Healthy dietary patterns and risk of prostate cancer in men at high genetic risk.

Prostate cancer has high heritability. Healthy lifestyle has been associated with lower lethal prostate cancer risk among men at increased genetic susceptibility, but the role of healthy dietary patterns remains unknown. We prospectively followed 10,269 genotyped men in the Health Professionals Follow-up Study (1993-2019). Genetic risk was quantified using an established polygenic risk score (PRS). Five dietary patterns were investigated: healthy eating index, Mediterranean, diabetes risk-reducing, hyperinsulinemic and inflammatory diet. Overall and lethal prostate cancer rates (metastatic disease/prostate cancer-specific death) were analyzed using multivariable Cox proportional hazards models. During 26 years of follow-up, 2133 overall and 253 lethal prostate cancer events were documented. In the highest PRS quartile, higher adherence to a diabetes risk-reducing diet was associated with lower rates of overall (top vs. bottom quintile HR [95% CI], 0.74 [0.58-0.94]) and lethal prostate cancer (0.43 [0.21-0.88]). A low insulinemic diet was associated with similar lower rates (overall, 0.76 [0.60-0.95]; lethal, 0.46 [0.23-0.94]). Other dietary patterns showed weaker, but similar associations. In the highest PRS quartile, men with healthy lifestyles based on body weight, physical activity, and low insulinemic diet had a substantially lower rate (0.26 [0.13-0.49]) of lethal prostate cancer compared with men with unhealthy lifestyles, translating to a lifetime risk of 3.4% (95% CI, 2.3%-5.0%) among those with healthy lifestyles and 9.5% (5.3%-16.7%) among those with unhealthy lifestyles. Our findings indicate that lifestyle modifications lowering insulin resistance and chronic hyperinsulinemia could be relevant in preventing aggressive prostate cancer among men genetically predisposed to prostate cancer.

Photo-Induced Disproportionation-Mediated Photodynamic Therapy: Simultaneous Oxidation of Tetrahydrobiopterin and Generation of Superoxide Radicals.

We herein present an approach of photo-induced disproportionation for preparation of Type-I photodynamic agents. As a proof of concept, BODIPY-based photosensitizers were rationally designed and prepared. The photo-induced intermolecular electron transfer between homotypic chromophores leads to the disproportionation reaction, resulting in the formation of charged intermediates, cationic and anionic radicals. The cationic radicals efficiently oxidize the cellularimportant coenzyme, tetrahydrobiopterin (BH4 ), and the anionic radicals transfer electrons to oxygen to produce superoxide radicals (O2 - ⋅). One of our Type-I photodynamic agents not only self-assembles in water but also effectively targets the endoplasmic reticulum. It displayed excellent photocytotoxicity even in highly hypoxic environments (2 % O2 ), with a half-maximal inhibitory concentration (IC50 ) of 0.96 µM, and demonstrated outstanding antitumor efficacy in murine models bearing HeLa tumors.

Associations between plant-based dietary patterns and risks of type 2 diabetes, cardiovascular disease, cancer, and mortality - a systematic review and meta-analysis.

BACKGROUND: Plant-based dietary patterns are gaining more attention due to their potential in reducing the risk of developing major chronic diseases, including type 2 diabetes (T2D), cardiovascular disease (CVD), cancer, and mortality, while an up-to-date comprehensive quantitative review is lacking. This study aimed to summarize the existing prospective observational evidence on associations between adherence to plant-based dietary patterns and chronic disease outcomes. METHODS: We conducted a systematic review and meta-analysis of evidence across prospective observational studies. The data sources used were PubMed and MEDLINE, Embase, Web of Science, and screening of references. We included all prospective observational studies that evaluated the association between adherence to plant-based dietary patterns and incidence of T2D, CVD, cancer, and mortality among adults (≥ 18 years). RESULTS: A total of 76 publications were identified, including 2,230,443 participants with 60,718 cases of incident T2D, 157,335 CVD cases, 57,759 cancer cases, and 174,435 deaths. An inverse association was observed between higher adherence to a plant-based dietary pattern and risks of T2D (RR, 0.82 [95% CI: 0.77-0.86]), CVD (0.90 [0.85-0.94]), cancer (0.91 [0.87-0.96]), and all-cause mortality (0.84 [0.78-0.92]) with moderate to high heterogeneity across studies (I2 ranged: 47.8-95.4%). The inverse associations with T2D, CVD and cancer were strengthened when healthy plant-based foods, such as vegetables, fruits, whole grains, and legumes, were emphasized in the definition of plant-based dietary patterns (T2D: 0.79 [0.72-0.87]; CVD: 0.85 [0.80-0.92]; cancer: 0.86 [0.80-0.92]; I2 ranged: 53.1-84.1%). Association for mortality was largely similar when the analyses were restricted to healthy plant-based diets (0.86 [0.80-0.92], I2 = 91.9%). In contrast, unhealthy plant-based diets were positively associated with these disease outcomes. Among four studies that examined changes in dietary patterns, increased adherence to plant-based dietary patterns was associated with a significantly reduced risk of T2D (0.83 [0.71-0.96]; I2 = 71.5%) and a marginally lower risk of mortality (0.95 [0.91-1.00]; I2 = 0%). CONCLUSIONS: Better adherence to plant-based dietary patterns, especially those emphasizing healthy plant-based foods, is beneficial for lowering the risks of major chronic conditions, including T2D, CVD, cancer, as well as premature deaths. REGISTRATION OF REVIEW PROTOCOL: This review was registered at the PROSPERO International Prospective Register of Systematic Reviews ( https://www.crd.york.ac.uk/PROSPERO/ ) with the registration number CRD42022290202.

Synthesis and biological evaluation of FICZ analogues as agonists of aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor involved in multiple biological processes including immune cell differentiation, intestinal function and inflammation. Based on the scaffold of naturally occurring AhR ligand 6-formylindolo (3,2-b) carbazole (FICZ, 2), a series of analogues has been designed, synthesized and evaluated by cell-based assays. The structure-activity relationships study has successfully led to the discovery of compound 11e with extremely potent activity.

Lignan Intake and Type 2 Diabetes Incidence Among US Men and Women.

Importance: Lignans are phytoestrogens abundant in Western diets and may be associated with type 2 diabetes (T2D) risk. Objective: To prospectively investigate associations between lignan intake and T2D incidence. Design, Setting, and Participants: Population-based cohort study of US men and women enrolled in the Nurses' Health Study (NHS, 1984-2018), NHSII (1991-2019), and Health Professionals Follow-Up Study (HPFS, 1986-2020), as well as 496 participants from the Men's Lifestyle Validation Study (MLVS). Participants were free of T2D, cardiovascular disease, and cancer at baseline. Data were analyzed from November 2022 to July 2023. Exposures: Total and individual lignans were assessed using a validated food frequency questionnaire, which was updated every 2 to 4 years. In the MLVS, lignan intake was measured using 2 sets of 7-day diet records (7DDRs). Main Outcomes and Measures: Incident T2D cases were confirmed using American Diabetes Association diagnostic criteria. Cox proportional hazards models were used to assess multivariable-adjusted associations. Results: The current study included 201 111 participants (mean [SD] age, 44.7 [10.1] years; 161 169 female participants [80.2%]; 2614 African American participants [1.3%], 1609 Asian participants [0.8%], 2414 Hispanic and other race or ethnicity participants [1.2%], and 194 474 White participants [96.7%]) from the HPFS, NHS, and NHSII studies. The median (IQR) total lignan intake of the highest quintile ranged from 355.1 (330.2-396.9) µg/d in NHS to 459.9 (422.2-519.5) µg/d in HPFS at the median follow-up time. Over 5 068 689 person-years, 20 291 incident cases of T2D were identified. Higher lignan intake was inversely associated with T2D incidence, except for lariciresinol. The multivariable-adjusted pooled hazard ratios (HRs) for the highest vs lowest quintiles were 0.87 (95% CI, 0.83-0.91) for total lignans, 0.72 (95% CI, 0.69-0.76) for secoisolariciresinol, 0.92 (95% CI, 0.87-0.96) for pinoresinol, 0.93 (95% CI, 0.89-0.98) for matairesinol, and 0.99 (95% CI, 0.94-1.04) for lariciresinol. Secoisolariciresinol intake exhibited a significant inverse association with T2D risk among individuals with obesity (HR, 0.75 for body mass index [BMI] ≥30; 95% CI, 0.71-0.79 vs HR, 0.82 for BMI <25; 95% CI, 0.81-0.83; P < .001 for interaction) and premenopausal women (HR, 0.67 for premenopausal women; 95% CI, 0.65-0.69 vs HR, 0.82 for the past use of hormones; 95% CI, 0.76-0.88; P = .003 for interaction). Dietary lignan assessed with 7DDRs was associated with lower HbA1c levels (percentage change range from -0.92% to 1.50%), as well as lower C-reactive protein levels and better lipid profiles. Conclusions and Relevance: This cohort study found that long-term lignan consumption was associated with a lower T2D risk, particularly among individuals with obesity and premenopausal women.

Phytosterol intake and risk of coronary artery disease: Results from 3 prospective cohort studies.

BACKGROUND: Phytosterols are structurally similar to cholesterol and partially inhibit intestinal absorption of cholesterol, although their impact on coronary artery disease (CAD) risk remains to be elucidated. OBJECTIVES: This study aimed to prospectively assess the associations between total and individual phytosterol intake and CAD risk in United States health professionals. METHODS: The analysis included 213,992 participants from 3 prospective cohorts-the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study-without cardiovascular disease or cancer at baseline. Diet was assessed using a validated food frequency questionnaire every 2-4 y since baseline. Associations between phytosterol intake and the risk of CAD, such as nonfatal myocardial infarction and fatal CAD, were evaluated using Cox proportional hazards regression models. RESULTS: More than 5,517,993 person-years, 8725 cases with CAD were documented. Comparing extreme quintiles, pooled hazard ratios (95% CIs) of CAD were 0.93 (0.86, 1.01; P-trend = 0.16) for total phytosterols, 0.89 (0.82, 0.96; P-trend = 0.05) for campesterol, 0.95 (0.88, 1.02; P-trend = 0.10) for stigmasterol, and 0.92 (0.85, 1.00; P-trend = 0.09) for ß-sitosterol. Nonlinear associations were observed for total phytosterols, campesterol, and ß-sitosterol: the risk reduction plateaued at intakes above ∼180, 30, and 130 mg/d, respectively (P-nonlinearity < 0.001). In a subset of participants (N range between 11,983 and 22,039), phytosterol intake was inversely associated with plasma concentrations of total cholesterol, triglycerides, high-density lipoprotein cholesterol, and IL-6 and positively associated with adiponectin, whereas no significant associations were observed for low-density lipoprotein cholesterol or C-reactive protein concentrations. CONCLUSIONS: Higher long-term intake of total and major subtypes of phytosterols may be associated with a modest reduction in CAD risk, displaying a nonlinear relationship that plateau at moderate intake levels. The role of phytosterols in preventing CAD warrants further investigation.

Discovery of adjuvants with antibacterial potentiation activity against carbapenemase-producing Enterobacterales based on in silico virtual screening.

Bacterial multi-drug resistance has become a concern worldwide, especially after the emergence of carbapenemases. Adjuvants with antibacterial potentiation activity can resensitise drug-resistant strains to carbapenems. However, only a few adjuvants with antibacterial potentiation activity are currently available in clinical practice. Here, we first docked the library containing more than 30,000 small molecules to carbapenemases including Klebsiella pneumoniae carbapenemase 2 (KPC-2) and New Delhi metallo-ß-lactamase-5 (NDM-5), through in silico virtual screening to obtain lead compounds against carbapenemase-producing Enterobacterales. Meanwhile, the in vitro antibacterial potentiation assays revealed that ibandronate, azacytidine, ribostamycin sulfate and cidofovir exhibited synergistic or additive activity in the presence of meropenem, with good biocompatibility based on red blood cell hemolysis and cell viability tests. Furthermore, the combination of meropenem and azacytidine showed high efficacy in a mouse sepsis model infected with an NDM-5-producing clinical strain, with a 100% survival rate, decreased bacterial burden and alleviated pathological deterioration. These results suggest that the virtual screening is a promising strategy to identify new antibiotic adjuvants targeting carbapenemase-producing Enterobacterales.

Associations between Per- and Polyfluoroalkyl Substances Exposures and Blood Lipid Levels among Adults-A Meta-Analysis.

BACKGROUND: Associations between per- and polyfluoroalkyl substances (PFAS) and blood lipid levels in humans were mixed. OBJECTIVES: The objective of this meta-analysis was to summarize associations between PFAS and blood lipids in adults. METHODS: A literature search was conducted on PubMed and Web of Science for articles published through 13 May 2022 that examined associations between PFAS and blood lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triacylglycerols (TGs). Inclusion criteria included the presence of associations between five PFAS (PFOA, PFOS, PFHxS, PFDA, and PFNA) and four blood lipid measures (TC, HDL-C, LDL-C, and TGs) in adults. Data on study characteristics and PFAS-lipid associations were extracted. Assessments of individual study quality were performed. Associations of changes of blood lipid levels corresponding to 1 interquartile range (IQR)-unit increase of blood PFAS levels were pooled using random effects models. Dose-response relationships were examined. RESULTS: Twenty-nine publications were included in the present analyses. Every IQR increase of PFOA was significantly associated with a 2.1-mg/dL increase in TC (95% CI: 1.2, 3.0), a 1.3-mg/dL increase in TGs (95% CI: 0.1, 2.4), and a 1.4-mg/dL increase in LDL-C (95% CI: 0.6, 2.2). PFOS was also significantly associated with TC and LDL-C levels, and the corresponding values were 2.6 (95% CI: 1.5, 3.6) and 1.9 (95% CI: 0.9, 3.0), respectively. Associations of PFOS and PFOA with HDL-C levels were largely null. For minor PFAS species, PFHxS was significantly associated with higher levels of HDL-C [0.8 (95% CI: 0.5, 1.2)]. Inverse associations were observed between PFDA and TGs [-5.0 (95% CI: -8.1, -1.9)] and between PFNA and TGs [-1.7 (95% CI: -3.5, -0.02)], whereas a positive association was observed between PFDA and HDL-C [1.4 (95% CI: 0.1, 2.7)]. Nonsignificant nonlinear dose-response relationships were identified for associations of PFOA and PFOS with certain blood lipids. DISCUSSION: PFOA and PFOS were significantly associated with TC and LDL-C levels in adults. Whether these findings may translate into an elevated cardiovascular disease risk associated with PFAS exposure warrants further investigation. https://doi.org/10.1289/EHP11840.

Low-Carbohydrate Diet Macronutrient Quality and Weight Change.

Importance: The associations of low-carbohydrate diets (LCDs) with long-term weight management remains unclear, and the source and quality of macronutrients within LCDs are less explored. Objectives: To prospectively examine associations between changes in LCD indices and weight change among US adults. Design, Setting, and Participants: This prospective cohort study included initially healthy participants at baseline from the Nurses' Health Study (NHS; 1986-2010), Nurses' Health Study II (NHSII; 1991-2015), and Health Professionals Follow-up Study (HPFS; 1986-2018). Data analysis was performed between November 2022 and April 2023. Exposures: Five LCD indices were examined: (1) a total LCD (TLCD) emphasizing overall lower carbohydrate intake; (2) an animal-based LCD (ALCD) that emphasized animal-sourced protein and fat; (3) a vegetable-based LCD (VLCD) that emphasized plant-sourced protein and fat; (4) a healthy LCD (HLCD) emphasizing less refined carbohydrates, more plant protein, and healthy fat; and (5) an unhealthy LCD (ULCD) emphasizing less healthful carbohydrates, more animal protein, and unhealthy fat. Main Outcomes and Measures: The outcome of interest was 4-year changes in self-reported body weight. Results: A total of 123 332 participants (mean [SD] age, 45.0 [9.7] years; 103 320 [83.8%] female) were included in this study. The median carbohydrate intake (as a percentage of energy) of the highest quintiles of TLCD score at baseline ranged from 38.3% in HPFS to 40.9% in NHSII. Mean weight gain over 4-year intervals among participants varied from 0.8 kg in the HPFS to 1.8 kg in the NHSII. After adjusting for demographics and baseline and concomitant changes of selected lifestyle factors, each 1-SD increase in TLCD score was associated with 0.06 (95% CI, 0.04-0.08) kg more weight gain over the 4-year periods. Similarly, participants gained 0.13 (95% CI, 0.11 to 0.14) kg per each 1-SD increase in ALCD score and 0.39 (95% CI, 0.37 to 0.40) kg per each 1-SD change in ULCD score. In contrast, each 1-SD increase in VLCD score was associated with 0.03 (95% CI, 0.01 to 0.04) kg less weight gain, and each 1-SD increase in HLCD score was associated with 0.36 (95% CI, 0.35 to 0.38) kg less weight gain. The associations were more pronounced among obese individuals (per 1-SD increase in HLCD score: BMI ≥30, 0.88 [95% CI, 0.80, 0.97] kg less weight gain; BMI <25, 0.23 [95% CI, 0.20, 0.26] kg less weight gain; P for interaction < .001). Conclusions and Relevance: These findings suggest that the quality of LCDs may play a critical role in modulating long-term weight change. Only LCDs that emphasized high-quality protein, fat, and carbohydrates from whole grains and other plant-based foods were associated with less weight gain.

Improving Healthy Food Choices in Low-Income Settings in the United States Using Behavioral Economic-Based Adaptations to Choice Architecture.

Low diet quality is a significant public health problem in the United States, especially among low-income populations. The food environment influences dietary choices. When applied to eating behavior, behavioral economics (BE) recognizes that decision biases instigated by a food environment saturated with unhealthy foods may lead people to purchase such foods, even when they possess the necessary information and skills to make healthy dietary choices. Choice architecture, a BE concept that involves modifying the appeal or availability of choices to "nudge" people toward a certain choice, retains freedom of choice but makes unhealthy options less convenient or visible. Choice architecture has been demonstrated to influence food choices in various settings, including supermarkets, convenience stores, and food pantries. These modifications are low-cost and feasible to implement, making them a viable strategy to help "nudge" patrons toward healthier choices in food establishments serving low-income populations, including food pantries and retailers accepting the Supplemental Nutrition Assistance Program. This narrative review searched, appraised, and underscored the strengths and limitations of extant research studies that used choice architecture adaptations to influence food choices among low-income populations in the United States. Findings from studies in food pantry settings suggest the potential of BE strategies to improve the healthfulness of food choices and dietary intake in low-income populations. In food retail settings, research suggests that BE strategies increase sales of healthy foods, like fruits and vegetables. We identify new areas of research needed to determine if BE-based modifications in low-income settings have sustained impacts on diet quality.

Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.

Histone deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed as cellular chemical tools to elucidate the function of HDAC6. Since HDAC6 has multiple domains that cannot be studied by HDAC6-selective inhibitors, CRISPR-CAS9 and siRNA/shRNA have been employed to elucidate the nonenzymatic functions of HDAC6. However, these genetic methods have many limitations. Proteolysis targeting chimera (PROTAC) is an emerging technology for the development of small molecules that can quickly remove the entire protein in cells. We previously developed multifunctional HDAC6 degraders that can recruit cereblon (CRBN) E3 ubiquitin ligase. These HDAC6 degraders can degrade not only HDAC6 but also neo-substrates of CRBN. They are excellent candidates for the development of anticancer therapeutics, but the multifunctional nature of the CRBN-based HDAC6 degraders has limited their utility as specific chemical probes for the study of HDAC6-related cellular pathways. Herein we report the development of the first cell-permeable HDAC6-selective degraders employing Von Hippel-Lindau (VHL) E3 ubiquitin ligase, which does not have any known neo-substrates. The DC50's of the most potent compound 3j are 7.1 nM and 4.3 nM in human MM1S and mouse 4935 cell lines, respectively. The D max's of 3j in these two cell lines are 90% and 57%, respectively.