J-shaped association between dietary thiamine intake and the risk of cognitive decline in cognitively healthy,older Chinese individuals

Background The prospective association of dietary thiamine intake with the risk of cognitive decline among the general older adults remains uncertain.Aims To investigate the association between dietary thiamine intake and cognitive decline in cognitively healthy,older Chinese individuals.Methods The study included a total of 3106 participants capable of completing repeated cognitive function tests.Dietary nutrient intake information was collected through 3-day dietary recalls and using a 3-day food-weighed method to assess cooking oil and condiment consumption.Cognitive decline was defined as the 5-year decline rate in global or composite cognitive scores based on a subset of items from the Telephone Interview for Cognitive Status-modified.Results The median follow-up duration was 5.9 years.There was a J-shaped relationship between dietary thiamine intake and the 5-year decline rate in global and composite cognitive scores,with an inflection point of 0.68 mg/day(95%confidence interval(Cl):0.56 to 0.80)and a minimal risk at 0.60-1.00 mg/day of dietary thiamine intake.Before the inflection point,thiamine intake was not significantly associated with cognitive decline.Beyond the inflection point,each unit increase in thiamine intake(mg/day)was associated with a significant decrease of 4.24(95%Cl:2.22 to 6.27)points in the global score and 0.49(95%Cl:0.23 to 0.76)standard units in the composite score within 5 years.A stronger positive association between thiamine intake and cognitive decline was observed in those with hypertension,obesity and those who were non-smokers(all p<0.05).Conclusions This study revealed a J-shaped association between dietary thiamine intake and cognitive decline in cognitively healthy,older Chinese individuals,with an inflection point at 0.68 mg/day and a minimal risk at 0.60-1.00 mg/day of dietary thiamine intake.

整合素α6靶向自组装促凋亡纳米多肽对中枢神经系统急性淋巴细胞白血病的靶向治疗

There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression.The targeted peptide D(RWYD)(abbreviated RD),with nanomolar affinity to integrinα6 was identified by peptide scanning techniques such as alanine scanning,truncation,and D-substitution.Herein,we developed a therapeutic nanoparticle based on the integrinα6-targeted peptide for treating CNS-ALL.The self-assembled proapoptotic nanopeptide_(D)(RWYD)-_(D)(KLAKLAK)_(2)-G_(D)(FFY)(abbreviated RD-KLA-Gffy)contains the integrinα6-targeted peptide RD,the well-known proapoptotic peptide_(D)(KLAKLAK)_(2)(abbreviated KLA),and the self-assembling tetrapeptide GD(FFY)(abbreviated Gffy).The functional mechanism of RD-KLA-Gffy is clarified using different experiments.Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis,thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity.Moreover,the combined use of RD-KLA-Gffy and methotrexate(MTX)shows a potent antitumor effect in treating CNS-ALL,indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX,which shows promise for application in CNS-ALL therapy.

Functional gastrointestinal disorders,mental health,genetic susceptibility,and incident chronic kidney disease

Background:Whether functional gastrointestinal disorders(FGIDs)are associated with the long-term risk of chronic kidney disease(CKD)remains unclear.We aimed to investigate the prospective association of FGIDs with CKD and examine whether mental health mediated the association.Methods:About 416,258 participants without a prior CKD diagnosis enrolled in the UK Biobank between 2006 and 2010 were included.Participants with FGIDs(including irritable bowel syndrome[IBS],dyspepsia,and other functional intestinal disorders[FIDs;mainly composed of constipation])were the exposure group,and non-FGID participants were the non-exposure group.The primary outcome was incident CKD,ascertained from hospital admission and death registry records.A Cox proportional hazard regression model was used to investigate the association between FGIDs and CKD,and the mediation analysis was performed to investigate the mediation proportions of mental health.Results:At baseline,33,156(8.0%)participants were diagnosed with FGIDs,including 21,060(5.1%),8262(2.0%),and 6437(1.6%)cases of IBS,dyspepsia,and other FIDs,respectively.During a mean follow-up period of 12.1 years,11,001(2.6%)participants developed CKD.FGIDs were significantly associated with a higher risk of incident CKD compared to the absence of FGIDs(hazard ratio[HR],1.36;95%confidence interval[CI],1.28-1.44).Similar results were observed for IBS(HR,1.27;95%CI,1.17-1.38),dyspepsia(HR,1.30;95%CI,1.17-1.44),and other FIDs(HR,1.60;95%CI,1.43-1.79).Mediation analyses suggested that the mental health score significantly mediated 9.05%of the association of FGIDs with incident CKD and 5.63-13.97%of the associations of FGID subtypes with CKD.Specifically,the positive associations of FGIDs and FGID subtypes with CKD were more pronounced in participants with a high genetic risk of CKD.Conclusion:Participants with FGIDs had a higher risk of incident CKD,which was partly explained by mental health scores and was more pronounced in those with high genetic susceptibility to CKD.

Mannose inhibits the growth of prostate cancer through a mitochondrial mechanism

The limited treatment options for advanced prostate cancer(PCa)lead to the urgent need to discover new anticancer drugs.Mannose,an isomer of glucose,has been reported to have an anticancer effect on various tumors.However,the anticancer effect of mannose in PCa remains unclear.In this study,we demonstrated that mannose inhibits the proliferation and promotes the apoptosis of PCa cells in vitro,and mannose was observed to have an anticancer effect in mice without harming their health.Accumulation of intracellular mannose simultaneously decreased the mitochondrial membrane potential,increased mitochondrial and cellular reactive oxygen species(ROS)levels,and reduced adenosine triphosphate(ATP)production in PCa cells.Mannose treatment of PCa cells induced changes in mitochondrial morphology,caused dysregulated expression of the fission protein,such as fission,mitochondrial 1(FIS1),and enhanced the expression of proapoptotic factors,such as BCL2-associated X(Bax)and BCL2-antagonist/killer 1(Bak).Furthermore,lower expression of mannose phosphate isomerase(MPI),the key enzyme in mannose metabolism,indicated poorer prognosis in PCa patients,and downregulation of MPI expression in PCa cells enhanced the anticancer effect of mannose.This study reveals the anticancer effect of mannose in PCa and its clinical significance in PCa patients.

A kidney-brain neural circuit drives progressive kidney damage and heart failure

Chronic kidney disease(CKD)and heart failure(HF)are highly prevalent,aggravate each other,and account for substantial mortality.However,the mechanisms underlying cardiorenal interaction and the role of kidney afferent nerves and their precise central pathway remain limited.Here,we combined virus tracing techniques with optogenetic techniques to map a polysynaptic central pathway linking kidney afferent nerves to subfornical organ(SFO)and thereby to paraventricular nucleus(PVN)and rostral ventrolateral medulla that modulates sympathetic outflow.This kidney-brain neural circuit was overactivated in mouse models of CKD or HF and subsequently enhanced the sympathetic discharge to both the kidney and the heart in each model.Interruption of the pathway by kidney deafferentation,selective deletion of angiotensin II type 1a receptor(AT1a)in SFO,or optogenetic silence of the kidney-SFO or SFO-PVN projection decreased the sympathetic discharge and lessened structural damage and dysfunction of both kidney and heart in models of CKD and HF.Thus,kidney afferent nerves activate a kidney-brain neural circuit in CKD and HF that drives the sympathetic nervous system to accelerate disease progression in both organs.These results demonstrate the crucial role of kidney afferent nerves and their central connections in engaging cardiorenal interactions under both physiological and disease conditions.This suggests novel therapies for CKD or HF targeting this kidney-brain neural circuit.

J-shaped association between dietary zinc intake and new-onset hypertension:a nationwide cohort study in China

We aimed to investigate the relationship of dietary zinc intake with new-onset hypertension among Chinese adults.A total of 12,177 participants who were free of hypertension at baseline from the China Health and Nutrition Survey were included.Dietary intake was assessed by three consecutive 24-h dietary recalls combined with a household food inventory.Participants with systolic blood pressure≥140 mmHg or diastolic blood pressure≥90 mmHg or diagnosed by a physician or under antihypertensive treatment during the follow-up were defined as having new-onset hypertension.During a median follow-up duration of 6.1 years,4269 participants developed new-onset hypertension.Overall,the association between dietary zinc intake and new-onset hypertension followed a J-shape(P for non-linearity<0.001).The risk of new-onset hypertension significantly decreased with the increment of dietary zinc intake(per mg/day:hazard ratio(HR)0.93;95%confidence interval(CI)0.88–0.98)in participants with zinc intake<10.9 mg/day,and increased with the increment of zinc intake(per mg/day:HR 1.14;95%CI 1.11–1.16)in participants with zinc intake≥10.9 mg/day.In conclusion,there was a J-shaped association between dietary zinc intake and new-onset hypertension in general Chinese adults,with an inflection point at about 10.9 mg/day.