Mandatory monthly outpatient visits could improve therapeutic inertia in patients with poorly controlled type 2 diabetes.

AIMS/INTRODUCTION: Delayed intensification of treatment, or therapeutic inertia, increases the risk of diabetic complications and death. The aim of this study was to determine the effect of mandatory monthly outpatient visits on therapeutic inertia in patients with suboptimal control of type 2 diabetes. MATERIALS AND METHODS: This retrospective cohort study used data from the Chang Gung Research Database and defined two study periods: the baseline period and the intervention period. The intervention period began when the Kaohsiung branch initiated a mandatory monthly outpatient visits program. Type 2 diabetes patients with baseline glycated hemoglobin (HbA1c) >7% and a follow-up HbA1c measurement were enrolled in each period, and divided into a Kaohsiung branch (intervention) group and the other branches (control) group. Therapy intensification was evaluated by comparing prescriptions after the follow-up HbA1c measurement with the prescriptions after the baseline HbA1c measurement. RESULTS: A total of 5,045 patients at the Kaohsiung branch and 13,400 participants at other branches were enrolled in the baseline period; and 5,573 and 15,603 patients, respectively, were enrolled in the intervention period. The adjusted odds ratio (AOR) for therapy intensification in patients with baseline HbA1c ≥9% was not significantly higher at 1.21 (95% CI, 1.00-1.47) in the intervention period at the Kaohsiung branch, but was significantly higher (AOR, 1.53; 95% CI, 1.02-2.30) in the subgroup with worsened HbA1c. CONCLUSIONS: Mandatory monthly outpatient visits could improve therapeutic inertia in patients with poorly controlled type 2 diabetes, especially in those with worsened control. The trajectory of HbA1c could significantly influence the assessment of the prevalence of therapeutic inertia.

The anti-SARS-CoV-2 effect and mechanism of Chiehyuan herbal oral protection solution.

The Chiehyuan herbal oral protection solution (GB-2) is a herbal mixture commonly utilized in Taiwan for combating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as per traditional Chinese medicine practices. This study assessed the clinical impact of GB-2 through prospective clinical trials. With twice-daily use for a week, GB-2 was shown to diminish the expression of angiotensin-converting enzyme 2 (ACE2) in oral mucosal cells. Moreover, after two weeks of use, it could reduce transmembrane protease, serine 2 (TMRPSS2) expression in these cells. Additionally, in vitro experiments demonstrated that GB-2 lessened the entry efficiency of the Omicron, L452R-D614G, T478K-D614G, and L452R-T478K-D614G variants of the SARS-CoV-2 pseudotyped lentivirus. It also impeded the interaction between ACE2 and the receptor-binding domain (RBD) presenting N501Y-K417N-E484A-G339D-Q493R-G496S-Q498R and L452R-T478K mutations. Glycyrrhizic acid, a major compound in GB-2, also hindered the entry of the Omicron variant (BA.1) of the SARS-CoV-2 pseudotyped lentivirus by obstructing the binding between ACE2 and the RBD presenting the N501Y-K417N-E484A-G339D-Q493R-G496S-Q498R mutation. To sum up, these findings suggest that GB-2 can decrease ACE2 and TMPRSS2 expression in oral mucosal cells. Both glycyrrhizic acid and GB-2 were found to reduce the entry efficiency of the Omicron variant (BA.1) of the SARS-CoV-2 pseudotyped lentivirus and block the binding between ACE2 and the RBD with the N501Y-K417N-E484A-G339D-Q493R-G496S-Q498R mutation. This evidence implies that GB-2 might be a potential candidate for further study as a preventative measure against SARS-CoV-2 infection.

Use of Traditional Chinese Medicine May Delay the Need for Insulin Treatment in Patients with Type 2 Diabetes: A Population-Based Cohort Study.

Objectives: Traditional Chinese medicine (TCM) has been shown to reduce insulin resistance and improve beta cell function in previous studies. The aim of this study was to assess whether the use of TCM can delay the need for insulin therapy in patients with type 2 diabetes. Design: Data on patients with type 2 diabetes who received medical treatment for the first time between 2000 and 2003 were obtained from National Health Insurance Research Database (NHIRD) in Taiwan. Among these patients, those with a cumulative use of TCM of more than 28 days were defined as TCM users, and the others as non-users. Kaplan-Meier analysis was used to evaluate the cumulative risk of initiating insulin therapy. Cox proportional hazards models with and without competing risk events were used to evaluate the association between the use of TCM and insulin therapy. Settings/Location: Data were obtained from National Health Insurance Research Database (NHIRD) in Taiwan. Subjects: Patients with type 2 diabetes who received medical treatment for the first time between 2000 and 2003. Interventions: Among these patients, those with a cumulative use of TCM of more than 28 days were defined as TCM users, and the others as non-users. Outcome measures: After 1:1 propensity score matching, both groups were tracked until the initiation of insulin therapy, death, or the end of 2013. Results: We identified 6524 TCM users and 6524 non-users. The TCM users had a significantly lower risk of insulin initiation in a dose-dependent manner (log-rank test p < 0.001). This effect was consistent across subgroups with different severities of diabetes, and remained significant in competing risk analysis (for TCM users with 28 to 83 days cumulative use, HR 0.78 [0.70-0.87], p < 0.0001; for TCM users with ≥ 84 days cumulative use, HR 0.47 [0.42-0.53], p < 0.0001). Conclusions: The use of TCM in addition to standard diabetes treatment may delay the need for insulin treatment in patients who received medical treatment for type 2 diabetes for the first time. This benefit was strongly dose-dependent and applicable in patients with different severities of diabetes.

Statin Use Improves Overall Survival of Patients with Gastric Cancer after Surgery and Adjuvant Chemotherapy in Taiwan: A Nationwide Matched Cohort Study.

Background: Numerous studies have revealed that statins have antitumor effects in vivo and in vitro. However, few studies have explored the relationship between statin use and the mortality of gastric cancer (GC) patients after treatments. This study examines the relationship between statin use and the overall survival (OS) of GC patients after surgery and adjuvant chemotherapy, using data from the nationwide cohort database of Taiwan. Methods: All patients newly diagnosed with GC from 1999 to 2008 in Taiwan were identified from the Registry of Catastrophic Illness Patients Database. Through propensity score matching, statin users were matched to statin non-users at a 1:4 ratio. The relationship between statin use and the OS of patients with GC was estimated through Cox regression models. Results: The study cohort included 1835 patients with GC who had received therapies during the study period. The death numbers among statin users (defined as those who used more than 28 cumulative defined daily doses (cDDDs)) and statin non-users were 138 and 895, respectively. A dose-response association was noted between statin use and the OS of patients with GC after treatments. The adjusted hazard ratios were 0.62 (95% confidence intervals (CI), 0.50-0.78) and 0.34 (95% CI, 0.26-0.45) for statin users administered 28-167 cDDDs and >168 cDDDs, respectively, compared with no statin use (<28 cDDDs). Conclusions: This study highlights that statin use may dose-dependently improve the OS of patients with GC after surgery and adjuvant chemotherapy in Taiwan. Additional studies are required to confirm the efficacy and safety of statin use.

Danshen Improves Survival of Patients With Breast Cancer and Dihydroisotanshinone I Induces Ferroptosis and Apoptosis of Breast Cancer Cells.

Danshen (salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. However, it is definite clinical effort and mechanism on breast cancer is unclear. In our study, we used the real-world database to investigate in vivo protective effort of danshen in the breast cancer patients through using population-based data from the Taiwan National Health Insurance Research Database (NHIRD). In vitro, human breast cancer cells (MCF-7 cells and MDA-MB-231 cells) were used to investigate the effect and the underlying mechanism through XTT assay, flow cytometry, glutathione peroxidase (GPX) activity assay, GSH (reduced glutathione)/GSSG (oxidized glutathione), malondialdehyde (MDA), and western blot analysis. The in vivo effect was investigated through a xenograft nude mouse model. We found that dihydroisotanshinone I (DT), a pure compound present in danshen, can inhibit the growth of breast carcinoma cells, including MCF-7 cells and MDA-MB-231 cells. Moreover, DT induced apoptosis and ferroptosis in these breast cancer cells. DT also repressed the protein expression of GPX4 (Glutathione peroxidase 4). For in vivo study, DT treatment also significantly inhibited the final tumor volume without adverse effects in a xenograft nude mouse model. In conclusion, danshen has protective efforts in breast cancer patients, which could be attributed to DT through inducing apoptosis and ferroptosis of breast cancer cells.

Very low-density lipoprotein (VLDL)-induced signals mediating aldosterone production.

Aldosterone, secreted by the adrenal zona glomerulosa, enhances sodium retention, thus increasing blood volume and pressure. Excessive production of aldosterone results in high blood pressure and contributes to cardiovascular and renal disease, stroke and visual loss. Hypertension is also associated with obesity, which is correlated with other serious health risks as well. Although weight gain is associated with increased blood pressure, the mechanism by which excess fat deposits increase blood pressure remains unclear. Several studies have suggested that aldosterone levels are elevated with obesity and may represent a link between obesity and hypertension. In addition to hypertension, obese patients typically have dyslipidemia, including elevated serum levels of very low-density lipoprotein (VLDL). VLDL, which functions to transport triglycerides from the liver to peripheral tissues, has been demonstrated to stimulate aldosterone production. Recent studies suggest that the signaling pathways activated by VLDL are similar to those utilized by AngII. Thus, VLDL increases cytosolic calcium levels and stimulates phospholipase D (PLD) activity to result in the induction of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression. These effects seem to be mediated by the ability of VLDL to increase the phosphorylation (activation) of their regulatory transcription factors, such as the cAMP response element-binding (CREB) protein family of transcription factors. Thus, research into the pathways by which VLDL stimulates aldosterone production may identify novel targets for the development of therapies for the treatment of hypertension, particularly those associated with obesity, and other aldosterone-modulated pathologies.

VLDL-activated cell signaling pathways that stimulate adrenal cell aldosterone production.

Aldosterone plays an important role in regulating ion and fluid homeostasis and thus blood pressure, and hyperaldosteronism results in hypertension. Hypertension is also observed with obesity, which is associated with additional health risks, including cardiovascular disease. Obese individuals have high serum levels of very low-density lipoprotein (VLDL), which has been shown to stimulate aldosterone production; however, the mechanisms underlying VLDL-induced aldosterone production are still unclear. Here we demonstrate in human adrenocortical carcinoma (HAC15) cells that submaximal concentrations of angiotensin II and VLDL stimulate aldosterone production in an additive fashion, suggesting the possibility of common mechanisms of action. We show using inhibitors that VLDL-induced aldosterone production is mediated by the PLC/IP3/PKC signaling pathway. Our results suggest that PKC is upstream of the extracellular signal-regulated kinase (ERK) activation previously observed with VLDL. An understanding of the mechanisms mediating VLDL-induced aldosterone production may provide insights into therapies to treat obesity-associated hypertension.

Aquaporin-3 re-expression induces differentiation in a phospholipase D2-dependent manner in aquaporin-3-knockout mouse keratinocytes.

Aquaporin-3 (AQP3) is a water and glycerol channel expressed in epidermal keratinocytes. Despite many studies, controversy remains about the role of AQP3 in keratinocyte differentiation. Previously, our laboratory has shown co-localization of AQP3 and phospholipase D2 (PLD2) in caveolin-rich membrane microdomains. We hypothesized that AQP3 transports glycerol and "funnels" this primary alcohol to PLD2 to form a pro-differentiative signal, such that the action of AQP3 to induce differentiation should require PLD2. To test this idea, we re-expressed AQP3 in mouse keratinocytes derived from AQP3-knockout mice. The re-expression of AQP3, which increased [3H]glycerol uptake, also induced mRNA and protein expression of epidermal differentiation markers such as keratin 1, keratin 10, and loricrin, with or without the induction of differentiation by an elevated extracellular calcium concentration. Re-expression of AQP3 had no effect on the expression of the proliferation markers keratin 5 and cyclin D1. Furthermore, a selective inhibitor of PLD2, CAY10594, and a lipase-dead (LD) PLD2 mutant, but not a LD PLD1 mutant, significantly inhibited AQP3 re-expression-induced differentiation marker expression with calcium elevation, suggesting a role for PLD2 in this process. Thus, our results indicate that AQP3 has a pro-differentiative role in epidermal keratinocytes and that PLD2 activity is necessary for this effect.

Determinants of the public intent to receive the seasonal influenza vaccine and protective behaviors: a population-based study in Taiwan.

BACKGROUND AND STUDY AIMS: this study aims to identify the determinants of perceived changes in protective behaviors against seasonal influenza and the intent to receive the seasonal influenza vaccine among Taiwanese in 2011. METHODS: During the early 2011-2012 influenza season, we conducted a nationwide survey with randomly stratified samples and collected 1400 self-reported questionnaires from respondents aged 15 years and above using the computer-aided telephone interviewing software in Taiwan. RESULTS: One-third of the respondents intended to receive the seasonal influenza vaccine. Knowledge of protective behaviors against influenza was the most common predictor of perceived changes in different protective behaviors and the intent to receive the seasonal influenza vaccine. Older respondents were significantly more inclined to perceive changes in protective behaviors than younger respondents (adjusted odds ratio [AOR] ranging from 1.7 to 2.5). Female respondents were significantly more likely to change their behavior in wearing a face mask (AOR=1.5; 95% CI, 1.09 to 2.07) and buying antimicrobial products (AOR=1.45; 95% CI, 1.09 to 1.92) compared with males. Furthermore, recipients of past H1N1 (AOR=4.45; 95% CI, 3.03 to 6.53) and seasonal influenza vaccines (AOR=6.1; 95% CI, 3.31 to 11.23) were more likely to obtain the seasonal influenza vaccine. In contrast, individuals aged 30-49 (AOR=0.53; 95% CI, 0.38 to 0.74) and females (AOR=0.65; 95% CI, 0.48 to 0.87) were significantly less likely to intend to receive the seasonal influenza vaccine. CONCLUSIONS: The findings suggest that the predictors of perceived changes in protective behaviors and intent to receive the seasonal influenza vaccine differ. We provide perspectives and suggestions for overcoming the perceived barriers and for developing targeted risk-communication campaigns.

The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells.

Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention.

Phospholipase D activity underlies very-low-density lipoprotein (VLDL)-induced aldosterone production in adrenal glomerulosa cells.

Aldosterone is the mineralocorticoid responsible for sodium retention, thus increased blood volume and pressure. Excessive production of aldosterone results in high blood pressure as well as renal disease, stroke, and visual loss via both direct effects and effects on blood pressure. Weight gain is often associated with increased blood pressure, but it remains unclear how obesity increases blood pressure. Obese patients typically have higher lipoprotein levels; moreover, some studies have suggested that aldosterone levels are also elevated and represent a link between obesity and hypertension. Very-low-density lipoprotein (VLDL) functions to transport triglycerides from the liver to peripheral tissues. Although previous studies have demonstrated that VLDL can stimulate aldosterone production, the mechanisms underlying this effect are largely unclear. Here we show for the first time that phospholipase D (PLD) is involved in VLDL-induced aldosterone production in both a human adrenocortical cell line (HAC15) and primary cultures of bovine zona glomerulosa cells. Our data also reveal that PLD mediates steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression via increasing the phosphorylation (activation) of their regulatory transcription factors. Finally, by using selective PLD inhibitors, our studies suggest that both PLD1 and PLD2 isoforms play an important role in VLDL-induced aldosterone production.

A role for phospholipase D in angiotensin II-induced protein kinase D activation in adrenal glomerulosa cell models.

The mineralocorticoid aldosterone plays an important role in regulating blood pressure, with excess causing hypertension and exacerbating cardiovascular disease. Previous studies have indicated a role for both phospholipase D (PLD) and protein kinase D (PKD) in angiotensin II (AngII)-regulated aldosterone production in adrenal glomerulosa cells. Therefore, the relationship between AngII-activated PLD and PKD was determined in two glomerulosa cell models, primary bovine zona glomerulosa (ZG) and HAC15 human adrenocortical carcinoma cells, using two inhibitors, 1-butanol and the reported PLD inhibitor, fluoro-2-indolyl des-chlorohalopemide (FIPI). FIPI was first confirmed to decrease PLD activation in response to AngII in the two glomerulosa cell models. Subsequently, it was shown that both 1-butanol and FIPI inhibited AngII-elicited PKD activation and aldosterone production. These results indicate that PKD is downstream of PLD and suggest that PKD is one of the mechanisms through which PLD promotes aldosterone production in response to AngII in adrenal glomerulosa cells.

IGF-1 induction by acylated steryl ß-glucosides found in a pre-germinated brown rice diet reduces oxidative stress in streptozotocin-induced diabetes.

BACKGROUND: The pathology of diabetic neuropathy involves oxidative stress on pancreatic ß-cells, and is related to decreased levels of Insulin-like growth factor 1 (IGF-1). Acylated steryl ß-glucoside (PR-ASG) found in pre-germiated brown rice is a bioactive substance exhibiting properties that enhance activity of homocysteine-thiolactonase (HTase), reducing oxidative stress in diabetic neuropathy. The biological importance of PR-ASG in pancreatic ß-cells remains unknown. Here we examined the effects of PR-ASG on IGF-1 and glucose metabolism in ß-cells exposed to oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, a pre-germinated brown rice (PR)-diet was tested in streptozotocin (STZ)-induced diabetic rats. Compared with diabetic rats fed control diets, the PR-diet fed rats showed an improvement of serum metabolic and neurophysiological parameters. In addition, IGF-1 levels were found to be increased in the serum, liver, and pancreas of diabetic rats fed the PR-diet. The increased IGF-1 level in the pancreas led us to hypothesize that PR-ASG is protective for islet ß-cells against the extensive injury of advanced or severe diabetes. Thus we examined PR-ASG to determine whether it showed anti-apoptotic, pro-proliferative effects on the insulin-secreting ß-cells line, INS-1; and additionally, whether PR-ASG stimulated IGF-1 autocrine secretion/IGF-1-dependent glucose metabolism. We have demonstrated for the first time that PR-ASG increases IGF-1 production and secretion from pancreatic ß-cells. CONCLUSION/SIGNIFICANCE: These findings suggest that PR-ASG may affect pancreatic ß-cells through the activation of an IGF-1-dependent mechanism in the diabetic condition. Thus, intake of pre-germinated brown rice may have a beneficial effect in the treatment of diabetes, in particular diabetic neuropathy.

Quality of sleep and quality of life in caregivers of breast cancer patient.

BACKGROUND: Sleep is an important issue for cancer patients and caregivers and poor sleep quality may have deleterious effects on health. This study will examine the correlation between sleep quality and quality of life of breast cancer caregivers. METHOD: A cross-sectional and correlational design was used to explore the relationship between sleep quality and the quality of life of caregivers. Sixty-one participants were identified by invasive early breast cancer patients, who were diagnosed within the period of 18-month period, as their primary caregivers. The World Health Organization Questionnaire on Quality of Life: BREF-Taiwan version (WHOQOL-BREF-TAIWAN) and the Chinese Pittsburgh Sleep Quality Index (CPSQI) were used to measure the quality of life and sleep quality of caregivers, respectively. RESULT: Eighty-nine percent of caregivers from this study reported possible sleep difficulties. The scores of CPSQI scores were negatively correlated with the score of every domain of the WHOQOL-BREF-TAIWAN. DISCUSSION: The results suggest that sleep quality may have an impact on several aspects of the quality of life of caregivers. Understanding the correlation between sleep quality and the quality of life of caregivers may assist health professionals in enhancing the sleep quality of caregivers and their ability to care for patients and themselves.