Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder with limited clinical treatments. The occurrence of PD includes both genetic and environmental toxins, such as the pesticides paraquat (PQ), as major contributors to PD pathology in both invertebrate and mammalian models. Calycosin, an isoflavone phytoestrogen, has multiple pharmacological properties, including neuroprotective activity. However, the paucity of information regarding the neuroprotective potential of calycosin on PQ-induced neurodegeneration led us to explore whether calycosin can mitigate PD-like phenotypes and the underlying molecular mechanisms. We used a PQ-induced PD model in Drosophila as a cost-effective in vivo screening platform to investigate the neuroprotective efficacy of natural compounds on PD. We reported that calycosin shows a protective role in preventing dopaminergic (DA) neuronal cell death in PQ-exposed Canton S flies. Calycosin-fed PQ-exposed flies exhibit significant resistance against PQ-induced mortality and locomotor deficits in terms of reduced oxidative stress, loss of DA neurons, the depletion of dopamine content, and phosphorylated JNK-caspase-3 levels. Additionally, mechanistic studies show that calycosin administration improves PQ-induced mitochondrial dysfunction and stimulates mitophagy and general autophagy with reduced pS6K and p4EBP1 levels, suggestive of a maintained energy balance between anabolic and catabolic processes, resulting in the inhibition of neuronal cell death. Collectively, this study substantiates the protective effect of calycosin against PQ-induced neurodegeneration by improving DA neurons’ survival and reducing apoptosis, likely via autophagy induction, and it is implicated as a novel therapeutic application against toxin-induced PD pathogenesis.

Chlorfenapyr is a new contact and stomach insecticide derived from natural pyrroles secreted by Streptomyces spp. It is a pro-insecticide and acts after metabolic transformation to its active metabolite tralopyril. Tralopyril is an uncoupler of oxidative phosphorylation in the mitochondria of the target insects and of experiment animals, leading to the disruption of adenosine triphosphate synthesis and death. Several fatal human poisonings had been reported and no blood chlorfenapyr or tralopyril measurements were available. The treatment remains supportive. A 32-year-old healthy man ingested 200 mL of 10% chlorfenapyr as a suicide attempt. Unfortunately, he succumbed at 157 h post-ingestion, shortly after having fever and seizures. His serum level of chlorfenapyr at 4 h post-exposure was 77.4 ng/mL, and was undetectable at 113 and 156 h, respectively. The serum levels of tralopyril were 723.6, 14,179, and 9654.2 ng/mL at 4, 113, and 156 h post-ingestion, respectively. The delay in the rise of serum tralopyril levels was noticeable, which seems to correlate with the patient’s signs and symptoms. The information may have therapeutic implications in the management of this deadly poisoning.

Our study aimed to determine the incidence and severity of obstructive sleep apnea (OSA) in patients with end-stage renal disease (ESRD) and also whether different dialysis modalities confer different risk and treatment response for OSA. We used Taiwan’s National Health Insurance Research Database for analysis and identified 29,561 incident dialysis patients as the study cohort between 2000 and 2011. Each dialysis patient was matched with four non-dialysis control cases by age, sex, and index date. Cox regression hazard models were used to identify the risk of OSA. The incidence rate of OSA was higher in the peritoneal dialysis (PD) cohort than the hemodialysis (HD) and control cohort (18.9, 7.03 vs. 5.5 per 10,000 person-years, respectively). The risk of OSA was significantly higher in the PD (crude subhazard ratio (cSHR) 3.50 [95% CI 2.71–4.50], p < 0.001) and HD cohort (cSHR 1.31 [95% CI 1.00–1.72], p < 0.05) compared with the control cohort. Independent risk factors for OSA in this population were age, sex, having coronary artery disease (CAD), hyperlipidemia, chronic obstructive pulmonary disease (COPD), and hypertension. Major OSA (MOSA) occurred in 68.6% in PD and 50.0% in HD patients with OSA. In the PD subgroup, the incidence of mortality was significantly higher in OSA patients without continuous positive airway pressure (CPAP) treatment compared with OSA patients undergoing CPAP treatment. The results of this study indicate that ESRD patients were at higher risk for OSA, especially PD patients, compared with control. The severity of OSA was higher in PD patients than HD patients. Treatment of MOSA with CPAP was associated with reduced mortality in PD patients.

Periodontal disease (POD) is associated with the risk of atherosclerotic vascular disease in patients on hemodialysis (HD). The association between POD treatment and cardiovascular diseases (CVDs) is still unknown. A total of 3613 patients who received HD and intensive POD treatment between 1 January 1998, and 31 December 2011 were identified from the National Health Insurance Research Database as the treatment cohort. The comparison cohort comprised patients without POD treatment who were matched to the patients in the treatment cohort at a 1:1 ratio by the propensity score. All CVDs defined by International Classification of Diseases, Ninth Revision (International Classification of Diseases, Ninth Revision (ICD-9)) codes were ascertained by hospital records for nonfatal events. The first CVD was used to define incidence. Relative risks were estimated by hazard ratios from the Cox proportional hazard model with adjustment for demographic variables and cardiovascular risk factors. Compared with the comparison cohort, the adjusted hazard ratio of hospitalization for CVDs was 0.78 (95% confidence interval = 0.73–0.84, p < 0.001) in the treatment cohort The treatment cohort exhibited significantly lower cumulative incidences of CVDs (log-rank test p < 0.001) and mortality (log-rank test p < 0.001). Intensive POD treatment was associated with reduced risks of CVDs and overall mortality in patients on HD.

Periodontitis is the most prevalent chronic inflammatory oral disease that is characterized by tooth loss and is commonly associated with several systemic inflammatory diseases. Some epidemiological studies suggest that those suffering from periodontitis might be at a greater risk of developing gastric Helicobacter pylori (Hp) infection; however, evidence that showing the association between periodontitis and the risk of gastric Hp infection is less clear. We conducted a large-scale, population-based study in Taiwan with a 13-year follow-up period to evaluate the risk of gastric Hp in a periodontitis patient cohort. To conduct this study, we used epidemiological data from the Taiwanese Longitudinal National Health Insurance Research Database (NHIRD) from 2000 to 2013. We selected 134,474 participants (64,868 males and 69,606 females with a minimum age of 20 years), with and without periodontitis, and matched patient cohort groups for age, sex, index year, and co-morbidities. The Cox proportional hazards regression model was used to examine the risk of gastric Hp infection in patients with periodontitis. Patients with periodontitis exhibited a higher risk of developing gastric Hp infection compared to those individuals/groups without periodontitis (1.35 vs. 0.87 per 1000 person-years, adjusted the hazards ratio (aHR 1.52), and 95% confidence intervals (CIs) 1.38–1.67, p < 0.001). The risk of gastric Hp infection persisted even after stratifying by age (aHR = 1.96 (1.79–2.13) for 50–64 years and 1.70 (1.49–1.94) for ≥65 years), gender (aHR = 1.20 (1.11–1.29) for men), and presence of comorbidities of hypertension (aHR = 1.24 (1.11–1.38)), hyperlipidemia (aHR = 1.28 (1.14–1.42)), COPD (aHR = 1.45 (1.31–1.61)), CLD (aHR = 1.62 (1.47–1.77)) and CKD (aHR = 1.44 (1.04–1.99)). Overall, our findings showed that periodontitis patients have a greater risk for gastric Hp than individuals without periodontitis. Clinicians should perform regular good oral hygiene practices, along with newer treatments, for patients with periodontitis, especially those at higher risk of gastric Hp infection.