Search Results (19)

Midkine (MDK) is a multifunctional protein that is secreted into the extracellular space. It functions as a cytokine or growth factor, modulating a variety of signaling pathways implicated in angiogenesis, antitumor immunity, metastasis, and therapy resistance. MDK overexpression has been documented in a variety of cancers, including those that affect women. MDK mediates its effects through activation of key signaling pathways such as MAPK/ERK, PI3K/AKT, and STAT3, which are pivotal for cell cycle progression, survival, and maintenance of stemness. Obesity and estrogen signaling, a known critical driver of women’s cancer, further elevate the levels of MDK. MDK’s effects are mediated by a variety of membrane receptors, such as integrins, protein tyrosine phosphatase ζ (PTPζ), anaplastic lymphoma kinase (ALK), and neurogenic locus notch homolog protein 2 (Notch2). Recently published studies have indicated that MDK is a potential therapeutic target and a biomarker for the progression of women’s cancer. In this review, we have provided a concise summary of the most recent papers that have examined the potential biomarker and therapeutic utility of MDK signaling in women’s cancer. Full article

Obesity is a condition of chronic low-grade inflammation affecting peripheral organs of the body, as well as the central nervous system. The adipose tissue dysfunction occurring under conditions of obesity is a key factor in the onset and progression of a variety of diseases, including neurodegenerative disorders. Mitochondria, key organelles in the production of cellular energy, play an important role in this tissue dysfunction. Numerous studies highlight the close link between obesity and adipocyte mitochondrial dysfunction, resulting in excessive ROS production and adipose tissue inflammation. This inflammation is transmitted systemically, leading to metabolic disorders that also impact the central nervous system, where pro-inflammatory cytokines impair mitochondrial and cellular functions in different areas of the brain, leading to neurodegenerative diseases. To date, several bioactive compounds are able to prevent and/or slow down neurogenerative processes by acting on mitochondrial functions. Among these, some molecules present in the Mediterranean diet, such as polyphenols, carotenoids, and omega-3 PUFAs, exert a protective action due to their antioxidant and anti-inflammatory ability. The aim of this review is to provide an overview of the involvement of adipose tissue dysfunction in the development of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, emphasizing the central role played by mitochondria, the main actors in the cross-talk between adipose tissue and the central nervous system. Full article

Introduction: Migraine is a prevalent neurological disorder characterized by recurrent headaches with autonomic and neurological symptoms, significantly impacting quality of life globally. Its pathogenesis involves genetic, neurological, inflammatory, and metabolic factors, with insulin resistance and metabolic dysfunction increasingly recognized as important contributors. Historically, it has been known that certain foods can trigger migraine attacks, which led for many years to the recommendation of elimination diets—now understood to primarily target histamine-rich foods. Over the past two decades, attention has shifted toward underlying metabolic disturbances, leading to the development of dietary approaches specifically aimed at addressing these dysfunctions. Methods: A scoping literature review was conducted using PubMed and Embase to evaluate the relationships among migraine, insulin-related mechanisms, neurogenic inflammation, and dietary interventions. Initial searches focused on “MIGRAINE AND (neurogenic inflammation)” (2019–15 April 2025), followed by expanded searches from 1950 onward using terms such as “MIGRAINE AND (insulin, insulin resistance, hyperinsulinism)”, and “MIGRAINE AND (diet, dietary, nutrition, nutritional)”. A specific search also targeted “(INSULIN OR insulin resistance OR hyperinsulinism) AND (neurogenic inflammation)”. Abstracts were screened, full texts were retrieved, and duplicates or irrelevant publications were excluded. No filters were applied by article type or language. Systematic reviews and meta-analyses were prioritized when available. Results: Migraine pathogenesis involves trigeminovascular system activation, neurogenic inflammation mediated by CGRP and PACAP, immune dysregulation, mast cell activation, and cortical spreading depression (CSD). Emerging evidence highlights significant associations between migraine, insulin resistance, and hyperinsulinism. Hyperinsulinism contributes to migraine through TRPV1 sensitization, increased CGRP release, oxidative stress, mitochondrial dysfunction, and systemic inflammation. Metabolic dysfunction, including obesity and insulin resistance, exacerbates migraine severity and frequency. Dietary interventions, particularly anti-inflammatory, Mediterranean, and ketogenic diets, show promise in reducing migraine frequency and severity through mechanisms involving reduced inflammation, oxidative stress, improved mitochondrial function, and glucose metabolism stabilization. Conclusions: The interplay between insulin resistance, metabolic dysfunction, and neuroinflammation is crucial in migraine pathophysiology. Targeted dietary interventions, including ketogenic and Mediterranean diets, demonstrate significant potential in managing migraines, emphasizing the need for personalized nutritional strategies to optimize therapeutic outcomes. Full article

This review describes our current understanding of the role of the mitochondria in the repurposing of the anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, and obesity. Metformin, the most prominent of these diabetes drugs, has been called the “Drug of Miracles and Wonders,” as clinical trials have found it to be beneficial for human patients suffering from these maladies. To promote viral replication in all infected human cells, SARS-CoV-2 stimulates the infected liver cells to produce glucose and to export it into the blood stream, which can cause diabetes in long COVID patients, and metformin, which reduces the levels of glucose in the blood, was shown to cut the incidence rate of long COVID in half for all patients recovering from SARS-CoV-2. Metformin leads to the phosphorylation of the AMP-activated protein kinase AMPK, which accelerates the import of glucose into cells via the glucose transporter GLUT4 and switches the cells to the starvation mode, counteracting the virus. Diabetes drugs also stimulate the unfolded protein response and thus mitophagy, which is beneficial for healthy aging and mental health. Diabetes drugs were also found to mimic exercise and help to reduce body weight. Full article

Emanating from several decades of study into the effects of the aging process after spinal cord injury (SCI), “accelerated aging” has become a common expression as the SCI accelerates the onset of age-related pathologies. However, the aging process follows a distinct trajectory, characterized by unique patterns of decline that differ from those observed in the general population without SCI. Aging brings significant changes to muscles, bones, and hormones, impacting overall physical function. Muscle mass and strength begin to decrease with a reduction in muscle fibers and impaired repair mechanisms. Bones become susceptible to fractures as bone density decreases. Hormonal changes combined with decreased physical activity accelerate the reduction of muscle mass and increase in body fat. Muscle atrophy and skeletal muscle fiber type transformation occur rapidly and in a unique pattern after SCI. Bone loss develops more rapidly and results in an increased risk of fractures in body regions unique to individuals with SCI. Other factors, such as excessive adiposity, decreased testosterone and human growth hormone, and increased systemic inflammation, contribute to a higher risk of neuropathically driven obesity, dyslipidemia, glucose intolerance, insulin resistance, and increasing cardiovascular disease risk. Cardiorespiratory changes after SCI result in lower exercise heart rates, decreased oxygenation, and mitochondrial dysfunction. While it is important to acknowledge the accelerated aging processes after SCI, it is essential to recognize the distinct differences in the aging process between individuals without physical disabilities and those with SCI. These differences, influenced by neuropathology, indicate that it may be more accurate to describe the aging process in individuals with chronic SCI as neurogenic accelerated aging (NAA). Research should continue to address conditions associated with NAA and how to ameliorate the accelerated rate of premature age-related conditions. This review focuses on the NAA processes and the differences between them and the aging process in those without SCI. Recommendations are provided to help slow the development of premature aging conditions. Full article

The hyperactivation of the sympathetic nervous system (SNS) is linked to obesity, hypertension, and type 2 diabetes, which are characterized by elevated norepinephrine (NE) levels. Previous research has shown increased sodium-dependent glucose cotransporter 1 (SGLT1) protein levels in kidneys of hypertensive rodents, prompting investigation into the expression of SGLT1 in various tissues, such as skeletal muscle. This study aimed to assess (i) whether skeletal muscle cells and tissue express SGLT1 and SGLT2 proteins; (ii) if NE increases SGLT1 levels in skeletal muscle cells, and (iii) whether the skeletal muscle of neurogenically hypertensive mice exhibits increased SGLT1 expression. We found that (i) skeletal muscle cells and tissue are a novel source of the SGLT2 protein and that (ii) NE significantly elevated SGLT1 levels in skeletal muscle cells. As SGLT2 inhibition (SGLT2i) with Empagliflozin increased SGLT1 levels, in vivo studies with the dual inhibitor SGLT1/2i, Sotagliflozin were warranted. The treatment of neurogenically hypertensive mice using Sotagliflozin significantly reduced blood pressure. Our findings suggest that SNS activity upregulates the therapeutic target, SGLT1, in skeletal muscle, potentially worsening cardiometabolic control. As clinical trial data suggest cardiorenal benefits from SGLT2i, future studies should aim to utilize SGLT1i by itself, which may offer a therapeutic strategy for conditions with heightened SNS activity, such as hypertension, diabetes, and obesity. Full article

Background: Chronic spinal cord injury (SCI) significantly accelerates morbidity and mortality, partly due to the increased risk of cardiometabolic diseases (CMD), including neurogenic obesity, dyslipidemia, and impaired glucose metabolism. While exercise and dietary interventions have shown some transient benefits in reducing CMD risk, they often fail to improve clinically relevant disease markers and cardiovascular events. Moreover, SCI also places caregiving demands on their caregivers, who themselves experience health and functional decline. This underscores the need for more substantial interventions that incorporate appropriate physical activity, heart-healthy nutrition, and behavioral support tailored to the SCI population. Objectives: This randomized clinical trial (RCT) protocol will (1) assess the health and functional effects, user acceptance, and satisfaction of a 6-month comprehensive therapeutic lifestyle intervention (TLI) adapted from the National Diabetes Prevention Program (DPP) for individuals with chronic SCI and (2) examine the impact of a complementary caregiver program on the health and function of SCI caregivers and evaluate user acceptance and satisfaction. Caregivers (linked with their partners) will be randomized to ‘behavioral support’ or ‘control condition’. Methods: Dyadic couples comprise individuals with SCI (18–65 years, >1-year post-injury, ASIA Impairment Scale A-C, injury levels C5-L1) and non-disabled SCI caregivers (18–65 years). Both groups undergo lock-step circuit resistance training, a calorie-restricted Mediterranean-style diet, and 16 educational sessions focused on diet/exercise goals, self-monitoring, psychological and social challenges, cognitive behavioral therapy, and motivational interviewing. The outcome measures encompass the cardiometabolic risks, cardiorespiratory fitness, inflammatory stress, multidimensional function, pain, life quality, independence, self-efficacy, program acceptance, and life satisfaction for SCI participants. The caregiver outcomes include multidimensional function, pain, quality of life, independence, and perceived caregiver burden. Discussion/Conclusions: This study evaluates the effects and durability of a structured, multi-modal intervention on health and function. The results and intervention material will be disseminated to professionals and consumers for broader implementation. Trial Registration: ClinicalTrials.gov, ID: NCT02853149 Registered 2 August 2016. Full article

Salt-tolerant plants, also known as halophytes, could provide a novel source of feedstock for biorefineries. After harvesting fresh shoots for food, the lignified fraction of Salicornia ramosissima J. Woods could be used to produce bioactive botanical extracts for high-value industries such as nutraceuticals, cosmetics, and biopharmaceuticals. The residual fraction after extraction can be further used for bioenergy or lignocellulose-derived platform chemicals. This work analysed S. ramosissima from different sources and growth stages. After pre-processing and extractions, the obtained fractions were analysed for their contents of fatty acids, pigments, and total phenolics. Extracts were also evaluated for their in vitro antioxidant properties and inhibitory effect towards enzymes related to diabetes, hyperpigmentation, obesity, and neurogenerative diseases. The ethanol extract from the fibre residue and the water extract from completely lignified plants showed the highest concentration of phenolic compounds along with the highest antioxidant potential and enzyme-inhibitory properties. Hence, they should be further explored in the context of biorefinery. Full article

Hyperactivation of the sympathetic nervous system (SNS) has been demonstrated in various conditions including obesity, hypertension and type 2 diabetes. Elevated levels of the major neurotransmitter of the SNS, norepinephrine (NE), is a cardinal feature of these conditions. Increased levels of the sodium glucose cotransporter 1 (SGLT1) protein have been shown to occur in the parotid and submandibular glands of hypertensive rodents compared to normotensive controls. However, there was a need to examine SGLT1 expression in other tissues, such as the kidneys. Whether NE may directly affect SGLT1 protein expression has not yet been investigated, although such a link has been shown for sodium glucose cotransporter 2 (SGLT2). Hence, we aimed to determine (i) whether our murine model of neurogenic hypertension displays elevated renal SGLT1 expression and (ii) whether NE may directly promote elevations of SGLT1 in human proximal tubule (HK2) cells. We did indeed demonstrate that in vivo, in our mouse model of neurogenic hypertension, hyperactivation of the SNS promotes SGLT1 expression in the kidneys. In subsequent in vitro experiments in HK2 cells, we found that NE increased SGLT1 protein expression and translocation as assessed by both specific immunohistochemistry and/or a specific SGLT1 ELISA. Additionally, NE promoted a significant elevation in interleukin-6 (IL-6) levels which resulted in the promotion of SGLT1 expression and proliferation in HK2 cells. Our findings suggest that the SNS upregulates SGLT1 protein expression levels with potential adverse consequences for cardiometabolic control. SGLT1 inhibition may therefore provide a useful therapeutic target in conditions characterized by increased SNS activity, such as chronic kidney disease. Full article

A growing body of evidence highlights the properties of flavonoids in natural foods for disease prevention. Due to their antioxidative, anti-inflammatory, and anti-carcinogenic activities, flavonoids have been revealed to benefit skeletal muscle, liver, pancreas, adipocytes, and neural cells. In this review, we introduced the basic classification, natural sources, and biochemical properties of flavonoids, then summarize the experimental results and underlying molecular mechanisms concerning the effects of flavonoid consumption on obesity, cancers, and neurogenerative diseases that greatly threaten public health. Especially, the dosage and duration of flavonoids intervening in these diseases are discussed, which might guide healthy dietary habits for people of different physical status. Full article

Spinal cord injury (SCI) results in a high prevalence of neurogenic obesity and metabolic dysfunction. The increased risk for neurogenic obesity and metabolic dysfunction is mainly due to the loss of energy balance because of significantly reduced energy expenditure following SCI. Consequently, excessive energy intake (positive energy balance) leads to adipose tissue accumulation at a rapid rate, resulting in neurogenic obesity, systemic inflammation, and metabolic dysfunction. The purpose of this article is to review the existing literature on nutrition, dietary intake, and nutrition education in persons with SCI as it relates to metabolic dysfunction. The review will highlight the poor dietary intakes of persons with SCI according to authoritative guidelines and the need for nutrition education for health care professionals and consumers. Nutrition education topics are presented in a module-based format with supporting literature. The authors emphasize the role of a diet consisting of low-energy, nutrient-dense, anti-inflammatory foods consistent with the Dietary Guidelines for Americans’ MyPlate to effectively achieve energy balance and reduce the risk for neurogenic obesity and metabolic dysfunction in individuals with SCI. Full article

Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research. Full article

Spinal cord injury (SCI) is a catastrophic event with multiple comorbidities including spastic paralysis, sensory loss, autonomic dysfunction with sympathetic blunting, neurogenic orthostatic hypotension, neurogenic restrictive and obstructive lung disease, neuropathic pain, spasticity, neurogenic bladder, neurogenic bowel, immobilization hypercalcemia, osteopenia/osteoporosis, neurogenic obesity, and metabolic dysfunction. Cervical and thoracic SCI is all too often accompanied by traumatic brain injury (TBI), which carries its own set of comorbidities including headaches, seizures, paroxysmal sympathetic hyperactivity, aphasia, dysphagia, cognitive dysfunction, memory loss, agitation/anxiety, spasticity, bladder and bowel incontinence, and heterotopic ossification. This manuscript will review the etiology and epidemiology of dual diagnoses, assessment of both entities, and discuss some of the most common comorbidities and management strategies to optimize functional recovery. Full article

Understanding the neurogenic causes of obesity may reveal novel drug targets to counter the obesity crisis and associated sequelae. Here, we investigate whether the deletion of GPR37L1, an astrocyte-specific orphan G protein-coupled receptor, affects whole-body energy homeostasis in mice. We subjected male Gpr37l1^−/− mice and littermate wildtype (Gpr37l1^+/+, C57BL/6J background) controls to either 12 weeks of high-fat diet (HFD) or chow feeding, or to 1 year of chow diet, with body composition quantified by EchoMRI, glucose handling by glucose tolerance test and metabolic rate by indirect calorimetry. Following an HFD, Gpr37l1^−/− mice had similar glucose handling, body weight and fat mass compared with wildtype controls. Interestingly, we observed a significantly elevated respiratory exchange ratio in HFD- and chow-fed Gpr37l1^−/− mice during daylight hours. After 1 year of chow feeding, we again saw no differences in glucose and insulin tolerance or body weight between genotypes, nor in energy expenditure or respiratory exchange ratio. However, there was significantly lower fat mass accumulation, and higher ambulatory activity in the Gpr37l1^−/− mice during night hours. Overall, these results indicate that while GPR37L1 may play a minor role in whole-body metabolism, it is not a viable clinical target for the treatment of obesity. Full article

Obesity is one of the biggest and most costly health challenges the modern world encounters. Substantial evidence suggests that the risk of metabolic syndrome or obesity formation may be affected at a very early stage of development, in particular through fetal and/or neonatal overfeeding. Outcomes from epidemiological studies indicate that maternal nutrition during pregnancy and lactation has a profound impact on adult neurogenesis in the offspring. In the present study, an intergenerational dietary model employing overfeeding of experimental mice during prenatal and early postnatal development was applied to acquire mice with various body conditions. We investigated the impact of the maternal high-energy diet during pregnancy and lactation on adult neurogenesis in the olfactory neurogenic region involving the subventricular zone (SVZ) and the rostral migratory stream (RMS) and some behavioral tasks including memory, anxiety and nociception. Our findings show that a maternal high-energy diet administered during pregnancy and lactation modifies proliferation and differentiation, and induced degeneration of cells in the SVZ/RMS of offspring, but only in mice where extreme phenotype, such as significant overweight/adiposity or obesity is manifested. Thereafter, a maternal high-energy diet enhances anxiety-related behavior in offspring regardless of its body condition and impairs learning and memory in offspring with an extreme phenotype. Full article