Xiaowen Ding

All Publications

• Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor. International journal of molecular sciences Jun, L., Ding, X. W., Robinson, M., Jafari, H., Knight, E., Geetha, T., Greene, M. W., Babu, J. R. 2024; 25 (8)

  Abstract

  Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.

  View details for DOI 10.3390/ijms25084307

  View details for PubMedID 38673892

  View details for PubMedCentralID PMC11050157

• Genistein: A focus on several neurodegenerative diseases. Journal of food biochemistry Li, R., Robinson, M., Ding, X., Geetha, T., Al-Nakkash, L., Broderick, T. L., Babu, J. R. 2022; 46 (7): e14155

  Abstract

  Neurodegenerative diseases are caused by the progressive loss of function or structure of nerve cells in the central nervous system. The most common neurodegenerative diseases include Alzheimer's disease, Huntington's disease, motor neuron disease, and Parkinson's disease. Although the physical or mental symptoms of neurodegenerative disease may be relieved by various treatment combinations, there are currently no strategies to directly slow or prevent neurodegeneration. Given the demographic evidence of a rapidly growing aging population and the associated prevalence of these common neurodegenerative diseases, it is paramount to develop safe and effective ways to protect against neurodegenerative diseases. Most neurodegenerative diseases share some common etiologies such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. Genistein is an isoflavone found in soy products that have been shown to exhibit antioxidant, anti-inflammation, and estrogenic properties. Increasing evidence indicates the protective potential of genistein in neurodegenerative disorders. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disease. PRACTICAL APPLICATIONS: Genistein is a naturally occurring isoflavone found mainly in soybean, but also green peas, legumes, and peanuts. Genistein is found to pass through the blood-brain barrier and possess a neuroprotective effect. In this review, we discuss studies in support of these actions and the underlying biological mechanisms. Together, these data indicate that genistein may hold neuroprotective effects in either delaying the onset or relieving the symptoms of neurodegenerative disease.

  View details for DOI 10.1111/jfbc.14155

  View details for PubMedID 35460092

• Effects of Genistein and Exercise Training on Brain Damage Induced by a High-Fat High-Sucrose Diet in Female C57BL/6 Mice. Oxidative medicine and cellular longevity Li, R., Ding, X., Geetha, T., Fadamiro, M., St Aubin, C. R., Shim, M., Al-Nakkash, L., Broderick, T. L., Babu, J. R. 2022; 2022: 1560435

  Abstract

  In recent decades, a shift in the nutritional landscape to the Western-style diet has led to an unprecedented rise in the prevalence of obesity and neurodegenerative diseases. Consumption of a healthy diet and engaging in regular physical activity represents safe and affordable approaches known to mitigate the adverse consequences of the Western diet. We examined whether genistein treatment, exercise training, and a combination treatment (genistein and exercise training) mitigated the effects of a Western diet-induced by high-fat, high-sugar (HFHS) in brain of female mice. HFHS increased the amyloid-beta (Aβ) load and phosphorylation of tau, apoptosis, and decreased brain-derived neurotrophic factor (BDNF) levels. Exercise training and genistein each afforded modest protection on Aβ accumulation and apoptosis, and both increased BDNF. The greatest neuroprotective effect occurred with combination treatment. BDNF and all markers of Aβ accumulation, phosphorylation of tau, and apoptosis were improved with combined treatment. In a separate series of experiments, PC12 cells were exposed to high glucose (HG) and palmitate (PA) to determine cell viability with genistein as well as in the presence of tamoxifen, an estrogen receptor antagonist, to assess a mechanism of action of genistein on cell apoptosis. Genistein prevented the neurotoxic effects of HG and PA in PC12 cells and tamoxifen blocked the beneficial effects of genistein on apoptosis. Our results indicate the beneficial effects of genistein and exercise training on HFHS-induced brain damage. The benefits of genistein may occur via estrogen receptor-mediated pathways.

  View details for DOI 10.1155/2022/1560435

  View details for PubMedID 35620577

  View details for PubMedCentralID PMC9129997

• Mitochondrial dysfunction and beneficial effects of mitochondria-targeted small peptide SS-31 in Diabetes Mellitus and Alzheimer's disease. Pharmacological research Ding, X. W., Robinson, M., Li, R., Aldhowayan, H., Geetha, T., Babu, J. R. 2021; 171: 105783

  Abstract

  Diabetes and Alzheimer's disease are common chronic illnesses in the United States and lack clearly demonstrated therapeutics. Mitochondria, the "powerhouse of the cell", is involved in the homeostatic regulation of glucose, energy, and reduction/oxidation reactions. The mitochondria has been associated with the etiology of metabolic and neurological disorders through a dysfunction of regulation of reactive oxygen species. Mitochondria-targeted chemicals, such as the Szeto-Schiller-31 peptide, have advanced therapeutic potential through the inhibition of oxidative stress and the restoration of normal mitochondrial function as compared to traditional antioxidants, such as vitamin E. In this article, we summarize the pathophysiological relevance of the mitochondria and the beneficial effects of Szeto-Schiller-31 peptide in the treatment of Diabetes and Alzheimer's disease.

  View details for DOI 10.1016/j.phrs.2021.105783

  View details for PubMedID 34302976

• Nerve growth factor in metabolic complications and Alzheimer's disease: Physiology and therapeutic potential. Biochimica et biophysica acta. Molecular basis of disease Ding, X. W., Li, R., Geetha, T., Tao, Y. X., Babu, J. R. 2020; 1866 (10): 165858

  Abstract

  As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline.

  View details for DOI 10.1016/j.bbadis.2020.165858

  View details for PubMedID 32531260

• Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model. Drug design, development and therapy Li, R. Z., Ding, X. W., Geetha, T., Al-Nakkash, L., Broderick, T. L., Babu, J. R. 2020; 14: 3325-3336

  Abstract

  Diabetes mellitus (DM)-induced brain damage is characterized by cellular, molecular and functional changes. The mechanisms include oxidative stress, neuroinflammation, reduction of neurotrophic factors, insulin resistance, excessive amyloid beta (Aβ) deposition and Tau phosphorylation. Both antidiabetic and neuroprotective effects of the phytoestrogen genistein have been reported. However, the beneficial effect of genistein in brain of the ob/ob mouse model of severe obesity and diabetes remains to be determined.In this study, female ob/ob mice and lean control mice were fed with either a standard diet or a diet containing genistein (600mg/kg) for a period of 4 weeks. Body weight was monitored weekly. Blood was collected for the measurement of glucose, insulin and common cytokines. Mice brains were isolated for Western immunoblotting analyses.Treatment with genistein reduced weight gain of ob/ob mice and decreased hyperglycemia compared to ob/ob mice fed the standard diet. The main findings show that genistein treatment increased insulin sensitivity and the expression levels of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factors (BDNF). In these mice, genistein also reduced Aβ deposition and the level of hyper-phosphorylated Tau protein.The results of our study indicate the beneficial effects of genistein in the obese diabetic mouse brain, including improving brain insulin signaling, increasing neurotrophic support, and alleviating Alzheimer's disease-related pathology.

  View details for DOI 10.2147/DDDT.S249608

  View details for PubMedID 32884237

  View details for PubMedCentralID PMC7443039