Loss of fragile WWOX gene leads to senescence escape and genome instability.

Induction of DNA damage response (DDR) to ensure accurate duplication of genetic information is crucial for maintaining genome integrity during DNA replication. Cellular senescence is a DDR mechanism that prevents the proliferation of cells with damaged DNA to avoid mitotic anomalies and inheritance of the damage over cell generations. Human WWOX gene resides within a common fragile site FRA16D that is preferentially prone to form breaks on metaphase chromosome upon replication stress. We report here that primary Wwox knockout (Wwox-/-) mouse embryonic fibroblasts (MEFs) and WWOX-knockdown human dermal fibroblasts failed to undergo replication-induced cellular senescence after multiple passages in vitro. Strikingly, by greater than 20 passages, accelerated cell cycle progression and increased apoptosis occurred in these late-passage Wwox-/- MEFs. These cells exhibited γH2AX upregulation and microsatellite instability, indicating massive accumulation of nuclear DNA lesions. Ultraviolet radiation-induced premature senescence was also blocked by WWOX knockdown in human HEK293T cells. Mechanistically, overproduction of cytosolic reactive oxygen species caused p16Ink4a promoter hypermethylation, aberrant p53/p21Cip1/Waf1 signaling axis and accelerated p27Kip1 protein degradation, thereby leading to the failure of senescence induction in Wwox-deficient cells after serial passage in culture. We determined that significantly reduced protein stability or loss-of-function A135P/V213G mutations in the DNA-binding domain of p53 caused defective induction of p21Cip1/Waf1 in late-passage Wwox-/- MEFs. Treatment of N-acetyl-L-cysteine prevented downregulation of cyclin-dependent kinase inhibitors and induced senescence in Wwox-/- MEFs. Our findings support an important role for fragile WWOX gene in inducing cellular senescence for maintaining genome integrity during DDR through alleviating oxidative stress.

Mangiferin Protects against Angiotensin-II-Enhanced Hypertrophic Markers and Apoptosis in H9c2 Cardiomyocytes.

Hypertrophic cardiomyopathy accompanies numerous cardiovascular diseases, and the intervention of cardiac hypertrophy is an important issue to prevent detrimental consequences. Mangiferin (MGN) is a glucosylxanthone found in Mangifera indica, which exhibits anti-oxidant and anti-inflammatory properties. Various studies have demonstrated the cardioprotective potential of MGN, but the mechanisms behind its beneficial effects have not been fully revealed. Here, angiotensin-II (Ang-II) was used to induce cardiac hypertrophy, and we examined cell size, expression of hypertrophy markers (e.g., ANP, BNP, and [Formula: see text]-MHC), and oxidative stress (e.g., the ratio of NADPH/NADP[Formula: see text], the expression of p22phox and p67phox, and ROS and SOD production) of cardiomyocytes. Moreover, we assessed the activation of mitogen-activated protein kinase (MAPK) signaling (e.g., p38 and ERK) and the NF-[Formula: see text]Bp65/iNOS axis. Additionally, an annexin V/PI assay was employed to evaluate whether MGN administration can attenuate Ang-II-elicited apoptosis. Lastly, the expression of Ang-II type 1 receptor (AT1) was measured to confirm its involvement in MGN-mediated protection. Our results showed that treatment with MGN attenuated the Ang-II-induced cell size, expression of hypertrophy markers, and oxidative stress in cardiomyocytes. MGN also abrogated the activation of MAPK signaling and the NF-[Formula: see text]Bp65/iNOS axis. Additionally, MGN prevented apoptosis and downregulated the elevation of AT1 in cardiomyocytes that had been exposed to Ang-II. Altogether, these results demonstrated the potential of using MGN to ameliorate the Ang-II-associated cardiac hypertrophy, which may be due to its anti-oxidant and anti-inflammatory effects through suppression of MAPK signaling and the NF-[Formula: see text]Bp65/iNOS axis.

Joint influence of architectural and spatiotemporal factors on the presence of Aedes aegypti in urban environments.

BACKGROUND: Urbanization has led to the proliferation of high-rise buildings, which have substantially influenced the distribution of dengue vectors, such as Aedes aegypti (L.). However, knowledge gaps exist regarding the individual and combined effects of architectural and spatiotemporal factors on dengue vector. This study investigated the interrelationship between Ae. aegypti presence, building architectural features, and spatiotemporal factors in urban environments. RESULTS: The mosquito Ae. aegypti presence varied by location and seasons, being higher in outdoor environments than in indoor environments. Lingya (Kaohsiung City, Taiwan) had the highest mosquito numbers, particularly in basement and first floor areas. Ae. aegypti was found on multiple floors within buildings, and their presence was greater in summer and autumn. The XGBoost model revealed that height within a building, temperature, humidity, resident density, and rainfall were key factors influencing mosquito presence, whereas openness had a relatively minor impact. CONCLUSION: To effectively address the problems caused by urbanization, the three-dimensional distribution of Ae. aegypti, including their spatial distribution across heights and areas within the urban environment, must be considered. By incorporating these multiple factors, this approach provides valuable insights for those responsible for urban planning and disease management strategies. Understanding the interplay between architectural features, environmental conditions, and the presence of Ae. aegypti is essential for developing targeted interventions and mitigating the adverse impacts of urbanization on public health. © 2023 Society of Chemical Industry.

Sesamin suppresses angiotensin-II-enhanced oxidative stress and hypertrophic markers in H9c2 cells.

Myocardial hypertrophy plays a crucial role in cardiovascular disease (CVD) development. Myocardial hypertrophy is an adaptive response by myocardial cells to stress after cardiac injury to maintain cardiac output and function. Angiotensin II (Ang-II) regulates CVD through the renin-angiotensin-aldosterone system, and its signaling in cardiac myocytes leads to excessive reactive oxygen species (ROS) production, oxidative stress, and inflammation. Sesamin (SA), a natural compound in sesame seeds, has anti-inflammatory and anti-apoptotic effects. This study investigated whether SA could attenuate hypertrophic damage and oxidative injuries in H9c2 cells under Ang-II stimulation. We found that SA decreased the cell surface area. Furthermore, Ang-II treatment reduced Ang-II-increased ANP, BNP, and ß-MHC expression. Ang-II enhanced NADPH oxidase activity, ROS formation, and decreased Superoxide Dismutase (SOD) activity. SA treatment reduces Ang-II-caused oxidative injuries. We also found that SA mitigates Ang-II-induced apoptosis and pro-inflammatory responses. In conclusion, SA could attenuate Ang-II-induced cardiac hypertrophic injuries by inhibiting oxidative stress, apoptosis, and inflammation in H9c2 cells. Therefore, SA might be a potential supplement for CVD management.

Dapagliflozin Mitigates Doxorubicin-Caused Myocardium Damage by Regulating AKT-Mediated Oxidative Stress, Cardiac Remodeling, and Inflammation.

Doxorubicin (Dox) is a commonly used anthracycline chemotherapy with a side effect of cardiotoxicity, which may increase the risk of heart failure for cancer patients. Although various studies have demonstrated the cardioprotective property of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, the detailed mechanism underlying its effect on Dox-induced cardiomyopathy is still limited. In this study, we showed that DAPA induced the activation of AKT/PI3K signaling in cardiac myoblast H9c2 cells following Dox treatment, leading to the upregulation of antioxidant HO-1, NQO1, and SOD, as well as an improved mitochondrial dysfunction via Nrf2. In addition, the reduced oxidative stress resulted in the downregulation of hypertrophy (ANP and BNP) and fibrosis (phospho-Smad3, collagen I, fibronectin, and α-SMA) markers. Furthermore, the inflammatory IL-8 concentration was inhibited after DAPA, possibly through PI3K/AKT/Nrf2/p38/NF-κB signaling. Moreover, our results were validated in vivo, and echocardiography results suggested an improved cardiac function in DAPA-receiving rats. In summary, we demonstrated that the administration of DAPA could mitigate the Dox-elicited cardiotoxicity by reducing oxidative stress, mitochondrial dysfunction, fibrosis, hypertrophy, and inflammation via PI3K/AKT/Nrf2 signaling.

The fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate and increased respiratory muscle function in patients with upper abdominal surgery: a randomized controlled trial.

BACKGROUND: Upper abdominal surgical treatment may reduce respiratory muscle function and mucociliary clearance, which might be a cause of postoperative pulmonary complications (PPCs). Threshold inspiratory muscle training (IMT) may serve as an effective modality to improve respiratory muscle strength and endurance in patients. However, whether this training could help patients with upper abdominal surgery remains to be determined. The aim of the present investigation was to determine the effect of a fully engaged IMT on PPCs and respiratory function in patients undergoing upper abdominal surgery. We hypothesized that the fully engaged IMT could reduce PPCs and improve respiratory muscle function in patients with upper abdominal surgery. METHODS: This is a randomized controlled trial (RCT) with 28 patients who underwent upper abdominal surgery. Patients were randomly assigned to the control (CLT) group or the IMT group. The CTL group received regular health care. The IMT group received 3 weeks of IMT with 50% of MIP as the initial intensity before the operation. The intensity of MIP increased by 5-10% per week. The IMT was continued for 4 weeks after the operation. The study investigated the outcomes including PPCs, respiratory muscle strength, diaphragmatic function, cardiopulmonary function, and quality of life (QoL). RESULTS: We found that IMT improved respiratory muscle strength and diaphragmatic excursion. IMT also had a beneficial effect on the incidence of postoperative pulmonary complications (PPCs) compared to CLT care. CONCLUSION: The results from this study revealed that IMT provided positive effects on parameters associated with the respiratory muscle function and reduced the incidence of PPCs. We propose that fully engaged IMT should be a part of clinical management in patients with upper abdominal surgery.KEY MESSAGESThe fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases maximal inspiratory pressure in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases diaphragm function in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases the quality of life in patients with upper abdominal surgery.

Quercetin Mitigates Cisplatin-Induced Oxidative Damage and Apoptosis in Cardiomyocytes through Nrf2/HO-1 Signaling Pathway.

Cisplatin is massively used to treat solid tumors. However, several severe adverse effects, such as cardiotoxicity, are obstacles to its clinical application. Cardiotoxicity may lead to congestive heart failure and even sudden cardiac death in patients receiving cisplatin. Therefore, finding a novel therapeutic strategy for the prevention of cisplatin-induced cardiotoxicity is urgent. Quercetin is a flavonol compound that can be found in dietary fruits and vegetables. The antioxidant function and anti-inflammatory capacity of quercetin have been reported. However, whether quercetin could protect against cisplatin-caused apoptosis and cellular damage in cardiomyocytes is still unclear. H9c2 cardiomyocytes were treated with cisplatin (40 µM) for 24 h to induce cellular damage with or without quercetin pretreatment. We found that quercetin activates Nrf2 and HO-1 expression, thereby mitigating cisplatin-caused cytotoxicity in H9c2 cells. Quercetin also increases SOD levels, maintains mitochondrial function, and reduces oxidative stress under cisplatin stimulation. Quercetin attenuates cisplatin-induced apoptosis and inflammation in H9c2 cardiomyocytes; however, these cytoprotective effects were diminished by silencing Nrf2 and HO-1. In conclusion, this study reports that quercetin has the potential to antagonize cisplatin-caused cardiotoxicity by reducing ROS-mediated mitochondrial damage and inflammation via the Nrf2/HO-1 and p38MAPK/NF-[Formula: see text]Bp65/IL-8 signaling pathway. This study provided the theoretical basis and experimental proof for the clinical application of quercetin as a new effective strategy to relieve chemotherapy-induced cardiotoxicity.

Effects of percutaneous vertebroplasty on respiratory parameters in patients with osteoporotic vertebral compression fractures.

Background: Vertebral compression fractures (VCFs) often occur in patients with osteoporosis. These fractures can also lead to postural changes. Several studies have shown that patients with vertebral compression fractures have a restrictive pattern in their pulmonary function. Percutaneous vertebroplasty (PVP) is the standard treatment for vertebral compression fractures, with the benefits of pain relief and enhancement of vertebral stability for partially collapsed vertebral bodies. However, the effects of PVP on short-term recovery of respiratory performance have not been investigated. Therefore, this study aimed to investigate the changes in pulmonary function, respiratory muscle strength, maximal voluntary ventilation (MVV), and chest mobility in patients with vertebral compression fractures after PVP.Methods: This research was approved by the clinic committee of the E-DA Hospital Institutional Review Board (EMRP07109N) and registered in the Thai Clinical Trials Registry (TCTR20211029005). We recruited 32 VCF patients. Four-time points were measured: before and after PVP and 1 and 3 weeks after PVP. We measured pulmonary function and maximum voluntary ventilation (MVV) by using spirometry. Respiratory muscle strength was assessed by using a respiratory pressure meter. The chest expansion test was used to evaluate chest mobility. A visual analogue scale (VAS) was used to assess resting and aggravated back pain.Results: Chest expansion and back pain improved at each time point after PVP. MVV showed significant progress at both 1 and 3 weeks after discharge. Forced expiratory volume in 1 second (FEV1) and maximal inspiratory muscle strength significantly improved 1 week after discharge.Conclusion: Taking all the data together, PVP not only can resolve severe back pain but can also provide excellent improvements in MVV and chest mobility in patients with vertebral compression fractures.

Low-level laser prevents doxorubicin-induced skeletal muscle atrophy by modulating AMPK/SIRT1/PCG-1α-mediated mitochondrial function, apoptosis and up-regulation of pro-inflammatory responses.

BACKGROUND: Doxorubicin (Dox) is a widely used anthracycline drug to treat cancer, yet numerous adverse effects influencing different organs may offset the treatment outcome, which in turn affects the patient's quality of life. Low-level lasers (LLLs) have resulted in several novel indications in addition to traditional orthopedic conditions, such as increased fatigue resistance and muscle strength. However, the mechanisms by which LLL irradiation exerts beneficial effects on muscle atrophy are still largely unknown. RESULTS: The present study aimed to test our hypothesis that LLL irradiation protects skeletal muscles against Dox-induced muscle wasting by using both animal and C2C12 myoblast cell models. We established SD rats treated with 4 consecutive Dox injections (12 mg/kg cumulative dose) and C2C12 myoblast cells incubated with 2 µM Dox to explore the protective effects of LLL irradiation. We found that LLL irradiation markedly alleviated Dox-induced muscle wasting in rats. Additionally, LLL irradiation inhibited Dox-induced mitochondrial dysfunction, apoptosis, and oxidative stress via the activation of AMPK and upregulation of SIRT1 with its downstream signaling PGC-1α. These aforementioned beneficial effects of LLL irradiation were reversed by knockdown AMPK, SIRT1, and PGC-1α in C2C12 cells transfected with siRNA and were negated by cotreatment with mitochondrial antioxidant and P38MAPK inhibitor. Therefore, AMPK/SIRT1/PGC-1α pathway activation may represent a new mechanism by which LLL irradiation exerts protection against Dox myotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis. CONCLUSION: Our findings may provide a novel adjuvant intervention that can potentially benefit cancer patients from Dox-induced muscle wasting.

Baicalin Enhances Chemosensitivity to Doxorubicin in Breast Cancer Cells via Upregulation of Oxidative Stress-Mediated Mitochondria-Dependent Apoptosis.

Doxorubicin (Dox) is an effective anthracycline anticancer drug. However, recent studies have revealed that Dox resistance is a highly critical issue, and a significant reason for treatment failure. Baicalin is a flavonoid component in the roots of Scutellaria baicalensis Georgi; however, whether baicalin can increase chemosensitivity in breast cancers is still unclear. In this study, we found that cellular apoptosis occurs when excessive intracellular ROS is generated, triggered by the dual intervention of baicalin and doxorubicin, which increases intracellular calcium [Ca2+]i concentrations. Increased [Ca2+]i concentrations decrease the mitochondrial membrane potential (△Ψm), thereby causing cellular apoptosis. Pretreatment with NAC (ROS inhibitor) or BATBA (Ca2+ chelator) reduces baicalin-induced chemosensitivity. The findings of this study demonstrate that the effect of baicalin on Dox treatment could enhance cytotoxicity toward breast cancer cells via the ROS/[Ca2+]i-mediated intrinsic apoptosis pathway-thus potentially lessening the required dosage of doxorubicin, and further exploring associated mechanisms in combined treatments for breast cancer clinical interventions in the future.

Dapagliflozin attenuates hypoxia/reoxygenation-caused cardiac dysfunction and oxidative damage through modulation of AMPK.

BACKGROUND: Emerging evidence demonstrated dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, prevented various cardiovascular events. However, the detailed mechanisms underlying its cardioprotective properties remained largely unknown. RESULTS: In the present study, we sought to investigate the effects of DAPA on the cardiac ischemia/reperfusion (I/R) injury. Results from in vitro experiments showed that DAPA induced the phosphorylation of AMPK, resulting in the downregulation of PKC in the cardiac myoblast H9c2 cells following hypoxia/reoxygenation (H/R) condition. We demonstrated that DAPA treatment diminished the H/R-elicited oxidative stress via the AMPK/ PKC/ NADPH oxidase pathway. In addition, DAPA prevented the H/R-induced abnormality of PGC-1α expression, mitochondrial membrane potential, and mitochondrial DNA copy number through AMPK/ PKC/ NADPH oxidase signaling. Besides, DAPA reversed the H/R-induced apoptosis. Furthermore, we demonstrated that DAPA improved the I/R-induced cardiac dysfunction by echocardiography and abrogated the I/R-elicited apoptosis in the myocardium of rats. Also, the administration of DAPA mitigated the production of myocardial infarction markers. CONCLUSIONS: In conclusion, our data suggested that DAPA treatment holds the potential to ameliorate the I/R-elicited oxidative stress and the following cardiac apoptosis via modulation of AMPK, which attenuates the cardiac dysfunction caused by I/R injury.

Anti-IL-20 Antibody Protects against Ischemia/Reperfusion-Impaired Myocardial Function through Modulation of Oxidative Injuries, Inflammation and Cardiac Remodeling.

Acute myocardial infarction (AMI) is the most critical event in the disease spectrum of coronary artery disease. To rescue cardiomyocytes in AMI, it is important to restore blood supply as soon as possible to reduce ischemia-induced injury. However, worse damage can occur during the reperfusion phase, called the reperfusion injury. Under ischemia/reperfusion (I/R) injury, elevated oxidative stress plays a critical role in regulation of apoptosis, inflammation and remodeling of myocardium. Our previous study has demonstrated that interleukin (IL)-20 is increased during hypoxia/reoxygenation stimulation and promotes apoptosis in cardiomyocytes. This study was, therefore, designed to investigate whether IL-20 antibody could reduce I/R-induced myocardial dysfunction. Results from this study revealed that IL-20 antibody treatment significantly suppressed I/R-induced nicotinamide adenine dinucleotide phosphate oxidase, oxidative stress, apoptosis, proinflammatory responses, cardiac fibrosis, and expression of cardiac remodeling markers in Sprague-Dawley rats. Plasma B-type natriuretic peptide level was also reduced by IL-20 antibody injection. IL-20 antibody treatment appeared to restore cardiac function under the I/R injury in terms of greater values of ejection fraction and fractional shortening compared to the control group. Two commonly used indicators of cardiac injury, lactate dehydrogenase and creatine kinase-MB, were also lower in the IL-20 antibody injection group. Taken together, our results suggested that IL-20 antibody holds the potential to reduce the I/R-elicited cardiac dysfunction by preventing cardiac remodeling.

Effects of Exercise in Patients Undergoing Chemotherapy for Head and Neck Cancer: A Pilot Randomized Controlled Trial.

BACKGROUND: Cisplatin administration may induce muscle atrophy, thereby reducing the fitness level of patients with head and neck cancer (HNC). To date, only animal studies have been conducted to test the effectiveness of exercise interventions in diminishing side effects of cisplatin. AIM: To determine whether exercise training improves physical fitness and health-related quality of life (HRQoL) in patients receiving chemotherapy for Head & Neck (H&N). MATERIAL AND METHODS: This pilot-randomized controlled trial was conducted on 57 participants receiving chemotherapy for HNC. The participants were randomized into an exercise group and a control group. The exercise group received moderate-intensity combined aerobic, resistance and flexibility exercises three times a week for eight weeks during chemotherapy. The control group received no specific information regarding exercise. The outcome measures including body composition, muscle strength, balance, flexibility, cardiovascular fitness and health-related quality of life (HRQoL) were assessed at baseline and eight weeks following baseline. RESULTS: The body composition (body fat percentage, p = 0.002; skeletal muscle percentage, p = 0.008), dynamic balance (p = 0.01), muscle strength (upper extremity, p = 0.037; lower extremity, p = 0.025) and HRQoL (p = 0.001) showed a significant difference between the exercise group and the control group eight weeks following baseline. Significant deteriorations were noted in flexibility, muscle strength, cardiovascular fitness and several domains of HRQoL scale in the control group at eight weeks following baseline. CONCLUSIONS: This study found that a combined aerobic, resistance and flexibility exercise program during chemotherapy may improve physical fitness (i.e., muscle strength, balance, flexibility and body composition) and HRQoL and alleviate the deterioration of cardiovascular fitness in patients with HNC. Further research studies with large sample sizes are warranted to investigate the long-term effects of exercise in this population.

Effect of Exercise Training on Exercise Tolerance and Level of Oxidative Stress for Head and Neck Cancer Patients Following Chemotherapy.

BACKGROUND: Chemotherapy decreases fitness performance via repression of cardiopulmonary function and oxidative stress. This study was designed to investigate whether exercise intervention could improve exercises capacity and reduce systemic oxidative stress in patients with head and neck (H&N) cancer receiving chemotherapy. METHODS: This is a single-center study. Forty-two H&N cancer patients who were undergoing chemotherapy were recruited in this study. An 8-week exercise intervention was performed by conducting the combination of aerobic and resistance exercise 3 days a week. The exercise training was conducted by a physiotherapist. The exercise capacity and exercise responses were measured from blood pressure (BP) and heart rate (HR). Oxidative stress markers from human plasma, such as total antioxidant capacity, 8-hydroxy-2'-deoxyguanosine, malondialdehyde, and carbonyl content, were tested by activity kits. RESULTS: We provide compelling evidence that exercise training ameliorated exercise responses and increased exercise capacity by repressing resting BP and increasing 1- and 3-min BP recovery. We also found the resting HR was reduced, and the 1- and 3-min HR recovery was increased after exercise training. In addition, the rating of perceived exertion after the peak exercise was reduced after exercise intervention. We also found that exercise training repressed oxidative stress markers by elevation of total antioxidant capacity and suppression of 8-OHd and carbonyl content in plasma. DISCUSSION: We clearly demonstrate that exercise can promote exercise capacity and reduce oxidative stress in H&N cancer patients receiving chemotherapy, which might guide new therapeutic approaches for cancer patients, especially those undergoing chemotherapy.

Early Moderate Intensity Aerobic Exercise Intervention Prevents Doxorubicin-Caused Cardiac Dysfunction Through Inhibition of Cardiac Fibrosis and Inflammation.

Doxorubicin (DOX) is known as an effective drug in the fight against various cancers. However, one of the greatest impediments is DOX-induced cardiomyopathy, which may potentially lead to heart failure. Accumulating evidence has shed light on the pathological mechanism of DOX-induced cardiotoxicity, but treatments to mitigate the cardiac damage are still required. In an attempt to address this issue, we evaluated whether exercise provides cardioprotective effects on the DOX-induced cardiotoxicity. We showed that treadmill exercise (3 times/week; 1-week of exercise acclimatization and 4-weeks of endurance exercise) during the DOX treatment successfully prevented the cardiac dysfunction. The DOX-stimulated expression of IκBα, NF-κB, COX-2, and IL-8 were all downregulated by exercise as well as the fibrosis factors (TGF-ß1, phosphorylated ERK, Sp1, and CTGF). Moreover, we showed that treadmill exercise diminished the expression of several cardiac remodeling-associated factors, such as FGF2, uPA, MMP2, and MMP9. These results were in line with the finding that exercise intervention reduced cardiac fibrosis and restored cardiac function, with higher values of ejection fraction and fractional shortening compared to the DOX-treated group. Two commonly used indicators of cardiac injury, lactate dehydrogenase, and creatine kinase-MB, were also decreased in the exercise group. Collectively, our results suggested that it may be beneficial to prescribe treadmill exercise as an adjunct therapy to limit cardiac damage caused by DOX.

Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3ß-mediated epileptic seizure activity in mice.

Human WWOX gene resides in the chromosomal common fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. Loss-of-function mutations in both alleles of WWOX gene lead to autosomal recessive abnormalities in pediatric patients from consanguineous families, including microcephaly, cerebellar ataxia with epilepsy, mental retardation, retinal degeneration, developmental delay and early death. Here, we report that targeted disruption of Wwox gene in mice causes neurodevelopmental disorders, encompassing abnormal neuronal differentiation and migration in the brain. Cerebral malformations, such as microcephaly and incomplete separation of the hemispheres by a partial interhemispheric fissure, neuronal disorganization and heterotopia, and defective cerebellar midline fusion are observed in Wwox-/- mice. Degenerative alterations including severe hypomyelination in the central nervous system, optic nerve atrophy, Purkinje cell loss and granular cell apoptosis in the cerebellum, and peripheral nerve demyelination due to Schwann cell apoptosis correspond to reduced amplitudes and a latency prolongation of transcranial motor evoked potentials, motor deficits and gait ataxia in Wwox-/- mice. Wwox gene ablation leads to the occurrence of spontaneous epilepsy and increased susceptibility to pilocarpine- and pentylenetetrazol (PTZ)-induced seizures in preweaning mice. We determined that a significantly increased activation of glycogen synthase kinase 3ß (GSK3ß) occurs in Wwox-/- mouse cerebral cortex, hippocampus and cerebellum. Inhibition of GSK3ß by lithium ion significantly abolishes the onset of PTZ-induced seizure in Wwox-/- mice. Together, our findings reveal that the neurodevelopmental and neurodegenerative deficits in Wwox knockout mice strikingly recapitulate the key features of human neuropathies, and that targeting GSK3ß with lithium ion ameliorates epilepsy.

Multimodal exercise ameliorates exercise responses and body composition in head and neck cancer patients receiving chemotherapy.

BACKGROUND: Studies have found that many chemotherapy drugs will produce multiple side effects and complications in cancer patients, especially in the case of the cardiovascular disease. This study was intended to investigate whether the exercise training intervention could improve the body composition and exercise responses of patients with head and neck (H&N) cancer who are receiving chemotherapy. METHODS: This is a randomized controlled trial. Eighty-four H&N patients were assigned to sedentary group or exercise group. The data were collected pretraining and posttraining, where the body composition, heart rate (HR), blood pressure (BP), rate-pressure product (RPP), and exercise capacity were measured. RESULTS: Our data reported that body weight and body mass index were decreased after 8 weeks of chemotherapy in the sedentary group but not in the exercise group. The decreased visceral fat and the increased skeletal muscle rate had been found in the exercise group after 8 weeks of training. In addition, in the exercise group, the HR, HR recovery, BP, BP recovery, RPP, and minutes walking distance were better than the sedentary group. Results from this study suggested exercise training significantly improved exercise responses and body composition. CONCLUSION: These findings suggested that exercise can help to promote cardiopulmonary fitness and exercise capacity for H&N cancer patients undergoing chemotherapy.

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-ß), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-ß binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.