Design, Synthesis, and In Vivo Evaluation of Isosteviol Derivatives as New SIRT3 Activators with Highly Potent Cardioprotective Effects.

Cardiovascular diseases (CVDs) persist as the predominant cause of mortality, urging the exploration of innovative pharmaceuticals. Mitochondrial dysfunction stands as a pivotal contributor to CVDs development. Sirtuin 3 (SIRT3), a prominent mitochondrial deacetylase known for its crucial role in protecting mitochondria against damage and dysfunction, has emerged as a promising therapeutic target for CVDs treatment. Utilizing isosteviol, a natural ent-beyerene diterpenoid, 24 derivatives were synthesized and evaluated in vivo using a zebrafish model, establishing a deduced structure-activity relationship. Among these, derivative 5v exhibited significant efficacy in doxorubicin-induced cardiomyopathy in zebrafish and murine models. Subsequent investigations revealed that 5v selectively elevated SIRT3 expression, leading to the upregulation of SOD2 and OPA1 expression, effectively preventing mitochondrial dysfunction, mitigating oxidative stress, and preserving cardiomyocyte viability. As a novel structural class of SIRT3 activators with robust therapeutic effects, 5v emerges as a promising candidate for further drug development.

IL-1α facilitates GSH synthesis to counteract oxidative stress in oral squamous cell carcinoma under glucose-deprivation.

Understanding the intrinsic mechanisms underpinning cancer metabolism and therapeutic resistance is of central importance for effective nutrition-starvation therapies. Here, we report that Interleukin 1A (IL1A) mRNA and IL-1α protein facilitate glutathione (GSH) synthesis to counteract oxidative stress and resistance against nutrition-starvation therapy in oral squamous cell carcinoma (OSCC). The expression of IL1A mRNA was elevated in the case of OSCC associated with unfavorable clinical outcomes. Both IL1A mRNA and IL-1α protein expression were increased under glucose-deprivation in vitro and in vivo. The transcription of IL1A mRNA was regulated in an NRF2-dependent manner in OSCC cell lines under glucose-deprivation. Moreover, the IL-1α conferred resistance to oxidative stress via GSH synthesis in OSCC cell lines. The intratumoral administration of siRNAs against IL1A mRNA markedly reversed GSH production and sensitized OSCC cells to Anlotinib in HN6 xenograft models. Overall, the current study demonstrates novel evidence that the autocrine IL-1α favors endogenous anti-oxidative process and confers therapeutic resistance to nutrition-starvation in OSCCs.

Sexual and Reproductive Health Outcomes Among Adolescent Females During the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) posed a significant threat to adolescents' sexual and reproductive health. In this study, we examined population-level pregnancy and sexual health-related care utilization among adolescent females in Ontario, Canada during the pandemic and evaluated relationships between these outcomes and key sociodemographic characteristics. METHODS: This was a population-based, repeated cross-sectional study of >630 000 female adolescents (12-19 years) during the prepandemic (January 1, 2018-February 29, 2020) and COVID-19 pandemic (March 1, 2020-December 31, 2022) periods. Primary outcome was pregnancy; secondary outcomes were contraceptive management visits, contraception prescription uptake, and sexually transmitted infection (STI) management visits. Poisson models with generalized estimating equations for clustered count data were used to model pre-COVID-19 trends and forecast expected rates during the COVID-19 period. Absolute rate differences between observed and expected outcome rates for each pandemic month were calculated overall and by urbanicity, neighborhood income, immigration status, and region. RESULTS: During the pandemic, lower-than-expected population-level rates of adolescent pregnancy (rate ratio 0.87; 95% confidence interval [CI]:0.85-0.88), and encounters for contraceptive (rate ratio 0.82; 95% CI:0.77-0.88) and STI management (rate ratio 0.52; 95% CI:0.51-0.53) were observed. Encounter rates did not return to pre-pandemic rates by study period end, despite health system reopening. Pregnancy rates among adolescent subpopulations with the highest pre-pandemic pregnancy rates changed least during the pandemic. CONCLUSIONS: Population-level rates of adolescent pregnancy and sexual health-related care utilization were lower than expected during the COVID-19 pandemic, and below-expected care utilization rates persist. Pregnancy rates among more structurally vulnerable adolescents demonstrated less decline, suggesting exacerbation of preexisting inequities.

Synthesis and neuroprotective effects of new genipin derivatives against glutamate-induced oxidative damage.

Glutamate-induced oxidative stress is well-known to play a crucial role in the development of neurodegenerative diseases, such as stroke. Genipin, a natural iridoid compound, has demonstrated potential neuroprotective properties but is unstable in physiological conditions. The present study aimed to develop new derivatives of genipin that exhibit improved stability and activity for the treatment of stroke. Nineteen new derivatives were thus designed and synthesized. Their neuroprotective effect against glutamate-induced injury was evaluated in HT22 cells. Among the newly synthesized derivatives, 3e demonstrated significantly greater neuroprotection and improved stability compared to genipin. Specifically, 0.01 µM of 3e was found to effectively attenuate glutamate-induced oxidative damage by inhibiting ROS over-accumulation, reducing MDA content, and restoring the endogenous antioxidative system. Further investigation revealed that 3e inhibited oxidative stress by downregulating the phosphorylation levels of p38 MAPK and activating Nrf2 and HO-1 proteins. These results suggested that 3e has the potential to serve as a promising candidate for the treatment of stroke by protecting against glutamate-induced oxidative stress.

Discovery of New D-Ring Modified Isosteviol Derivatives as Potent Cardioprotective Agents against Oxidative Stress-Trigged Damage.

Cardiovascular diseases (CVDs) are a major global health concern, and oxidative stress is known to play a central role in their pathogenesis. The identification of new agents capable of inhibiting oxidative stress presents a promising strategy for preventing and treating CVDs. Natural products and their derivatives offer a valuable source for drug discovery, and isosteviol, a readily available natural product, is known to exhibit cardioprotective effects. In this study, 22 new D-ring modified isosteviol derivatives were synthesized and evaluated for their cardioprotective effect in vivo using the zebrafish cardiomyopathy model. The findings revealed that derivative 4e exhibited the most potent cardioprotective effect, surpassing its parent compound isosteviol and the positive drug levosimendan. At 1 µM, derivative 4e significantly protected the cardiomyocytes from injury, while at 10 µM it effectively maintained normal heart phenotypes, preventing cardiac dysfunction in zebrafish. Further investigation demonstrated that 4e protected cardiomyocytes from oxidative stress-induced damage by inhibiting reactive oxygen species overaccumulation, activating superoxide dismutase 2 expression, and enhancing the endogenous antioxidant defense system. These results suggest that isosteviol derivatives, particularly 4e, have the potential to serve as a novel class of cardioprotective agents for the prevention and treatment of CVDs.

Cyclic stretch promotes vascular homing of endothelial progenitor cells via Acsl1 regulation of mitochondrial fatty acid oxidation.

Endothelial progenitor cells (EPCs) play an important role in vascular repair and re-endothelialization after vessel injury. EPCs in blood vessels are subjected to cyclic stretch (CS) due to the pulsatile pressure, but the role of CS in metabolic reprogramming of EPC, particularly its vascular homing and repair, is largely unknown. In the current study, physiological CS applied to EPCs at a magnitude of 10% and a frequency of 1 Hz significantly promoted their vascular adhesion and endothelial differentiation. CS enhanced mitochondrial elongation and oxidative phosphorylation (OXPHOS), as well as adenosine triphosphate production. Metabolomic study and Ultra-high performance liquid chromatography-mass spectrometry assay revealed that CS significantly decreased the content of long-chain fatty acids (LCFAs) and markedly induced long-chain fatty acyl-CoA synthetase 1 (Acsl1), which in turn facilitated the catabolism of LCFAs in mitochondria via fatty acid ß-oxidation and OXPHOS. In a rat carotid artery injury model, transplantation of EPCs overexpressing Acsl1 enhanced the adhesion and re-endothelialization of EPCs in vivo. MRI and vascular morphology staining showed that Acsl1 overexpression in EPCs improved vascular repair and inhibited vascular stenosis. This study reveals a mechanotransduction mechanism by which physiological CS enhances endothelial repair via EPC patency.

Changes in Service Delivery and Access to Rheumatologists Before and During the COVID-19 Pandemic in a Canadian Universal Healthcare Setting.

OBJECTIVE: To describe changes in service delivery and access to rheumatologists before and during the coronavirus disease 2019 (COVID-19) pandemic periods. METHODS: We conducted a population-based study in Ontario, Canada. Patient visits with rheumatologists were ascertained using billing claims data. Contact with rheumatologists was defined separately by the type of patient encounter (including office visits, telemedicine visits, and new patient consultations). Changes in the total weekly volume of encounters and monthly rates after COVID-19 public health measures were imposed were compared to expected baseline rates determined before pandemic onset (March 17, 2020). RESULTS: In the year prior to the pandemic, there were 289,202 patients (of which 96,955 were new consults) seen by 239 rheumatologists. In the 1 year following the pandemic onset, there were 276,686 patients (of which 86,553 were new consults) seen by 247 rheumatologists. In March 2020, there was an immediate 75.9% decrease in outpatient office visits and a rapid rise in telemedicine visits. By September 2021, 49.7% of patient encounters remained telemedicine visits. For new patient consultations, there was an immediate 50% decrease in visits at the pandemic onset, with 54.8% diverted to telemedicine visits in the first year of the pandemic versus 37.4% by September 2021. New rheumatology consultation rates continued decreasing over the study period. CONCLUSION: Rheumatology care delivery has shifted due to the pandemic, with telemedicine increasing sharply early in the pandemic and persisting over time. The pandemic also negatively affected access to rheumatologists, resulting in fewer new consultations and raising concerns for potential delays to diagnosis.

Identifying Patterns of Primary Care Antibiotic Prescribing for a Spinal Cord Injury (SCI) Cohort Using an Electronic Medical Records (EMR) Database.

Background: Individuals with a spinal cord injury (SCI) are considered higher users of antibiotics. However, to date there have been no detailed studies investigating outpatient antibiotic use in this population. Objectives: (1) To describe primary care antibiotic prescribing patterns in adults with SCI rostered to a primary care physician (PCP), and (2) to identify patient or PCP factors associated with number of antibiotics prescribed and antibiotic prescription duration. Methods: A retrospective cohort study using linked health administrative and electronic medical records (EMR) databases from January 1, 2013 to December 31, 2015 among 432 adults with SCI in Ontario, Canada. Negative binomial regression analyses were conducted to identify patient or physician factors associated with number of antibiotics prescribed and prescription duration. Results: During the study period, 61.1% of the SCI cohort received an antibiotic prescription from their PCP. There were 59.8% of prescriptions for urinary tract infections (UTI) and 24.6% of prescriptions for fluoroquinolones. Regression analysis found catheter use was associated with increased number of antibiotics prescribed (relative risk [RR] = 3.1; 95% CI, 2.3-4.1; p < .001) and late career PCPs, compared to early-career PCPs, prescribed a significantly longer duration (RR = 1.8; 95% CI, 1.1-3.1; p = .02). Conclusion: UTIs were the number one prescription indication, and fluoroquinolones were the most prescribed antibiotic. Catheter use was associated with number of antibiotics, and PCP's years of practice was associated with duration. The study provided important information about primary care antibiotic prescribing in the SCI population and found that not all individuals received frequent antibiotics prescriptions.

Synthesis and in vivo evaluation of new steviol derivatives that protect against cardiomyopathy by inhibiting ferroptosis.

Cardiovascular diseases (CVDs) remain the leading cause of death globally. Inhibiting ferroptosis and thus preventing cardiac cell death is a promising and effective strategy for cardiomyopathy prevention and therapy. Steviol, an ent-kaurene diterpenoid, possesses broad-spectrum bioactivity. In the present study, with the aim to discover new agents for CVDs treatment, 30 derivatives of steviol, including 22 new ones, were synthesized, and evaluated their protective activity in vivo using the doxorubicin (DOX) induced zebrafish cardiomyopathy model. Our results firstly demonstrated that steviol has promising cardioprotective activity and further modification of steviol can greatly improve the activity. Among the new derivatives, 16d and 16e show the most potent activity. Both 16d (1 µM) and 16e (0.1 µM) effectively maintain the normal heart shape and prevent the cardiac dysfunction impaired by DOX in zebrafish. Their therapeutic efficacy is much superior to the parent natural product, steviol, and positive drug, levosimendan. Further study demonstrated that 16d and 16e inhibit DOX-induced ferroptosis and thus protect cardiomyopathy, by suppressing the glutathione depletion, iron accumulation, and lipid peroxidation, decreasing reactive oxygen species overaccumulation, and restoring the mitochondrial membrane potential. Consequently, due to their unique structure and significant cardioprotective activity with ferroptosis inhibition, new steviol derivatives 16d and 16e merit further research for the development of new cardioprotective drug candidates.

Anti-Human CD9 Fab Fragment Antibody Blocks the Extracellular Vesicle-Mediated Increase in Malignancy of Colon Cancer Cells.

Intercellular communication between cancer cells themselves or with healthy cells in the tumor microenvironment and/or pre-metastatic sites plays an important role in cancer progression and metastasis. In addition to ligand-receptor signaling complexes, extracellular vesicles (EVs) are emerging as novel mediators of intercellular communication both in tissue homeostasis and in diseases such as cancer. EV-mediated transfer of molecular activities impacting morphological features and cell motility from highly metastatic SW620 cells to non-metastatic SW480 cells is a good in vitro example to illustrate the increased malignancy of colorectal cancer leading to its transformation and aggressive behavior. In an attempt to intercept the intercellular communication promoted by EVs, we recently developed a monovalent Fab fragment antibody directed against human CD9 tetraspanin and showed its effectiveness in blocking the internalization of melanoma cell-derived EVs and the nuclear transfer of their cargo proteins into recipient cells. Here, we employed the SW480/SW620 model to investigate the anti-cancer potential of the anti-CD9 Fab antibody. We first demonstrated that most EVs derived from SW620 cells contain CD9, making them potential targets. We then found that the anti-CD9 Fab antibody, but not the corresponding divalent antibody, prevented internalization of EVs from SW620 cells into SW480 cells, thereby inhibiting their phenotypic transformation, i.e., the change from a mesenchymal-like morphology to a rounded amoeboid-like shape with membrane blebbing, and thus preventing increased cell migration. Intercepting EV-mediated intercellular communication in the tumor niche with an anti-CD9 Fab antibody, combined with direct targeting of cancer cells, could lead to the development of new anti-cancer therapeutic strategies.

Conspiracy Theories, Psychological Distress, and Sympathy for Violent Radicalization in Young Adults during the COVID-19 Pandemic: A Cross-Sectional Study.

The COVID-19 pandemic has spread uncertainty, promoted psychological distress, and fueled interpersonal conflict. The concomitant upsurge in endorsement of COVID-19 conspiracy theories is worrisome because they are associated with both non-adherence to public health guidelines and intention to commit violence. This study investigates associations between endorsement of COVID-19 conspiracy theories, support for violent radicalization (VR) and psychological distress among young adults in Canada. We hypothesized that (a) endorsement of COVID-19 conspiracy theories is positively associated with support for VR, and (b) psychological distress modifies the relationship between COVID-19 conspiracy theories and support for VR. A total of 6003 participants aged 18-35 years old residing in four major Canadian cities completed an online survey between 16 October 2020 and 17 November 2020, that included questions about endorsement of COVID-19 conspiracy theories, support for VR, psychological distress, and socio-economic status. Endorsement of conspiracy theories was associated with support for VR in multivariate regression (ß = 0.88, 95% confidence interval (CI) 0.80-0.96). There is a significant interaction effect between endorsement of COVID-19 conspiracy theories and psychological distress (ß = 0.49, 95% CI 0.40-0.57). The magnitude of the association was stronger in individuals reporting high psychological distress (ß = 1.36, 95% CI 1.26-1.46) compared to those reporting low psychological distress (ß = 0.47, 95% CI 0.35-0.59). The association between endorsement of COVID-19 conspiracy theories and VR represents a public health challenge requiring immediate attention. The interaction with psychological distress suggests that policy efforts should combine communication and psychological strategies to mitigate the legitimation of violence.

US Health Care Spending by Payer and Health Condition, 1996-2016.

Importance: US health care spending has continued to increase and now accounts for 18% of the US economy, although little is known about how spending on each health condition varies by payer, and how these amounts have changed over time. Objective: To estimate US spending on health care according to 3 types of payers (public insurance [including Medicare, Medicaid, and other government programs], private insurance, or out-of-pocket payments) and by health condition, age group, sex, and type of care for 1996 through 2016. Design and Setting: Government budgets, insurance claims, facility records, household surveys, and official US records from 1996 through 2016 were collected to estimate spending for 154 health conditions. Spending growth rates (standardized by population size and age group) were calculated for each type of payer and health condition. Exposures: Ambulatory care, inpatient care, nursing care facility stay, emergency department care, dental care, and purchase of prescribed pharmaceuticals in a retail setting. Main Outcomes and Measures: National spending estimates stratified by health condition, age group, sex, type of care, and type of payer and modeled for each year from 1996 through 2016. Results: Total health care spending increased from an estimated $1.4 trillion in 1996 (13.3% of gross domestic product [GDP]; $5259 per person) to an estimated $3.1 trillion in 2016 (17.9% of GDP; $9655 per person); 85.2% of that spending was included in this study. In 2016, an estimated 48.0% (95% CI, 48.0%-48.0%) of health care spending was paid by private insurance, 42.6% (95% CI, 42.5%-42.6%) by public insurance, and 9.4% (95% CI, 9.4%-9.4%) by out-of-pocket payments. In 2016, among the 154 conditions, low back and neck pain had the highest amount of health care spending with an estimated $134.5 billion (95% CI, $122.4-$146.9 billion) in spending, of which 57.2% (95% CI, 52.2%-61.2%) was paid by private insurance, 33.7% (95% CI, 30.0%-38.4%) by public insurance, and 9.2% (95% CI, 8.3%-10.4%) by out-of-pocket payments. Other musculoskeletal disorders accounted for the second highest amount of health care spending (estimated at $129.8 billion [95% CI, $116.3-$149.7 billion]) and most had private insurance (56.4% [95% CI, 52.6%-59.3%]). Diabetes accounted for the third highest amount of the health care spending (estimated at $111.2 billion [95% CI, $105.7-$115.9 billion]) and most had public insurance (49.8% [95% CI, 44.4%-56.0%]). Other conditions estimated to have substantial health care spending in 2016 were ischemic heart disease ($89.3 billion [95% CI, $81.1-$95.5 billion]), falls ($87.4 billion [95% CI, $75.0-$100.1 billion]), urinary diseases ($86.0 billion [95% CI, $76.3-$95.9 billion]), skin and subcutaneous diseases ($85.0 billion [95% CI, $80.5-$90.2 billion]), osteoarthritis ($80.0 billion [95% CI, $72.2-$86.1 billion]), dementias ($79.2 billion [95% CI, $67.6-$90.8 billion]), and hypertension ($79.0 billion [95% CI, $72.6-$86.8 billion]). The conditions with the highest spending varied by type of payer, age, sex, type of care, and year. After adjusting for changes in inflation, population size, and age groups, public insurance spending was estimated to have increased at an annualized rate of 2.9% (95% CI, 2.9%-2.9%); private insurance, 2.6% (95% CI, 2.6%-2.6%); and out-of-pocket payments, 1.1% (95% CI, 1.0%-1.1%). Conclusions and Relevance: Estimates of US spending on health care showed substantial increases from 1996 through 2016, with the highest increases in population-adjusted spending by public insurance. Although spending on low back and neck pain, other musculoskeletal disorders, and diabetes accounted for the highest amounts of spending, the payers and the rates of change in annual spending growth rates varied considerably.

Health Care Spending on Diabetes in the U.S., 1996-2013.

OBJECTIVE: Health care spending on diabetes in the U.S. has increased dramatically over the past several decades. This research describes health care spending on diabetes to quantify how that spending has changed from 1996 to 2013 and to determine what drivers are increasing spending. RESEARCH DESIGN AND METHODS: Spending estimates were extracted from the Institute for Health Metrics and Evaluation's Disease Expenditure 2013 database. Estimates were produced for each year from 1996 to 2013 for each of 38 age and sex groups and six types of care. Data on disease burden were extracted from the Global Burden of Disease 2016 study. We analyzed the drivers of spending by measuring the impact of population growth and aging and changes in diabetes prevalence, service utilization, and spending per encounter. RESULTS: Spending on diabetes in the U.S. increased from $37 billion (95% uncertainty interval $32-$42 billion) in 1996 to $101 billion ($97-$107 billion) in 2013. The greatest amount of health care spending on diabetes in 2013 occurred in prescribed retail pharmaceuticals (57.6% [53.8-62.1%] of spending growth) followed by ambulatory care (23.5% [21.7-25.7%]). Between 1996 and 2013, pharmaceutical spending increased by 327.0% (222.9-456.6%). This increase can be attributed to changes in demography, increased disease prevalence, increased service utilization, and, especially, increases in spending per encounter, which increased pharmaceutical spending by 144.0% (87.3-197.3%) between 1996 and 2013. CONCLUSIONS: Health care spending on diabetes in the U.S. has increased, and spending per encounter has been the biggest driver. This information can help policy makers who are attempting to control future spending on diabetes.

Factors Associated With Increases in US Health Care Spending, 1996-2013.

Importance: Health care spending in the United States increased substantially from 1995 to 2015 and comprised 17.8% of the economy in 2015. Understanding the relationship between known factors and spending increases over time could inform policy efforts to contain future spending growth. Objective: To quantify changes in spending associated with 5 fundamental factors related to health care spending in the United States: population size, population age structure, disease prevalence or incidence, service utilization, and service price and intensity. Design and Setting: Data on the 5 factors from 1996 through 2013 were extracted for 155 health conditions, 36 age and sex groups, and 6 types of care from the Global Burden of Disease 2015 study and the Institute for Health Metrics and Evaluation's US Disease Expenditure 2013 project. Decomposition analysis was performed to estimate the association between changes in these factors and changes in health care spending and to estimate the variability across health conditions and types of care. Exposures: Change in population size, population aging, disease prevalence or incidence, service utilization, or service price and intensity. Main Outcomes and Measures: Change in health care spending from 1996 through 2013. Results: After adjustments for price inflation, annual health care spending on inpatient, ambulatory, retail pharmaceutical, nursing facility, emergency department, and dental care increased by $933.5 billion between 1996 and 2013, from $1.2 trillion to $2.1 trillion. Increases in US population size were associated with a 23.1% (uncertainty interval [UI], 23.1%-23.1%), or $269.5 (UI, $269.0-$270.0) billion, spending increase; aging of the population was associated with an 11.6% (UI, 11.4%-11.8%), or $135.7 (UI, $133.3-$137.7) billion, spending increase. Changes in disease prevalence or incidence were associated with spending reductions of 2.4% (UI, 0.9%-3.8%), or $28.2 (UI, $10.5-$44.4) billion, whereas changes in service utilization were not associated with a statistically significant change in spending. Changes in service price and intensity were associated with a 50.0% (UI, 45.0%-55.0%), or $583.5 (UI, $525.2-$641.4) billion, spending increase. The influence of these 5 factors varied by health condition and type of care. For example, the increase in annual diabetes spending between 1996 and 2013 was $64.4 (UI, $57.9-$70.6) billion; $44.4 (UI, $38.7-$49.6) billion of this increase was pharmaceutical spending. Conclusions and Relevance: Increases in US health care spending from 1996 through 2013 were largely related to increases in health care service price and intensity but were also positively associated with population growth and aging and negatively associated with disease prevalence or incidence. Understanding these factors and their variability across health conditions and types of care may inform policy efforts to contain health care spending.

Melatonin treatment induces apoptosis through regulating the nuclear factor-κB and mitogen-activated protein kinase signaling pathways in human gastric cancer SGC7901 cells.

Melatonin, which is synthesized by the pineal gland and released into the blood, exhibits antitumor properties. However, the mechanisms underlying these effects, particularly in stomach cancer, remain unknown. In the present study, the effect of melatonin on the nuclear factor (NF)-κB signaling pathway and the mitogen-activated protein kinase signaling pathway, involving p38 and c-Jun-N-terminal kinase (JNK), were investigated in SGC7901 gastric cancer cells. In addition, the effect of melatonin on the survival, migration and apoptosis of these cells was investigated in vitro in order to evaluate the use of melatonin for the treatment of gastric cancer. The results of the present study revealed that melatonin decreased the viability and migration of SGC7901 cells. Furthermore, melatonin induced apoptosis. Melatonin was identified to elevate the expression levels of phosphorylated (p)-p38 and p-JNK protein, and decrease the expression level of nucleic p-p65. These results suggest that the protein levels of p65, p38 and JNK are associated with the survival of SGC7901 cells following treatment with melatonin. The optimal concentration of melatonin was demonstrated to be 2 mM, which significantly induced apoptosis following a 24 h treatment period. These findings suggest that conflicting growth signals in cells may inhibit the efficacy of melatonin in the treatment of gastric cancer. Therefore, adjunct therapy would be required to improve the efficacy of melatonin in the treatment of cancer.

Melatonin induces cell apoptosis in Mia PaCa-2 cells via the suppression of nuclear factor-κB and activation of ERK and JNK: A novel therapeutic implication for pancreatic cancer.

Melatonin is synthesized by the pineal gland and is released into the blood. In the last several years, some studies have shown that melatonin has anticancer properties; however, the mechanisms behind the antitumour traits are unclear, especially in pancreatic cancer. Therefore, in the present study, we investigated the antitumour effects of melatonin on the human pancreatic carcinoma cell line MIA PaCa­2 and explored its biological mechanisms. MIA PaCa­2 cells were treated with melatonin, and we used a CCK­8 assay to evaluate the cell viability. We also used flow cytometry to observe cell apoptosis and western blot analysis to assess the protein expression. Our study found that melatonin inhibited cell viability, suppressed colony formation and reduced cell migration and invasion and induced cell apoptosis in MIA PaCa­2 cells. Our results showed that melatonin treatment inhibited NF­κB p65 activation. Moreover, melatonin treatment activated the mitogen­activated protein kinase pathways (c­jun N­terminal kinase and extracellular­regulated kinase 1/2), which increased Bax protein expression and caspase­3 cleavage and decreased Bcl­2 protein expression. These new developments demonstrate that melatonin plays a potential role in anticancer treatment and may act as an effective therapeutic agent in the future.

Trends in cervical cancer in young women in Hubei, China.

AIMS: This study was performed to determine whether the incidence of cervical cancer in women aged 35 or younger has changed for the past 30 years and to examine the clinical characteristics of the cases. METHODS: The clinical and pathological data of 6257 patients with cervical cancer treated between January 1975 and December 2009 were retrospectively analyzed. RESULTS: The prevalence of young (≤ 35 years old) patients steadily increased from 2.8% to 15.7% for the past 30 years. The ratio of adenocarcinoma also rose from 1975-1979 to 2005-2009. In an analysis by age group, in group A, adenocarcinoma was found in 17% (≤ 35 years old); in group B, 7.1% (> 35 years old) [χ² = 78.92, P < 0.0001]. The clinical presentation presented showed that 36.4% of patients presented mainly postcoital bleeding in group A, whereas the symptom of irregular genital bleeding predominated in group B (P < 0.0001). The patients detected by routine cytological screening in group A (8.7%) were more than the patients in group B (3%). CONCLUSIONS: The prevalence of cervical cancer in young women has been increasing steadily in Hubei, China. It is necessary for all sexually active women and women aged 35 years or even younger to undergo cervical cancer screening.