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Background Prolonged life expectancy is associated with increased prevalence of chronic diseases. The aim of this study was to determine the different disability trajectories for the top ten leading causes of death in Taiwan . Methods A total of 2,431 participants aged 50–96 in 1996 from the Taiwan longitudinal study on aging (TLSA) who died from 1996 to 2016 were analyzed. Integration of Cause of Death Data and TLSA helped sort out participants who had died from the ten leading causes of death. The level of physical disability was evaluated with the Activities of Daily Living Scale (ADLs), ranging from 0 to 6 points, in 1996, 1999, 2003, 2007, and 2011. A multilevel model was used to investigate the levels and rates of change in disability development before death. Results The outcome of the research showed that the earliest group to experience physical limitation was individuals living with diabetes. The groups with the highest ADL scores were participants with diabetes, cerebrovascular disease, and hypertension-related diseases. Most groups reach ADL scores ≥ 1 (mild-level) during 4–6 years before death except chronic hepatitis and cirrhosis and injury. Conclusions People who had died from the ten leading causes of death experienced different disability trajectories before death. The trajectory of the participants who had died from diabetes showed a unique pattern with the earliest occurrence and more severe deterioration in terms of development of disabilities. Disability trajectories provide a prediction of survival status for middle-aged and older adults associated with the ten leading causes of death.

To explore the dominant indications and laws of acupoint compatibility of Yinbai (SP1) by using modern statistics and data mining techniques.Literature about indications and acupoint prescriptions of SP1 published before October of 1949 were retrieved from booksBefore October of 1949, the single SP1 acupoint was usually used to treat 12 types of diseases (mainly the internal diseases as asthma, abdominal distension, vomiting, etc.), and the compound prescriptions of SP1 were usually used to treat 20 types of diseases (mainly the internal diseases as insomnia and dreamful sleep, blood syndrome, etc.), and its adjunct acupoints belong to the first three meridians: the Foot Yangming Stomach Meridian, Foot Taiyang Bladder Meridian and Foot Taiyin Spleen Meridian. After October of 1949, the single SP1 was used to dominantly treat 2 types of diseases (mainly the gynecological diseases as metrorrhagia and metrostaxis, and hypermenorrhea, etc.), and the compound prescriptions of SP1 were frequently used to treat 10 diseases (metrorrhagia and metrostaxis, sequela of apoplexy, mental disorders, insomnia and dreamful sleep, etc.), and the adjunct acupoints of compound prescriptions belong to the first three meridians, namely the Foot Taiyin Spleen Meridian, Concept Vessel and Foot Yangming Stomach Meridian. Before and after October of 1949, the adjunct acupoints with the highest degree of correlation were Lidui (ST45), Shaoshang(LU11), Zusanli(ST36), Sanyinjiao (SP9), and Guanyuan (CV4). Cluster analysis showed that 9 effective clusters obtained may be used as potential prescriptions of SP1, and association rule analysis displayed that the first three strongly connected acupoint matching groups were: SP1-ST45, SP1-LU11, and SP1-ST36 frequently used before October of 1949, and SP1-SP9, SP1-ST36 and SP1-CV4 employed after October of 1949.Data mining technology reveals that acupoint SP1 alone is mainly used to treat internal diseases before 1949, and gynecological diseases after 1949; and compound acupoint recipes of SP1 are mainly to treat the internal diseases before 1949, and the gynecological diseases and mental disorders after 1949 in China. The frequently employed adjunct acupoints of SP1 are ST45, LU11, ST36, SP9 and CV4 both before and after 1949.

Background This study examines correlates of disabilities related to ADL, IADL, mobility, and frailty in men and women with a nationally representative sample of older adults living in the community. Methods A total of 10,898 noninstitutionalized Taiwanese nationals aged 65 years and older enrolled in the 2001 (N = 2,064), 2005 (N = 2,727), 2009 (N = 2,904), and 2013 (N = 3,203) National Health Interview Survey (NHIS) were analyzed. Results The prevalence of mobility disabilities and frailty in older adults in Taiwan decreased during the past decade ($${\chi }_{Mobility}^{2}= -5.4$$ χ Mobility 2 = - 5.4 , $${\chi }_{Frailty}^{2}= -6.2$$ χ Frailty 2 = - 6.2 ). Exercise, social engagement, and tea and coffee intake were found to be associated with lower levels of all types of disabilities in both men and women. In addition, a diet based on carbohydrates, falls, depressive symptomatology, lung and metabolic diseases were risks for most of the disabilities under consideration. Gender-specific independent correlates included: being married (OR = 0.63, 95%CI: 0.40–0.98), eggs/beans/fish/meat consumption (OR = 0.35, 95% CI = 0.16–0.80); depressive symptoms, obesity and cataracts, which were associated with higher IADL (OR = 3.61, 1.63, and 1.18, respectively) and frailty limitations (OR = 10.89, 1.27, and 1.20, respectively) in women. Cognitive impairment was found to be an important correlate for ADL limitations in men (OR = 3.64, 95%CI: 2.38–5.57). Conclusions Exercise, social participation and diet (more tea and coffee intake and lower carbohydrates) were correlates for lower levels of disability. Some gender-specific correlates were also identified, including associations of disability with depressive symptoms, obesity, and cataracts that were more distinct in women, and lower levels of disability which were especially significant in men who were married, eat more eggs, beans, fish, and meat, and those free from cognitive impairment.

Several studies have demonstrated increased postoperative mortality rates in patients on chronic hemodialysis compared with non-dialyzed patients. However, limited studies have examined factors that may contribute to postoperative mortality.In this retrospective cohort study, data were collected from 9,140 dialysis and 45,725 non-dialysis patients undergoing surgery between 2007 to 2009 from Taiwan's National Health Insurance Registry Database. Patient demographics, comorbidities, and anesthesia duration were used to compare 30-day postoperative mortality differences in dialysis patients.Dialysis patients undergoing first-time surgery were significantly older, more likely male, and possessed more comorbidities. Overall, dialysis patients had significantly higher all-cause postoperative mortality (odds ratio, 15.005; 95% confidence interval, 11.917-18.893). Gender (hazard ratio [HR], 0.762), age (HR, 1.012), longer duration of inhalation general anesthesia (HR, 1.113), and comorbidities of hypertension (HR, 0.759), diabetes (HR, 1.339), congestive heart failure (HR, 1.232), coronary artery disease (HR, 1.326), cerebral vascular accident (HR, 1.312), intracranial hemorrhage (HR, 6.765), gastrointestinal bleeding (HR, 1.396), and liver cirrhosis (HR, 2.027), independently increased postoperative mortality risk in dialysis patients. Of the comorbidities, intracranial hemorrhage posed the greatest risk.Patient demographics, anesthesia factors, and comorbidities help dialysis patients understand their postoperative mortality. These potential risk factors also inform anesthesiologists and surgeons weight perioperative conditions in dialysis patients before surgery.

Hyperthermia is one therapeutic tool for damaging and killing cancer cells, with minimal injury to normal tissues. However, its cytotoxic effects alone are insufficient for quantitative cancer cell death. To overcome this limitation, several studies have explored non-toxic enhancers for hyperthermia-induced cell death. Capsaicin may be applicable as a therapeutic tool against various types of cancer. In the present study, we employed nonivamide, a less-pungent capsaicin analogue, to investigate its possible enhancing effects on hyperthermia-induced apoptosis; moreover, we analyzed its molecular mechanism. Treatment of U937 cells at 44 °C for 15 min, combined with nonivamide 50 μM, revealed enhancement of apoptosis. Significant increases in reactive oxygen species generation, mitochondrial dysfunction, and cleaved caspase-3 were observed during the combined treatment; these were accompanied by an increase in pro-apoptotic Bcl-2 family proteins and a decrease in anti-apoptotic Bcl-2 proteins. In addition, significant increases in p-JNK and p-p38 were detected, following the combined treatment. In conclusion, nonivamide enhanced hyperthermia-induced apoptosis via a mitochondrial-caspase dependent pathway. The underlying mechanism may include elevation of intracellular reactive oxygen species, mitochondrial dysfunction, and increased activation of JNK and p38.

Melatonin, a safe endogenous hormone and a natural supplement, has recently been recognized to have antiproliferative effects and the ability to sensitize cells to other anticancer therapies. Phenylarsine oxide (PAO) has anticancer potential but it is considered as a toxic agent. In this study we combined melatonin to reduce the toxicity while securing the anti-cancer effects of PAO. Cell viability was determined by MTT assay, whereas cytotoxic assays were performed using an LDH cytotoxicity assay kit. Cell cycle analysis, Annexin V/PI staining, the mitochondrial membrane potential (MMP), mitochondrial calcium and reactive oxygen species (ROS) generation were analyzed using flow cytometry. Sytox stained cells were visualized by fluorescence microscopy and the expression of proteins was detected by western blotting. Melatonin increased the anticancer potential of PAO by decreasing the cell viability and increasing LDH release in various cancer cells. The mode of cell death was determined to be typical apoptosis, as evidenced by Annexin V/PI-stained cells, PARP cleavage, and caspase-3 activation, and with significant modulations in the expression of proapoptotic, antiapoptotic and cell cycle-related proteins. ROS generation played a critical role in induction of cell death by this combined treatment, which is validated by reversal of cytotoxicity upon cotreatment with NAC. Furthermore, the activation of MAPKs, especially JNK, contributed to the induction of cell death, accompanied by endoplasmic reticulum stress and autophagy, affirmed by the abrogation of cytotoxicity after JNK-IN-8 and TUDCA application. Melatonin showed promising potential as a chemotherapeutic agent in combination with PAO to achieve a better anticancer response.

Recent research suggests that melatonin (Mel), an endogenous hormone and natural supplement, possesses anti-proliferative effects and can sensitise cells to anti-cancer therapies. Although shikonin (SHK) also possesses potential anti-cancer properties, the poor solubility and severe systemic toxicity of this compound hinders its clinical usage. In this study, we combined Mel and SHK, a potentially promising chemotherapeutic drug combination, with the aim of reducing the toxicity of SHK and enhancing the overall anti-cancer effects. We demonstrate for the first time that Mel potentiates the cytotoxic effects of SHK on cancer cells by inducing oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Particularly, Mel-SHK treatment induced oxidative stress, increased mitochondrial calcium accumulation and reduced the mitochondrial membrane potential in various cancer cells, leading to apoptosis. This drug combination also promoted endoplasmic reticulum (ER) stress, leading to AKT dephosphorylation. In HeLa cells, Mel-SHK treatment reduced SIRT3/SOD2 expression and SOD2 activity, while SIRT3 overexpression dramatically reduced Mel-SHK-induced oxidative stress, ER stress, mitochondrial dysfunction and apoptosis. Hence, we propose the combination of Mel and SHK as a novel candidate chemotherapeutic regimen that targets the SIRT3/SOD2-AKT pathway in cancer., Highlights • Melatonin (Mel) greatly sensitises cancer cells to toxic effect of shikonin (SHK). • SIRT3/SOD2-AKT induced-excessive oxidative stress is the key node in Mel-SHK therapy. • ER stress and mitochondrial dysfunction is also associated in the cell death. • Mel-SHK is a novel candidate for advanced chemotherapeutic regimen.

Dihydromyricetin (DMY) is a traditional herbal medicine, with a wide range of biological activities. Extreme hyperthermia (HT) can suppress the immune system; thus, protection of the immune system is beneficial in heat-related diseases, including heatstroke. In our study, we revealed the protective effect of DMY against HT-induced apoptosis and analysed the underlying molecular mechanisms. We incubated human myelomonocytic lymphoma U937 cells at 44 °C for 30 min with or without DMY and followed by further incubation for 6 h at 37 °C. Cell viability was determined by the CCK-8 assay. DMY did not cause any cytotoxic effects in U937 cells even at high doses. HT treatment alone induced significant apoptosis, which was detected by DNA fragmentation and Annexin V/PI double staining. Mitochondrial dysfunction was identified by loss of mitochondrial membrane potential (MMP) during heat stimulation. Apoptotic related proteins were involved, truncated Bid and caspase-3 were upregulated, and Mcl-1 and XIAP were downregulated. We also identified the related signalling pathways, such as the MAPK and PI3K/AKT pathways. However, changes in HT were dramatically reversed when the cells were pretreated with DMY before exposure to HT. Overall, MAPKs and PI3K/AKT signalling, mitochondrial dysfunction, and caspase-mediated pathways were involved in the protective effect of DMY against HT-induced apoptosis in U937 cells, which was totally reversed by DMY pretreatment. These findings indicate a new clinical therapeutic strategy for the protection of immune cells during heatstroke.

Chemoresistance is one of the major obstacles in chemotherapy-based hepatocellular carcinoma (HCC) intervention. Aluminum (Al) is an environmental pollutant that plays a vital role in carcinogenesis, tumorigenesis, and metastasis. However, the effect of Al on chemoresistance remains unknown. 5-Fluorouracil (5-FU) is a widely used antitumor drug. Therefore, we investigated the effects of aluminum chloride (AlCl3 ) on the chemoresistance of HepG2 cells to 5-FU and explored the underlying mechanisms of these effects. The results demonstrated that AlCl3 pretreatment attenuated 5-FU-induced apoptosis through Erk activation and reversed 5-FU-induced cell cycle arrest by downregulating p-Chk2Thr68 levels. In addition, AlCl3 markedly increased the levels of proteins associated with cell migration, such as MMP-2 and MMP-9. Further investigation demonstrated that an Erk inhibitor (U0126) reversed the AlCl3 -induced decrease in apoptosis, enhancement of cell cycle progression, promotion of cell migration, and attenuation of oxidative stress. In summary, AlCl3 induced chemoresistance to 5-FU in HepG2 cells. The present study suggests a potential influence of AlCl3 on 5-FU therapy. These findings may help others to understand and properly address the resistance of HCC to chemotherapeutic agents.

BACKGROUND Hyperthermia (HT) has been used widely for cancer therapy, and the development of modern devices has made it more efficient. Shikonin (SHK) is a natural naphthoquinone derivative from a Chinese herb. Although the anticancer properties of SHK are evident, the underlying molecular mechanisms are not fully understood. OBJECTIVE In this study, the effects of combining low doses of SHK with mild HT were investigated in the U937 cell line. METHODS The cells were subjected to HT at 44°C for 10 min with or without SHK pretreatment, and parameters reflecting apoptosis, ROS generation and intracellular calcium elevation were evaluated by using DNA fragmentation, flow cytometry, and western blot analyses. RESULTS SHK 0.5 µM significantly enhanced HT-induced apoptosis as indicated by DNA fragmentation and caspase-3 activation with increased generation of ROS and elevation of intracellular calcium. The combined treatment also synergistically activated proapoptotic proteins and inactivated anti-apoptotic proteins. Furthermore, the phosphorylation of JNK and PKC- δ and the dephosphorylation of ERK and AKT were the upstream effects that may have compounded the induction of apoptosis. The modulatory effects of HT and SHK were abrogated with the employment of NAC and JNK-IN-8 by inactivating the MAPK pathway and cleavage of caspase-3. Intracellular calcium was also elevated and was found to be responsible for the induction of cell death evident by the DNA fragmentation with or without the employment of BAPTA-AM. CONCLUSION Conclusively, this study provides persuasive evidence that SHK in combination with HT is a propitious therapeutic way for augmentation of apoptosis and hence suggest a novel strategy for treating cancers.

Background/Aims: Hyperthermia is a widely used therapeutic tool for cancer therapy and a well-known inducer of apoptosis. Although the flavonoid compound baicalin (BCN) is a potent anticancer agent for several human carcinomas, it is less potent in the human U937 myelomonocytic leukemia cell line. To explore any enhancing effects of BCN on hyperthermia-induced apoptosis, this study investigated the combined effects and apoptotic mechanisms of hyperthermia and BCN in U937 cells. Methods: U937 cells were heat treated at 44ºC for 12 min with or without pre-treatment with BCN (10-50 µM) and then incubated for 6 h at 37 ºC with 5% CO2 and 95% air. Cell viability was analyzed by Trypan blue exclusion assay. Apoptosis was examined by DNA fragmentation, fluorescence microscopy and flow cytometry. Generation of mitochondrial trans-membrane potential (MMP), mitochondrial calcium, and reactive oxygen species (ROS) was also detected by flow cytometry. The expression of proteins related to apoptosis and signaling pathways was determined by western blotting. Results: Hyperthermia alone did not reduce cell viability or induce notable levels of apoptosis, but combined hyperthermia and BCN treatment markedly augmented apoptosis by upregulating proapoptotic proteins and suppressing antiapoptotic proteins, culminating in caspase-3 activation. Mitochondrial transmembrane potential was significantly decreased, and generation of reactive oxygen species (ROS) and suppression of antioxidant enzymes were marked. Furthermore, with the combined treatment, the phosphorylated forms of JNK and p38 showed increased expression, whereas AKT was dephosphorylated. JNK-IN-8 (a JNK inhibitor) and NAC (a ROS scavenger) abrogated the apoptotic effects of the combined treatment, significantly protecting the cells and indicating the involvement of high ROS generation and the MAPK pathway in the underlying molecular mechanism. Conclusion: This study provides compelling evidence that hyperthermia, in combination with BCN, is a promising therapeutic strategy for enhancement of apoptosis and suggest a promising therapeutic approach for cancer.

Fenvalerate (Fen), a synthetic pyrethroid insecticide, is widely used in agricultural, domestic and veterinary applications. Fen induces abnormal cell proliferation and apoptosis, which are linked to its hazardous effects. However, this view is controversial and the underlying molecular mechanisms remain elusive. In the present study, the effects of Fen on cadmium (Cd)-induced apoptosis and the associated molecular mechanisms were investigated in human myeloid leukemia U937 cells. U937 cells were treated with 50 μm cadmium chloride (CdCl2 ) with or without Fen pretreatment at 1-50 μm. Apoptosis was evaluated by externalization of phosphatidylserine on the plasma membrane. The expression levels of apoptosis-related proteins, including Bcl-2 family members were determined by western blot analysis. The results revealed that pretreatment with Fen at 20 μm for 12 hours significantly inhibited Cd-induced apoptosis. Decreased expression of pro-apoptotic Bcl-2 family proteins (Noxa and Bid) and increased expression of anti-apoptotic proteins (Bcl-xL, Mcl-1 and XIAP) were observed after combined treatment with Fen and CdCl2 . Phosphorylation of ERK and AKT was increased, while phosphorylation of JNK was decreased by the combined treatment, compared with CdCl2 treatment alone. In conclusion, Fen decreased apoptotic sensitivity induced by Cd in U937 cells. This effect was associated with activation of ERK and AKT, suppression of JNK and changes in expression of Bcl-2 family proteins and XIAP. The present findings suggest a potential influence of Fen on Cd toxicity via suppression of apoptosis. Fen decreased apoptotic sensitivity induced by Cd, and thus it may contribute carcinogenic risk and influence on cancer therapy.

BACKGROUND: The safety and health benefits of Tai Chi mind-body exercise has been documented in a large number of clinical studies focused on specific diseases and health conditions. The objective of this systematic review is to more comprehensively summarize the evidence base of clinical studies of Tai Chi for healthcare. METHODS AND FINDINGS: We searched for all types of clinical studies on Tai chi in PubMed, the Cochrane Library and four major Chinese electronic databases from their inception to July 2013. Data were analyzed using SPSS17.0 software. A total of 507 studies published between 1958 and 2013 were identified, including 43 (8.3%) systematic reviews of clinical studies, 255 (50.3%) randomized clinical trials, 90 (17.8%) non-randomized controlled clinical studies, 115 (22.7%) case series and 4 (0.8%) case reports. The top 10 diseases/conditions was hypertension, diabetes, osteoarthritis, osteoporosis or osteopenia, breast cancer, heart failure, chronic obstructive pulmonary disease, coronary heart disease, schizophrenia, and depression. Many healthy participants practiced Tai Chi for the purpose of health promotion or preservation. Yang style Tai Chi was the most popular, and Tai Chi was frequently practiced two to three 1-hour sessions per week for 12 weeks. Tai Chi was used alone in more than half of the studies (58.6%), while in other studies Tai Chi was applied in combination with other therapies including medications, health education and other physical therapies. The majority of studies (94.1%) reported positive effects of Tai Chi, 5.1% studies reported uncertain effects and 0.8% studies reported negative effects. No serious adverse events related to Tai Chi were reported. CONCLUSIONS: The quantity and evidence base of clinical studies on Tai Chi is substantial. However, there is a wide variation in Tai Chi intervention studied and the reporting of Tai Chi intervention needs to be improved. Further well-designed and reported studies are recommended to confirm the effects of Tai Chi for the frequently reported diseases/conditions.

To study the difference of plasma actual bicarbonate between the children with growth hormone deficiency (GHD) and idopathatic short stature (ISS) and to value the plasma bicarbonate standard deviation scores (SDS) in diagnosis of GHD.Forty-seven short stature children were divided into two groups (GHD and ISS) according to the peak GH response to provocative test. Plasma actual bicarbonate concentrations anion gap (AG), base excess and electrolytes were measured in 47 children with short stature before GH provocative tests.The mean plasma actual bicarbonate concentrations, bicarbonate SDS were (22.60+/-1.29)mmol/L and -0.27+/-0.98 respectively in GHD children, which were significantly lower than those of ISS children (P0.01), whereas AG was higher than that of ISS children [(11.73+/-4.52 vs 7.87+/-1.70) mmol/L], P0.01. Seventy-two percent of patients with bicarbonate SDSor=1 s were diagnosed as GHD.Plasma actual bicarbonate concentrations and bicarbonate SDS are lower in patients with GHD than those in patients with idopathatic short stature. Evaluation of plasma bicarbonate SDS of short stature children can predict the probability of GHD, especially when bicarbonate SDS is less than 1 s.