasound attenuation (BUA, in decibels per megahertz), imaging speed of sound (SOS, in meters per second), stiffness index (SI) and T-score of each participant. Bone mineral density (BMD) was estimated using the equation BMD = 0.002592 × (BUA + SOS) − 3.687 (g/cm2). (3) Results: significant differences were observed between the healthy control and the PD group: the T-score was lower in the PD group (p < 0.05) and SOS was higher in Parkinson's disease patients (p < 0.05), while 28.6% of the PD patients were osteoporotic with T-score values lower than −1.5 compared to 16.7% of osteoporotic individuals in the control group (p < 0.01). Regarding the sex, there were significant differences (p < 0.05) between the females of the PD group vs. control group, showing a significant difference in the SI (71.4 ± 14.7 vs. 87.8 ± 12), T-score (−2.19 ± 1.1 vs. −0.15 ± 0.8), BUA (104.5 ± 13 vs. 116 ± 10.6) and BMD (0.49 ± 0.09 vs. 0.60 ± 0.08), with no difference in the comparison between the male groups; and the comparison between both sexes in T-score only showed significant differences for the PD group (p < 0.05), with worse bone quality in women. (4) Conclusions: this study shows poorer bone quality in female patients with PD, who have a higher percentage of osteoporosis than healthy patients. The QUS technique of the calcaneus seems adequate for these determinations in patients with Parkinson's disease.

Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the loss of upper and lower motor neurons (MNs) in the cerebral cortex, brainstem and spinal cord, with consequent weakness, atrophy and the progressive paralysis of all muscles. There is currently no medical cure, and riluzole and edaravone are the only two known approved drugs for treating this condition. However, they have limited efficacy, and hence there is a need to find new molecules. Dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase (5AR) enzymes, the therapeutic purposes of which, to date, are the treatment of benign prostatic hyperplasia and androgenic alopecia, shows great anti-ALS properties by the molecular-topology methodology. Based on this evidence, this review aims to assess the effects of dutasteride on testosterone (T), progesterone (PROG) and 17ß-estradiol (17BE) as a therapeutic alternative for the clinical improvement of ALS, based on the hormonal, metabolic and molecular pathways related to the pathogenesis of the disease. According to the evidence found, dutasteride shows great neuroprotective, antioxidant and anti-inflammatory effects. It also appears effective against glutamate toxicity, and it is capable of restoring altered dopamine activity (DA). These effects are achieved both directly and through steroid hormones. Therefore, dutasteride seems to be a promising molecule for the treatment of ALS, although clinical studies are required for confirmation.

Role of Haptoglobin as a Marker of Muscular Improvement in Patients with Multiple Sclerosis after Administration of Epigallocatechin Gallate and Increase of Beta-Hydroxybutyrate in the Blood: A Pilot Study.

Here, we report on the role of haptoglobin (Hp), whose expression depends on the synthesis of interleukin 6 (IL-6), related to the pathogenesis of multiple sclerosis (MS), as a possible marker of muscle improvement achieved after treatment with the polyphenol epigallocatechin gallate (EGCG) and an increase in the ketone body beta-hydroxybutyrate (BHB) in the blood. After 4 months of intervention with 27 MS patients, we observed that Hp does not significantly increase, alongside a significant decrease in IL-6 and a significant increase in muscle percentage. At the same time, Hp synthesis is considerably and positively correlated with IL-6 both before and after treatment; while this correlation occurs significantly reversed with muscle percentage before treatment, no correlation is evident after the intervention. These results seem to indicate that Hp could be a marker of muscle status and could be a diagnosis tool after therapeutic intervention in MS patients.

The Impact of Microbiota on the Pathogenesis of Amyotrophic Lateral Sclerosis and the Possible Benefits of Polyphenols. An Overview.

The relationship between gut microbiota and neurodegenerative diseases is becoming clearer. Among said diseases amyotrophic lateral sclerosis (ALS) stands out due to its severity and, as with other chronic pathologies that cause neurodegeneration, gut microbiota could play a fundamental role in its pathogenesis. Therefore, polyphenols could be a therapeutic alternative due to their anti-inflammatory action and probiotic effect. Thus, the objective of our narrative review was to identify those bacteria that could have connection with the mentioned disease (ALS) and to analyze the benefits produced by administering polyphenols. Therefore, an extensive search was carried out selecting the most relevant articles published between 2005 and 2020 on the PubMed and EBSCO database on research carried out on cell, animal and human models of the disease. Thereby, after selecting, analyzing and debating the main articles on this topic, the bacteria related to the pathogenesis of ALS have been identified, among which we can positively highlight the presence mainly of Akkermansia muciniphila, but also Lactobacillus spp., Bifidobacterium spp. or Butyrivibrio fibrisolvens. Nevertheless, the presence of Escherichia coli or Ruminococcus torques stand out negatively for the disease. In addition, most of these bacteria are associated with molecular changes also linked to the pathogenesis of ALS. However, once the main polyphenols related to improvements in any of these three ALS models were assessed, many of them show positive results that could improve the prognosis of the disease. Nonetheless, epigallocatechin gallate (EGCG), curcumin and resveratrol are the polyphenols considered to show the most promising results as a therapeutic alternative for ALS through changes in microbiota.

Possible Role of Butyrylcholinesterase in Fat Loss and Decreases in Inflammatory Levels in Patients with Multiple Sclerosis after Treatment with Epigallocatechin Gallate and Coconut Oil: A Pilot Study.

(1) Background. Multiple sclerosis (MS) is characterised by the loss of muscle throughout the course of the disease, which in many cases is accompanied by obesity and related to inflammation. Nonetheless, consuming epigallocatechin gallate (EGCG) and ketone bodies (especially ß-hydroxybutyrate (ßHB)) produced after metabolising coconut oil, have exhibited anti-inflammatory effects and a decrease in body fat. In addition, butyrylcholinesterase (BuChE), seems to be related to the pathogenesis of the disease associated with inflammation, and serum concentrations have been related to lipid metabolism. Objective. The aim of the study was to determine the role of BuChE in the changes caused after treatment with EGCG and ketone bodies on the levels of body fat and inflammation state in MS patients. (2) Methods. A pilot study was conducted for 4 months with 51 MS patients who were randomly divided into an intervention group and a control group. The intervention group received 800 mg of EGCG and 60 mL of coconut oil, and the control group was prescribed a placebo. Fat percentage and concentrations of the butyrylcholinesterase enzyme (BuChE), paraoxonase 1 (PON1) activity, triglycerides, interleukin 6 (IL-6), albumin and ßHB in serum were measured. (3) Results. The intervention group exhibited significant decreases in IL-6 and fat percentage and significant increases in BuChE, ßHB, PON1, albumin and functional capacity (determined by the Expanded Disability Status Scale (EDSS)). On the other hand, the control group only exhibited a decrease in IL-6. After the intervention, BuChE was positively correlated with the activity of PON1, fat percentage and triglycerides in the intervention group, whereas these correlations were not observed in the control group (4). Conclusions. BuChE seems to have an important role in lipolytic activity and the inflammation state in MS patients, evidenced after administering EGCG and coconut oil as a ßHB source.

Muscle Function Differences between Patients with Bulbar and Spinal Onset Amyotrophic Lateral Sclerosis. Does It Depend on Peripheral Glucose?

BACKGROUND: One of the pathogenic mechanisms of ALS disease is perturbed energy metabolism particularly glucose metabolism. Given the substantial difference in the severity and the prognosis of the disease, depending on whether it has a bulbar or spinal onset, the aim of the study was to determine metabolic differences between both types of ALS, as well as the possible relationship with muscle function. MATERIALS AND METHODS: A descriptive, analytical, quantitative, and transversal study was carried out in hospitals and Primary Care centers in the region of Valencia, Spain. Fasting glucose and alkaline phosphatase (AP) levels in venous blood, muscle percentage, fat percentage, muscle strength (MRC scale), and functional capacity (Barthel Index) were measured in 31 patients diagnosed with ALS (20 with spinal onset ALS and 11 with bulbar onset ALS). A healthy control of 29 people was included. RESULTS: No significant differences were observed in blood AP and glucose levels between spinal onset and bulbar onset ALS patients. However, a significant positive correlation was observed between the mean values of both substances in patients with spinal onset ALS. Moreover, a lower percentage of muscle mass and a higher percentage of fat mass were also seen in spinal ALS patients, who also presented lower muscle strength and lower functional capacity. CONCLUSION: The results of this study seem to point to a possible difference in the peripheral use of glucose between patients with bulbar onset ALS and spinal onset ALS, who appear to have possible insulin resistance. These metabolic differences could explain the lower muscle percentage and lower muscular function in spinal onset ALS patients, although further studies are required.

The Impact of Epigallocatechin Gallate and Coconut Oil Treatment on Cortisol Activity and Depression in Multiple Sclerosis Patients.

(1) Background: Multiple sclerosis (MS) is pathogenically characterized by high oxidative stress and symptomatically by progressive muscle loss and increased body fat associated with the presence of depression. Epigallocatechin gallate (EGCG) (particularly present in green tea) and ketone bodies (in particular beta-hydroxybutyrate (BHB)), whose main source is coconut oil, have shown emotional benefits and body fat loss. The aim of this study was to assess the impact of EGCG and coconut oil on cortisol activity related to fat loss and depression in MS patients. (2) Methods: The study involved 51 MS patients who were randomly divided into an intervention group or a control group. The intervention group received 800 mg of EGCG and 60 mL of coconut oil, which were included in their daily diet for four months. The control group received placebo and all patients followed an isocaloric diet. A blood sample was collected before and after the four-month period, and levels of cortisol, albumin and BHB were measured in serum. In addition, immediately before and after the intervention, anthropometric variables were measured: waist-to-hip ratio (WHR), body fat mass percentage, fat weight, total weight, and muscle mass percentage. Depression was assessed with the Beck Depression Inventory II (BDI-II). (3) Results: No significant changes were obtained in cortisol levels in any of the groups, and there was a significant increase in albumin in the blood of the intervention group only that could lead to a decrease in serum free cortisol. In addition, it was observed a significant decrease in levels of depression and abdominal fat. (4) Conclusions: EGCG combined with coconut oil increase the concentration of albumin in blood and produce less depression in MS patients.

Nicotinamide Riboside and Pterostilbene Cooperatively Delay Motor Neuron Failure in ALS SOD1G93A Mice.

Oxidative stress-induced damage is a major mechanism in the pathophysiology of amyotrophic lateral sclerosis (ALS). A recent human clinical trial showed that the combination of nicotinamide riboside (NR) and pterostilbene (PT), molecules with potential to interfere in that mechanism, was efficacious in ALS patients. We examined the effect of these molecules in SOD1G93A transgenic mice, a well-stablished model of ALS. Assessment of neuromotor activity and coordination was correlated with histopathology, and measurement of proinflammatory cytokines in the cerebrospinal fluid. Cell death, Nrf2- and redox-dependent enzymes and metabolites, and sirtuin activities were studied in isolated motor neurons. NR and PT increased survival and ameliorated ALS-associated loss of neuromotor functions in SOD1G93A transgenic mice. NR and PT also decreased the microgliosis and astrogliosis associated with ALS progression. Increased levels of proinflammatory cytokines were observed in the cerebrospinal fluid of mice and humans with ALS. NR and PT ameliorated TNFα-induced oxidative stress and motor neuron death in vitro. Our results support the involvement of oxidative stress, specific Nrf2-dependent antioxidant defenses, and sirtuins in the pathophysiology of ALS. NR and PT interfere with the mechanisms leading to the release of proapoptotic molecular signals by mitochondria, and also promote mitophagy.

Poor Bone Quality in Patients With Amyotrophic Lateral Sclerosis.

Objective: Musculoskeletal functional deterioration in Amyotrophic lateral sclerosis (ALS) is associated with an increase in bone fractures. The purpose of this study was to evaluate the influence of sex, ALS type, on bone quality in patients with ALS compared to healthy controls. The impact on bone health of the clinical status and some metabolic parameters was also analyzed in ALS patients. Methods: A series of 33 voluntary patients with ALS, and 66 healthy individuals matched in sex and age underwent assessment of bone mass quality using quantitative ultrasound (QUS) of the calcaneus. Ultrasonic broadband attenuation (BUA), the speed of sound (SOS), stiffness index and T-score were measured. Bone mineral density (BMD) was estimated using standard equations. Apart from fat and muscle mass percentage determinations, clinical baseline measures in ALS patients included ALSFRS-R score, Barthel index for activities of daily living, pulmonary function measured using FVC, and muscular strength assessed by a modified MRC grading scale. Laboratory tests included serum calcium, 25-HO-cholecalciferol (Vitamin D), alkaline phosphatase (ALP), T4 and TSH. Results: All bone parameters evaluated were statistically significant lower in ALS patients than in healthy controls. ALS females showed significantly lower bone parameters than healthy females. According to the estimated BMD, there were 25 ALS patients (75.8%) and 36 (54.5%) healthy individuals showing an osteoporotic profile (BMD <0.700 g/cm2). Only 16.7% of the ALS females had T-scores indicative of healthy bones. There was no correlation between any of the clinical parameters analyzed and the bone QUS measurements. Vitamin D and TSH levels positively correlated with all the bone parameters. Conclusions: This study confirms that ALS patients, particularly females, exhibited deteriorated bone health as compared to healthy individuals. These structural bone changes were independent of ALS subtype and clinical status. Bone health in ALS patients seems to be related to certain metabolic parameters such as Vitamin D and TSH levels.

Vitamin B1 Intake in Multiple Sclerosis Patients and its Impact on Depression Presence: A Pilot Study.

Vitamin B1, or thiamine, is one of the most relevant vitamins in obtaining energy for the nervous system. Thiamine deficiency or lack of activity causes neurological manifestations, especially symptoms of depression, intrinsic to multiple sclerosis (MS) and related to its pathogenesis. On this basis, the aim of this study was to determine the possible relationship between the nutritional habits of patients with MS and the presence of depression. Therefore, a cross-sectional and observational descriptive study was conducted. An analysis of dietary habits and vitamin B1 consumption in a Spanish population of 51 MS patients was performed by recording the frequency of food consumption. Results showed a vitamin B1 intake within the established range, mainly provided by the consumption of ultra-processed products such as cold meats or pastries, and a total carbohydrate consumption lower than recommended, which stands out for its high content of simple carbohydrates deriving from processed foods such as dairy desserts, juice, snacks, pastries, chocolate bars, soft drinks and fermented alcohol. In addition, a significant negative correlation between depression and the intake of thiamine and total carbohydrates was observed. These findings could explain the influence of MS patients' eating habits, and consequently vitamin B1 activity, on depression levels.

Possible Reduction of Cardiac Risk after Supplementation with Epigallocatechin Gallate and Increase of Ketone Bodies in the Blood in Patients with Multiple Sclerosis. A Pilot Study.

Multiple sclerosis (MS) is a neurodegenerative disease that causes anthropometric changes characterised by functional disability, increase in fat mass, and decrease in lean mass. All these variables are related to a greater cardiac risk. The polyphenol epigallocatechin gallate (EGCG) and an increase in ketone bodies in the blood have been shown to have beneficial effects on anthropometric and biochemical variables related to cardiovascular activity. The aim of this study was to analyse the impact of the intervention with EGCG and ketone bodies on cardiac risk in MS patients. A population of 51 MS patients were randomly assigned to a control group and an intervention group (daily dose of 800 mg of EGCG and 60 mL of coconut oil). Both groups followed an isocaloric diet for 4 months. Levels of beta-hydroxybutyrate (BHB), albumin, paraoxonase 1 (PON1) and C-reactive protein (CRP) were measured in serum before and after the intervention, as well as determining functional ability, waist circumference, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), fat percentage and muscle percentage. After 4 months, in the intervention group there was a significant increase in BHB, PON1 and albumin, while CRP did not vary; a significant decrease in cardiac risk associated with a significant decline in WHR; as well as a significant increase in muscle percentage. By contrast, these changes were not observed in the control group. Finally, results from analysis of variance (ANOVA) revealed a significant time-condition interaction effect, observing that WHtR and fat mass decreased in the intervention group, while they increased in the control group.