Surface Expression of Kynurenine 3-Monooxygenase Promotes Proliferation and Metastasis in Triple-Negative Breast Cancers.

Kynurenine 3-monooxygenase (KMO) is the pivotal enzyme in the kynurenine pathway and is located on the mitochondrial outer membrane. The dysregulation of KMO leads to various neurodegenerative diseases; however, it is rarely mentioned in cancer progression. Our previous study showed that KMO overexpression in canine mammary gland tumors (cMGT) is associated with poor prognosis in cMGT patients. Surprisingly, it was also found that KMO can be located on the cell membranes of cMGT cells, unlike its location in normal cells, where KMO is expressed only within the cytosol. Since cMGT and human breast cancer share similar morphologies and pathogenesis, this study investigated the possibility of detecting surface KMO in human breast cancers and the role of surface KMO in tumorigenesis. Using immunohistochemistry (IHC), flow cytometry (FC), immunofluorescence assay (IFA), and transmission electron microscopy (TEM), we demonstrated that KMO can be aberrantly and highly expressed on the cell membranes of breast cancer tissues and in an array of cell lines. Masking surface KMO with anti-KMO antibody reduced the cell viability and inhibited the migration and invasion of the triple-negative breast cancer cell line, MDA-MB-231. These results indicated that aberrant surface expression of KMO may be a potential therapeutic target for human breast cancers.

Recommendations for treating stage I-III periodontitis in the Taiwanese population: A consensus report from the Taiwan Academy of Periodontology.

BACKGROUND/PURPOSE: Based on the fundamental of the S3-level clinical practice guideline (CPG) for treating stage I-III periodontitis developed by the European Federation of Periodontology (EFP), this consensus report aimed to develop treatment recommendations for treating periodontitis in the Taiwanese population. METHODS: The report was constructed by experts from the Taiwan Academy of Periodontology. The following topics were reviewed: (a) the prevalence of periodontitis in Asia and current status of treatment in Taiwan; (b) specific anatomical considerations for treating periodontitis in Asians; (d) educational and preventive interventions and supragingival plaque control; (d) subgingival instrumentation and adjunctive treatment; (e) surgical periodontal therapy; and (f) maintenance and supportive periodontal care. Recommendations were made according to the evidences from the EFP CPG, the published literature and clinical studies in Asians, and the expert opinions. RESULTS: The treatment recommendations for the Taiwanese population were generally in parallel with the EFP CPG, and extra cautions during treatment and maintenance phases were advised due to the anatomical variations, such as shorter root trunk, higher prevalence of supernumerary distolingual root and lingual bony concavity in mandibular posteriors, and thinner anterior labial plate, of the Asian population. CONCLUSION: The EFP CPG could be adopted for treating periodontitis and maintaining periodontal health of the Taiwanese population, and anatomical variations should be cautious when the treatment is delivered.

Hypoglycaemic episodes increase the risk of ventricular arrhythmia and sudden cardiac arrest in patients with type 2 diabetes-A nationwide cohort study.

BACKGROUND: The impact of hypoglycaemic episode (HE) on the risk of ventricular arrhythmia (VA) and sudden cardiac arrest (SCA) remains unclear. We hypothesized that HE increases the risk of both VA and SCA and that glucose-lowering agents causing HE also increase the risk of VA/SCA in patients with type 2 diabetes (T2D). METHODS: Patients aged 20 years or older with newly diagnosed T2D were identified using the Taiwan National Health Insurance Database. HE was defined as the presentation of hypoglycaemic coma or specified/unspecified hypoglycaemia. The control group consisted of T2D patients without HE. The primary outcome was the occurrence of VA (including ventricular tachycardia and fibrillation) and SCA during the defined follow-up periods. A multivariate Cox hazards regression model was used to evaluate the hazard ratio (HR) for VA or SCA. RESULTS: A total of 54 303 patients were screened, with 1037 patients with HE assigned to the HE group and 4148 frequency-matched patients without HE constituting the control group. During a mean follow-up period of 3.3 ± 2.5 years, 29 VA/SCA events occurred. Compared with the control group, HE group had a higher incidence of VA/SCA (adjusted HR: 2.42, P = .04). Patients who had used insulin for glycaemic control showed an increased risk of VA/SCA compared with patients who did not receive insulin (adjusted HR: 3.05, P = .01). CONCLUSIONS: The HEs in patients with T2D increased the risk of VA/SCA, compared with those who did not experience HEs. Use of insulin also independently increased the risk of VA/SCA.

Evaluation of the protective effects of chondroitin sulfate oligosaccharide against osteoarthritis via inactivation of NLRP3 inflammasome by in vivo and in vitro studies.

Osteoarthritis (OA) is the most prevalent degenerative arthritis disease linked to aging, obesity, diet, and accumulation of octacalcium phosphate (OCP) crystals in joints. Current research has focused on inflammation and chondrocytes apoptosis as underlying OA mechanisms. Inflammatory cytokines like IL-1ß activate matrix metalloproteinase-13 (MMP-13) and aggrecanase (the member of A Disintegrin and Metalloproteinase with Thrombospondin motifs family, ADAMTS), leading to cartilage matrix degradation. The NLRP3 inflammasome also contributes to OA pathogenesis by maturing IL-1ß. Natural products like chondroitin sulfate oligosaccharides (oligo-CS) show promise in OA treatment by inhibiting inflammation. Our study evaluates the protective effects of oligo-CS against OA by targeting NLRP3 inflammation. Stimulating human SW1353 chondrocytes and human mononuclear macrophage THP-1 cells with OCP showed increased NLRP3 inflammation initiation, NF-κB pathway activation, and the production of inflammatory cytokines (IL-1ß, IL-6) and the metabolic index (MMP-13, ADAMTS-5), leading to cartilage matrix degradation. However, oligo-CS treatment significantly reduced inflammation. In a 28-day in vivo study with C57BL/6 female mice, OCP was injected into their right knee and oligo-CS was orally administered. The OCP group exhibited significant joint space narrowing and chondrocyte loss, while the oligo-CS group maintained cartilage integrity. Oligo-CS groups also regulated gut microbiota composition to a healthier state. Taken together, our findings suggest that oligo-CS can be considered as a protective compound against OA.

Alleviation of Hyperuricemia by Strictinin in AML12 Mouse Hepatocytes Treated with Xanthine and in Mice Treated with Potassium Oxonate.

Hyperuricemia, an abnormally high level of blood uric acid, is a major risk factor for gout. Although xanthine oxidase inhibitors were clinically used to lower blood uric acid level, the concerned side effects restricted their utilization. In this study, strictinin, an abundant polyphenol in Pu'er tea, was evaluated for its preventive effects on hyperuricemia. The results showed that the xanthine oxidase activity, uric acid production, and inflammation in AML12 mouse hepatocytes treated with xanthine were significantly reduced by the supplementation of strictinin. Detailed analyses revealed that strictinin inhibited xanthine-induced NLRP3 inflammasome activation. Consistently, the elevated blood uric acid level and the enhanced xanthine oxidase activity in mice treated with potassium oxonate were effectively diminished by strictinin supplementation. Moreover, for the first time, strictinin was found to promote healthy gut microbiota. Overall, strictinin possesses a great potential to be utilized as a functional ingredient for the prevention of hyperuricemia.

The Lysosome in Malignant Melanoma: Biology, Function and Therapeutic Applications.

Lysosomes are membrane-bound vesicles that play roles in the degradation and recycling of cellular waste and homeostasis maintenance within cells. False alterations of lysosomal functions can lead to broad detrimental effects and cause various diseases, including cancers. Cancer cells that are rapidly proliferative and invasive are highly dependent on effective lysosomal function. Malignant melanoma is the most lethal form of skin cancer, with high metastasis characteristics, drug resistance, and aggressiveness. It is critical to understand the role of lysosomes in melanoma pathogenesis in order to improve the outcomes of melanoma patients. In this mini-review, we compile our current knowledge of lysosomes' role in tumorigenesis, progression, therapy resistance, and the current treatment strategies related to lysosomes in melanoma.

The effects of carbon monoxide releasing molecules on paraquat-induced pulmonary interstitial inflammation and fibrosis.

Paraquat, an herbicide used extensively worldwide, can cause severe toxicity in humans and animals, leading to irreversible, lethal lung fibrosis. The potential of CO-releasing molecules (CORMs), substances that release CO (Carbon monoxide) within animal tissues, for treating paraquat-induced ROS generation and inflammation is investigated here. Our results show that the fast CO releaser CORM-3 (4-20 µM) acts as a potential scavenger of free radicals and decreases fibrosis progression by inhibiting paraquat-induced overexpression of connective tissue growth factor and angiotensin II in MRC-5 cells. The slow CO releaser CORM-A1 (5 mg/kg) clearly decreased expression of the lung profibrogenic cytokines COX-2, TNF-α, and α-SMA and serum hydroxyproline, resulting in a lower mortality rate in paraquat-treated mice. Mice treated with higher-dose CORM-A1 (10 mg/kg) had relatively intact lung lobes and fewer fibrotic patches by gross observation, with less collagen deposition, mesangial matrix accumulation, and pulmonary fibrosis resulting from the mitigation of TGF-ß overexpression. In conclusion, our data demonstrate for the first time that CORM-A1 alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ, would be an attractive therapeutic approach to attenuate the progression of pulmonary fibrosis following PQ exposure.

3-MCPD and glycidol coexposure induces systemic toxicity and synergistic nephrotoxicity via NLRP3 inflammasome activation, necroptosis, and autophagic cell death.

3-Monochloropropane-1,2-diol (3-MCPD), 2,3-epoxy-1-propanol (glycidol), and their esters are well-known food contaminants mainly formed by the heat processing of certain refined oils and coexist in various kinds of foodstuffs. However, the combined health effect and the underlying mechanism of 3-MCPD and glycidol coexposure are not well-understood. In this study, we investigated the systemic toxicity effects and the nephrotoxicity mechanisms of 3-MCPD and glycidol coexposure with in vitro and in vivo models, and next-generation sequencing (NGS) analysis. It was found that 3-MCPD and glycidol coexposure for 28 days synergistically induced toxicity in the kidney, lung, testis, and heart in C57BL/6 mice. Kidney was the most sensitive organ to coexposure, and the coexposure had a synergistic effect on inflammation and cytotoxicity through activation of the NLRP3 inflammasome, and the induction of necroptosis, and autophagic cell death in NRK-52E cells. Moreover, the NGS results revealed the genes changes associated with nephrotoxicity, inflammation and with the broad toxicity effects induced by 3-MCPD or glycidol alone or in combination, which were consistent with the results of in vitro and in vivo models. In summary, we report for the first time of the comprehensive toxicity effects and the mechanisms caused by 3-MCPD and glycidol coexposure.

Advanced Age and Chronic Kidney Disease Modify the Association Between Metabolic Syndrome and Frailty Among Community-Dwelling Elderly.

Metabolic syndrome (MetS) predisposes older adults to the development of frailty. However, previous studies have not explored factors that may influence the association between MetS and the risk of frailty in this population. Community-dwelling older adults (≥65 years of age) were prospectively identified and enrolled between 2013 and 2016. MetS and frailty were defined based on the American Association of Clinical Endocrinologists and Study of Osteoporotic Fractures criteria, respectively. Multiple logistic regression with frailty/prefrailty as the dependent variable was used to examine the relationship between MetS and frailty/prefrailty, supplemented by subgroup analyses of the influence of aging and chronic kidney disease (CKD). Among 2862 elderly (73.4 ± 6.7 years), 17.5% and 17.3%, respectively, had MetS and frailty/prefrailty, among whom 74 (2.6%) and 420 (14.7%) had frailty and prefrailty. The presence of MetS (odds ratio [OR] 2.53, p < 0.001), higher age (OR 1.05, p < 0.001), and CKD (OR 1.42, p = 0.006) were associated with a significantly higher risk of frailty/prefrailty. Furthermore, among those ≥80 years of age, the association between MetS and frailty/prefrailty disappeared (p = 0.329). Among those with CKD, the presence of MetS was significantly associated with a progressively higher risk of frailty/prefrailty (for stage 3 or higher and for stage 3b or higher, OR 6.4 and 12.4, p < 0.001 and = 0.009, respectively). In conclusion, aging and CKD modified the association between MetS and frailty. These findings may assist in devising case-specific care plans for elderly with MetS by refocusing our attention on those at high risk of developing frailty/prefrailty.

Induction of Autophagy by Pterostilbene Contributes to the Prevention of Renal Fibrosis via Attenuating NLRP3 Inflammasome Activation and Epithelial-Mesenchymal Transition.

Chronic kidney disease (CKD) is recognized as a global public health problem. NLRP3 inflammasome activation has been characterized to mediate diverse aspect mechanisms of CKD through regulation of proinflammatory cytokines, tubulointerstitial injury, glomerular diseases, renal inflammation, and fibrosis pathways. Autophagy is a characterized negative regulation mechanism in the regulation of the NLRP3 inflammasome, which is now recognized as the key regulator in the pathogenesis of inflammation and fibrosis in CKD. Thus, autophagy is undoubtedly an attractive target for developing new renal protective treatments of kidney disease via its potential effects in regulation of inflammasome. However, there is no clinical useful agent targeting the autophagy pathway for patients with renal diseases. Pterostilbene (PT, trans-3,5-dimethoxy-4-hydroxystilbene) is a natural analog of resveratrol that has various health benefits including autophagy inducing effects. Accordingly, we aim to investigate underlying mechanisms of preventive and therapeutic effects of PT by reducing NLRP3 inflammasome activation and fibrosis through autophagy-inducing effects. The renal protective effects of PT were evaluated by potassium oxonate (PO)-induced hyperuricemia and high adenine diet-induced CKD models. The autophagy induction mechanisms and anti-fibrosis effects of PT by down-regulation of NLRP3 inflammasome are investigated by using immortalized rat kidney proximal tubular epithelial NRK-52E cells. To determine the role of autophagy induction in the alleviating of NLRP3 inflammasome activation and epithelial-mesenchymal transition (EMT), NRK-52E with Atg5 knockdown [NRK-Atg5-(2)] cells were applied in the study. The results indicated that PT significantly reduces serum uric acid levels, liver xanthine oxidase activity, collagen accumulation, macrophage recruitment, and renal fibrosis in CKD models. At the molecular levels, pretreatment with PT downregulating TGF-ß-triggered NLRP3 inflammasome activation, and subsequent EMT in NRK-52E cells. After blockage of autophagy by treatment of Atg5 shRNA, PT loss of its ability to prevent NLRP3 inflammasome activation and EMT. Taken together, we suggested the renal protective effects of PT in urate nephropathy and proved that PT induces autophagy leading to restraining TGF-ß-mediated NLRP3 inflammasome activation and EMT. This study is also the first one to provide a clinical potential application of PT for a better management of CKD through its autophagy inducing effects.

Clinical effectiveness of International Team for Oral Implantology dental implant treatment in Taiwan: a seven-year longitudinal study.

BACKGROUND: International Team for Oral Implantology (ITI) dental implant has been clinically tested for the most parts of the world, especially in Europe and America, and has not been conducted on Asian population. The purpose of this study was to evaluate the cumulative survival and success rates over 7 years of ITI dental implants. MATERIALS: The ITI dental implant system has been used in the Dental Department of Chi Mei Medical Center since August of 1997. At the end of 2005, 717 solid-screw implants had been placed and loaded at least 6 months in 316 patients. The patient population included 145 males and 171 females, with a mean age of 43.18 +/- 11.60 years. The follow-up interval was from 6 months after the prosthesis was completed to 7 years. The success criteria of dental implant survival was based on Buser et al, Clin Oral Implants Res. 1990;1:33-40. RESULTS: Most implants (486, 67.8%) were placed in the mandible and 231 (32.2%) were placed in the maxilla. Two implants were removed before prostheses fabrication because of postsurgical infections. One implant was removed due to a periapical infection of an adjacent natural tooth. The life table analysis of survival rate and success rate were 99.58% and 96.13%, respectively. CONCLUSION: This 7-year clinical effectiveness study demonstrated this dental implant system gave a clinical reliable result in a Taiwanese population.

Rhythm control better prevents stroke and mortality than rate control strategies in patients with atrial fibrillation - A nationwide cohort study.

BACKGROUND: Atrial fibrillation (AF) increases the risk of stroke and mortality. However, rhythm control strategy did not reduce cardiovascular risks in short-term studies. We hypothesize that rhythm control better prevents stroke and mortality than rate control in AF patients over a long-term period. METHODS: AF patients aged ≥18 years were identified from Taiwan National Insurance Database. Patients using anti-arrhythmia drugs to control rhythm at a >30 defined daily dose (DDD) were defined as the rhythm control group. Patients who used rate control medications for >30 DDDs constituted the rate control group. Multivariate Cox hazards regression model was used to evaluate the hazard ratio (HR) for major adverse cardiovascular events (MACE), including ischemic/hemorrhagic stroke and mortality. RESULTS: A total of 11,968 AF patients were enrolled, and 2850 of them (654 in rhythm control group; 2196 in rate control group) were analyzed. During a 6.3 ±â€¯3.7 year's follow-up, a total of 1101 MACE occurred. Compared to rate control group, rhythm control group displayed a lower rate of ischemic stroke (adjusted HR: 0.65, p = 0.002) and mortality (adjusted HR: 0.81, p = 0.009). The rhythm control group showed a lower incidence of MACE than that of the rate control group (adjusted HR: 0.82, p = 0.009). The reduction of stroke (p = 0.004), mortality (p = 0.006), and MACE (p = 0.007) risk was observed particularly in rhythm control patients with a CHA2DS2-VASc score of ≥3. CONCLUSIONS: In patients with AF, rhythm control better prevents MACE risk than rate control over a long-term period, particularly in those at high risk (CHA2DS2-VASc score ≥3) for stroke.

Data for rate versus rhythm control strategy on stroke and mortality in patients with atrial fibrillation.

The data relates to the cohort of patients with atrial fibrillation (AF) from the National Health Insurance Research Database of Taiwan, "Rhythm Control Better Prevents Stroke and Mortality than Rate Control Strategies in Patients with Atrial Fibrillation - A Nationwide Cohort Study" (Weng et al., in press). The AF patients might receive either rate or rhythm control strategy according to the medication used. The baseline medication in rate and rhythm control groups was included in this dataset. Multivariate Cox hazards regression model was used to evaluate the hazard ratio (HR) for major adverse cardiovascular events (MACE), including ischemic/hemorrhagic stroke and mortality in AF patients receiving rate or rhythm control. The occurrence of MACE was identified from the ICD-9 CM codes. The data also contains the HR for MACE stratified by the CHA2DS2-VASc score, baseline characteristics, and the duration of strategy employed of the AF patients.

A comprehensive periodontal treatment project: The periodontal status, compliance rates, and risk factors.

BACKGROUND/PURPOSE: The comprehensive periodontal treatment project (CPTP) is being implemented in Taiwan since 2010. This retrospective study compared the periodontal status, compliance rates, and influence of risk factors for periodontal recurrence and tooth loss among groups of patients who accepted CPTP and conventional periodontal treatment (CPT). MATERIALS AND METHODS: A total of 161 patients who received periodontal therapy were investigated and divided into compliant (n = 94) and noncompliant (n = 67) groups. Patients in the compliant group were further assigned to two subgroups: CPT with a postcard recall (PR) system (CPT + PR, n = 48) and CPTP with a PR system (CPTP + PR, n = 46). Demographic characteristics and periodontal parameters, including the probing pocket depth (PPD), bleeding on probing (BOP), and plaque control record (PCR), were collected for comparison between the subgroups. The risk factors for periodontal recurrence and tooth loss were statistically analyzed. RESULTS: The 161 patients were followed-up for a mean of 3.8 years. The patients in the CPTP + PR subgroup exhibited shallower PPD, less BOP, improved PCR, and fewer tooth loss. Age, smoking, PPD ≥7 mm, and PCR ≥30% were associated with periodontal recurrence, whereas age, diabetes, BOP ≥30%, and duration of the follow-up period were correlated with tooth loss. PR apparently increased the compliance rate of patients (27.3% vs. 77.7%). CONCLUSION: CPTP with PR led to an optimal and stable periodontal status in patients. Compliant patients maintained a significantly improved periodontal status as compared with noncompliant patients.