Factors affecting cognitive frailty improvement and progression in Taiwanese older adults.

BACKGROUND: Knowledge of predictors of cognitive frailty (CF) trajectories is required to develop preventive strategies to delay or reverse the progression from CF to dementia and other adverse outcomes. This 2-year prospective study aimed to investigate factors affecting the progression and improvement of CF in older Taiwanese adults. METHODS: In total, 832 community-dwelling people aged ≥ 65 years were eligible. Fried's five frailty criteria were used to measure prefrailty and frailty, while cognitive performance was assessed by the Clinical Dementia Rating and Mini-Mental State Examination. Each component of reversible CF and potentially reversible CF was assigned a score, with a total score ranging 0 to 5 points. Two annual follow-up CF assessments were conducted. The group-based trajectory model was applied to identify latent CF trajectory groups, and a multinomial logistic regression was used to examine relationships of explanatory variables with CF trajectories. RESULTS: According to data on 482 subjects who completed the two annual follow-ups, three CF trajectories of robust, improvement, and progression were identified. After adjusting for the baseline CF state, CF progression was significantly associated with an older age (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.02 ~ 1.14), a lower Tinetti balance score (OR = 0.72; 95% CI, 0.54 ~ 0.96), a slower gait (OR = 0.98; 95% CI, 0.97 ~ 0.99), and four or more comorbidities (OR = 2.65; 95% CI, 1.19 ~ 5.90), while CF improvement was not significantly associated with any variable except the baseline CF state. In contrast, without adjusting for the baseline CF state, CF progression was significantly associated with an older age, female sex, balance scores, gait velocity, regular exercise, the number of comorbidities, and depression, while CF improvement was significantly associated with female sex, balance scores, and the number of comorbidities. CONCLUSIONS: The baseline CF state, an older age, poorer balance, slower gait, and a high number of comorbidities may contribute to CF progression, while the baseline CF state may account for associations of engaging in regular exercise and depression with CF development.

Risk factors of knee reinjury after anterior cruciate ligament reconstruction.

PURPOSE: This study aimed to investigate whether the return to level I sports, concomitant injuries, foot-related problems, and other factors would increase the risk of knee reinjury after anterior cruciate ligament reconstruction (ACLR). METHODS: This study used a prospective cohort study design. Online enrolment from August 2018 to January 2019 in ACL Community Indonesia recruited 148 patients who had undergone ACLR less than one month prior to injury. Knee injury occurrence after ACLR was diagnosed through a physical examination and positive MRI or arthroscopic findings. RESULTS: During the study, 55 knee reinjuries occurred. The proportional hazards model analysis revealed that the risk of knee reinjury at 12 and 24 months for patients who returned to level I sports (hazards ratio (HR)=3.17 and HR=3.90, respectively) was significantly higher than that of the patients who did not return to sports and that the risk for those who returned to level II/III sports did not significantly increase at 12 or 24 months. Patients with concomitant meniscus injury had a significantly higher risk of knee reinjury at 12 and 24 months (HR=3.33 and HR=2.25, respectively) than those without, and the risk of knee reinjury for patients with concomitant posterior cruciate ligament injury was significantly higher at 12 months (HR=3.05) but not at 24 months. Fewer knee symptoms after ACLR were significantly associated with a lower risk of knee reinjury (HR=0.98) at 12 and 24 months. CONCLUSIONS: The return to level I sports, concomitant meniscus and posterior cruciate ligament injury, and knee symptoms after ACLR may increase the risk of knee reinjury for post-ACLR patients.

Predictors of incident reversible and potentially reversible cognitive frailty among Taiwanese older adults.

BACKGROUND: Few studies emphasize on predictors of incident cognitive frailty (CF) and examine relationships between various gait characteristics and CF. Therefore, we conducted a 2-year prospective study to investigate potential predictors, including gait characteristics, of incident reversible CF (RCF) and potentially RCF (PRCF) among Taiwanese older adults. METHODS: Eligible participants were individuals aged ≥ 65 years, who could ambulate independently, and did not have RCF/PRCF at the baseline. The baseline assessment collected information on physical frailty and cognitive measures, in addition to sociodemographic and lifestyle characteristics, preexisting comorbidities and medications, gait characteristics, Tinetti's balance, balance confidence as assessed by Activities-specific Balance Confidence (ABC) scale, and the depressive status as assessed by the Geriatric Depression Scale. The Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale, and Digit Symbol Substitution Test were used to evaluate cognitive functions. Incident RCF and PRCF were ascertained at a 2-year follow-up assessment. RESULTS: Results of the multinomial logistic regression analysis showed that incident RCF was significantly associated with older age (odds ratio [OR] = 1.05) and lower ABC scores (OR = 0.97). Furthermore, incident PRCF was significantly associated with older age (OR = 1.07), lower ABC scores (OR = 0.96), the presence of depression (OR = 3.61), lower MMSE scores (OR = 0.83), slower gait velocity (OR = 0.97), and greater double-support time variability (OR = 1.09). CONCLUSIONS: Incident RCF was independently associated with older age and lower balance confidence while incident PRCF independently associated with older age, reduced global cognition, the presence of depression, slower gait velocity, and greater double-support time variability. Balance confidence was the only modifiable factor associated with both incident RCF and PRCF.

Specific cognitive domains and frailty trajectories among older Taiwanese adults.

Objective: To investigate the associations of specific cognitive functions and with the frailty trajectory among older Taiwanese adults.Methods: At baseline, 730 community-dwelling older adults were recruited from outpatient clinics of a general hospital. Frailty status was defined using phenotype criteria. Global cognition was assessed using the modified Telephone Interview of Cognitive Status and Mini-Mental State Examination (MMSE). The Mattis Dementia Rating Scale (MDRS) and Digit Symbol Substitution Test were used to evaluate 6 cognitive domains: attention, initiation/perseveration, construction, conceptualization, memory, and processing speed. The group-based trajectory model was used to identify latent frailty trajectory groups and the multinomial logistic regression was to examine the relationships of specific cognitive functions with frailty trajectory.Results: Among 485 participants (168 men, 317 women, and mean age: 71.1 ± 5.5 years) completed 2 annual follow-up assessments, three frailty trajectory groups of improvement, no-change, and progression were identified. After adjusting for baseline frailty status, age, sex, global cognition, regular exercise habit, and number of comorbidities, higher scores on MDRS's initiation/perseveration (odds ratio [OR] = 0.85; 95% CI = 0.75-0.95) and attention (OR = 0.63; 95% CI = 0.38-1.00), respectively, were significantly associated with lower risk of frailty progression. Conversely, no significant association was detected between MMSE or TICSM scores and frailty improvement or progression.Conclusion: Specific cognitive functions of initiation/perseveration and attention, rather than global cognition, may be more useful to predict frailty progression, thus allowing the identification of at-risk older adults.

Effects of home-based computerized cognitive training and tai chi exercise on cognitive functions in older adults with mild cognitive impairment.

BACKGROUND: A randomized trial was conducted to investigate the effects of computerized cognitive training (CCT) and tai chi exercise (TCE) vs. health education (HE) on cognitive functions in 189 older adults with mild cognitive impairment (MCI). METHODS: Cognitive functions were assessed by the five-domain Mattis Dementia Rating Scale (MDRS) (attention, initiation/perseveration, construction, conceptualization, and memory) and the modified Telephone Interview of Cognitive Status (TICS-M), while the timed up and go (TUG), Tinetti's balance, activities of daily living (ADLs), and Activities-specific Balance Confidence (ABC) were also evaluated. Each intervention was delivered once a week for 6 months. All outcomes were followed up at 6 and 12 months of the study. RESULTS: Compared to HE, CCT increased scores on the MDRS's total, initiation/perseveration, construction, and conceptualization domains and on the TICS-M at 6 months and those on the MDRS's total, attention, construction, conceptualization, and memory domains and on the TICS-M at 12 months; TCE increased scores on the MDRS's total and construction domains and on the TICS-M at 6 months and those on the MDRS's total, attention, initiation/perseveration, and conceptualization domains and on the TICS-M at 12 months. Moreover, CCT improved the TUG at 6 and 12 months and Tinetti's balance at 12 months, and TCE improved the TUG at 6 and 12 months, Tinetti's balance, and ABC at 6 and 12 months, and ADLs at 12 months. CONCLUSIONS: The effects of CCT and TCE on improving global cognition and certain cognitive domains for older MCI adults may have been small but they lasted for at least 12 months.

Gender Differences in Personal and Situational Risk Factors for Traumatic Brain Injury Among Older Adults.

OBJECTIVE: To investigate differences between older men and women in Taiwan in personal and situational risk factors for sustaining a traumatic brain injury (TBI) versus soft-tissue injury (STI) due to a fall. DESIGN: Matched case-control study. PARTICIPANTS AND SETTINGS: Cases were defined as patients with a primary diagnosis of TBI due to a fall and were identified from those 60 years or older who visited the emergency department (ED) of 3 university-affiliated hospitals in 2015. Matched by the same hospital ED, gender, and time of falling, 3 controls who had no TBI and who had sustained only soft-tissue injury (STI) due to falling were selected for comparison with each case. Personal factors and situational exposures were compared between the control and case groups. In total, 96 cases and 288 controls in men and 72 cases and 216 controls in women participated in this study. MAIN MEASURES: Personal factors (sociodemographic and lifestyle factors, medical characteristics, and functional abilities) and situational exposures (location, activities before the fall, center-of-mass change, type of fall, falling direction, protective response, and impact during the fall). RESULTS: In men, after adjusting for other variables, older age (odds ratio [OR] = 1.04), regular alcohol use (OR = 2.03), an indoor fall (OR = 1.92), activity of getting in/out of bed (OR = 2.56), a fall due to dizziness (OR = 4.09), and falling backward (OR = 2.95) were independently associated with a higher odds of TBI. In women, an older age (OR = 1.03), the presence of Parkinson disease (OR = 10.4), activities of toileting (OR = 2.50), getting in/out of bed (OR = 4.90), and negotiating stairs (OR = 7.13), a fall due to dizziness (OR = 5.05), and falling backward (OR = 2.61) were independently associated with a higher odds of TBI. CONCLUSIONS: Our results demonstrated similarities and differences in personal and situational risk factors for fall-related TBIs versus STIs between older men and women, and gender differences should be considered when developing intervention strategies.

Effects of Kinesio Taping and Transcutaneous Electrical Nerve Stimulation Combined With Active Stretching on Hamstring Flexibility.

ABSTRACT: Adhitya, IPGS, Yu, W-Y, Bass, P, Kinandana, GP, and Lin, M-R. Effects of Kinesio taping and transcutaneous electrical nerve stimulation combined with active stretching on hamstring flexibility. J Strength Cond Res 36(11): 3087-3092, 2022-Active stretching (AS), Kinesio taping (KT), and transcutaneous electrical nerve stimulation (TENS) are frequently used to ameliorate pain and improve the ranges of motion (ROM) of athletes; however, the effectiveness of KT and TENS combined with AS in ameliorating short hamstring syndrome is yet to be determined. In this single-blinded randomized trial, 135 male soccer players with bilateral short hamstring syndrome were assigned to 3 intervention groups-AS, KT + AS, and TENS + AS-through block randomization. Each subject received the intervention twice per week for 4 weeks. The ROM of both legs was assessed through passive knee extension and straight leg raising tests at baseline and the end of the intervention. After the 4-week intervention, significant ROM changes in both legs were detected in the AS (9.5°-18.4°), KT + AS (14.9°-22.4°), and TENS + AS (14.9°-22.3°) groups. Compared with the AS group, both the KT + AS (3.8°-5.7°) and TENS + AS (3.9°-5.7°) groups showed significantly increased ROM in both legs over the intervention period, and no significant differences were observed in ROM changes between the KT + AS and TENS + AS groups. In conclusion, both KT and TENS in combination with AS may increase ROM more than AS alone, and the improvements obtained using KT with AS and TENS with AS may be similar.

Variations in situational risk factors for fractures of the distal forearm, hip, and vertebrae in older women.

BACKGROUND: Situational factors during a fall among three common types of fractures of the distal forearm, hip, and vertebrae among older women in Taiwan were investigated. METHODS: In 2016 ~ 2017, study participants were identified from those aged ≥65 years who visited emergency departments due to a fall in two university-affiliated hospitals in Taipei. In addition to individual characteristics, situational factors during the fall (location, activity, change of center of mass, fall mode, fall direction, initiating a protective response, and being hit) were collected. A sample of 203 distal-forearm fractures, 189 vertebral fractures, and 375 hip fractures was recruited, while 717 women with a soft-tissue injury were used as a control group. The identification of situational risk factors for each type of fracture was validated by using those who sustained one of the other two types of fracture as a control group. RESULTS: After adjusting for age and other individual characteristics, compared to soft-tissue injuries, distal-forearm fractures were significantly more likely to occur with slips (odds ratio [OR] = 11.0; 95% confidence interval [CI] = 4.76 ~ 25.4), trips (OR = 3.40; 95% CI = 1.42 ~ 8.17), step-downs (OR = 4.95; 95% CI = 2.15 ~ 11.4), and from sideways falls (OR = 1.73; 95% CI = 1.12 ~ 2.67) and significantly less likely to occur indoors (OR = 0.62; 95% CI = 0.42 ~ 0.90) or from backwards falls (OR = 0.62; 95% CI = 0.41 ~ 0.95). Hip fractures were significantly more likely to occur with step-downs (OR = 1.76; 95% CI = 1.13 ~ 2.75) and from backwards (OR = 3.16; 95% CI = 2.15 ~ 4.64) or sideways falls (OR = 5.56; 95% CI = 3.67 ~ 8.41) and significantly less likely when hitting an object (OR = 0.26; 95% CI = 0.13 ~ 0.52) or initiating a protective response (OR = 0.58; 95% CI = 0.36 ~ 0.93). Vertebral fractures were significantly more likely to occur with slips (OR = 2.42; 95% CI = 1.30 ~ 4.50), step-downs (OR = 2.53; 95% CI = 1.43 ~ 4.48), and backwards falls (OR = 2.15; 95% CI = 1.39 ~ 3.32). Similar results were found in the validation analyses. CONCLUSIONS: Large variations in situational risk factors for the three types of fracture in older women existed. A combination of individual and situational risk factors may display a more-comprehensive risk profile for the three types of fracture, and an intervention that adds training programs on safe landing strategies and effective compensatory reactions may be valuable in preventing serious injuries due to a fall.

Effects of Computerized Cognitive Training and Tai Chi on Cognitive Performance in Older Adults With Traumatic Brain Injury.

OBJECTIVE: To compare the effects of computerized cognitive training (CCT) and tai chi (TC) with usual care (UC) on cognitive functions and secondary outcomes in older adults with traumatic brain injury. PARTICIPANTS AND SETTINGS: Ninety-six patients aged 55 years and older who had a diagnosis of traumatic brain injury requiring hospital admission. DESIGN: Randomized controlled trial. MAIN MEASURES: The Mattis Dementia Rating Scale (MDRS), Mini-Mental State Examination, modified Telephone Interview of Cognitive Status, and Trail Making Tests A and B. RESULTS: Compared with UC, CCT increased scores on the MDRS's total, attention, and memory and those on the Mini-Mental State Examination and Telephone Interview of Cognitive Status over the 6-month intervention; TC increased scores on the MDRS's total and conceptualization and those on the Mini-Mental State Examination over the 6-month intervention, while it also increased scores on the MDRS's total and initiation/preservation and those on the Telephone Interview of Cognitive Status and reduced the time to complete the Trail Making Test B over the 12-month study. Furthermore, compared with UC, CCT increased handgrip strength and TC reduced the time to complete 5 sit-to-stands over the 6-month intervention. CONCLUSION: Both CCT and TC may improve global cognition and different specific cognitive domains in older traumatic brain injury patients; the TC's effect may last for at least an additional 6 months.

Risk Factors for Injuries From Physical Violence in African Women in the Gambia.

BACKGROUND: Physical violence against women is a major public health problem in African countries; however, no studies have focused on factors associated with violent injuries to women in Africa. OBJECTIVES: A matched case-control study was conducted to investigate risk factors for injuries from physical violence against African women in The Gambia. METHODS: Over a 12-month study period, study participants were recruited from emergency departments of eight government-managed health care facilities. Cases were female patients aged ≥ 15 years who had been violently injured. Matched by the health facility, date of injury, sex, and age, a control patient for each case was selected from those injured due to nonviolent mechanisms. RESULTS: In total, 194 case-control pairs were recruited. Results of a conditional logistic regression showed that being a Fula (odds ratio [OR] 2.45; 95% confidence interval [CI] 1.06-5.66), living in an extended family compound (OR 3.07; 95% CI 1.22-7.72), having six or more female siblings (OR 3.10; 95% CI 1.38-6.97), having been raised by grandparents (OR 3.34; 95% CI 1.06-10.51), and having been verbally (OR 3.04; 95% CI 1.56-5.96) or physically abused (OR 3.36; 95% CI 1.34-8.39) in the past 12 months were significantly associated with injury from physical violence. CONCLUSION: Most risk factors identified for violent injury among African women are unique to the studied geography. Violence prevention programs, if designed based on these identified risk factors, may be more effective for this population.

Risk Factors for Recurrent Injuries from Physical Violence Among African Men in The Gambia.

While men are known to be at high risk of recurrent injuries from physical violence, the risk factors in African men have not been investigated. We conducted a matched case-control study to identify factors associated with recurrent injuries from physical violence in The Gambia. Eligible participants were injured male patients aged ≥ 15 years. Over the 12-month study period, 257 cases with recurrent injuries from physical violence, and 257 control patients each from two control groups (violence controls and nonviolence controls) were recruited from eight emergency rooms located in six districts of the Greater Banjul Metropolitan Area, The Gambia. The two control groups matched cases at the same health facility, date of injury, and age, in which violence controls (VCs) experienced only one violence-related injury in the past 12 months and nonviolence controls (NCs) experienced no violence-related injuries. Results of the multivariable conditional logistic regression showed that for both the VC and NC groups, a polygamous family (ORVC, 3.62; ORNC, 2.79), > 8 family members (ORVC, 5.60; ORNC, 4.81), being brought up by a family relative (ORVC, 5.17; ORNC, 2.11), having smoked cigarettes in the past week (ORVC, 3.53; ORNC, 4.03), and perceiving no family support (ORVC, 1.12; ORNC, 1.19) were significantly associated with the occurrence of recurrent violent injuries. Furthermore, compared to the NCs, three additional factors of > 2 male siblings (ORNC, 1.84), low household income (ORNC, 3.11), and alcohol consumption in the past week (ORNC, 4.66) were significantly associated with the occurrence of recurrent violent injuries. These findings may fill in a knowledge gap that will be beneficial for developing effective intervention programs to reduce recurrent injuries from physical violence among African men.

New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms.

A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms.

Risk Factors for Traumatic Brain Injuries During Falls in Older Persons.

OBJECTIVE: To identify risk factors for traumatic brain injuries (TBIs) during falls in older Taiwanese people. PARTICIPANTS: Case patients consisted of 113 patients aged 60 years or older with a moderate/severe TBI due to a fall. Two control groups: (1) 339 older patients with a soft-tissue injury; and (2) 113 with a mild-TBI due to a fall. Proxies were required to provide information for a considerable number of patients. DESIGN: Matched case-control study. SETTINGS: The emergency departments of 3 general hospitals. MEASURES: Sociodemographic, lifestyle behavior, chronic condition, medication use, functional abilities, and fall-related characteristics. RESULTS: When patients with a soft-tissue injury were assigned to the control group, men were 2.06-fold more likely to have a moderate/severe TBI than women. Subjects who took antiarrhythmics within 4 hours of a fall were 2.59-fold more likely to have a moderate/severe TBI than those who took none. Subjects who were negotiating stairs and getting in/out of the bed/chair were 3.12-fold and 2.97-fold, respectively, more likely to have a moderate/severe TBI than those who fell while walking. Falling backward and sideways was 4.07-fold and 2.30-fold, respectively, more likely to cause a moderate/severe TBI than falling forward. When patients with a mild-TBI were assigned to the control group, results were similar, with the exception that the effect of antiarrhythmic use became nonsignificant and subjects who took 2 or more medications were 3.07-fold more likely to have a moderate/severe TBI than those who took none. CONCLUSION: Avoiding a head impact during a backward or sideways fall, reducing unnecessary use of polypharmacy and antiarrhythmics, and maintaining safety during stair negotiation and bed/chair transfer may protect an elderly person from a severe brain injury.

A scintillation proximity assay for histone demethylases.

Covalent modifications, such as methylation and demethylation of lysine residues in histones, play important roles in chromatin dynamics and the regulation of gene expression. The lysine demethylases (KDMs) catalyze the demethylation of lysine residues on histone tails and are associated with diverse human diseases, including cancer, and are therefore proposed as targets for the therapeutic modulation of gene transcription. High-throughput assays have been developed to find inhibitors of KDMs, most of which are fluorescence-based assays. Here we report the development of a coupled scintillation proximity assay (SPA) for 3 KDMs: KDM1A (LSD1), KDM3A (JMJD1A), and KDM4A (JMJD2A). In this assay methylated peptides are first demethylated by a KDM, and a protein methyltransferase (PMT) is added to methylate the resulting peptide with tritiated S-(5'-adenosyl)-l-methionine. The enzyme activities were optimized and kinetic parameters were determined. These robust coupled assays are suitable for screening KDMs in 384-well format (Z' factors of 0.70-0.80), facilitating discovery of inhibitors in the quest for cancer therapeutics.

Polygonum viviparum L. induces vasorelaxation in the rat thoracic aorta via activation of nitric oxide synthase in endothelial cells.

BACKGROUND: In the past several decades, Polygonum viviparum L. (PV) was reported to have antibacterial, antiulcer, antioxidant, antitumor, anti-inflammatory, and antiarthritic properties. The anti-inflammatory pathway was recently elucidated through cytosolic nuclear factor E2-related factor 2 (Nrf2) activation and heme oxygenase (HO)-1 protein expression. PV is a perennial herb and widely distributed in high-elevation mountain regions, such as the Tibetan Plateau. In Tibetan traditional medicine, PV is usually used to boost the blood circulation to dissipate blood stasis. Therefore, this study focused on how PV improves the vascular circulation and acts on vascular tissues. METHODS: In this study, we isolated aortas from Sprague-Dawley rats (male, weight about 250~350 g), and detected the effects of PV on phenylephrine (PE)-induced contraction and cyclic guanosine 3',5'-monophosphate (cGMP) formation using aortic rings. In addition, human umbilical vein endothelial cells (HUVECs) were used to exam nitric oxygen (NO) synthase (NOS) activity by directly measuring NO production in the culture medium. Endothelial (e) NOS phosphorylation, and cytosolic Nrf2 and HO-1 expressions were measured using a Western blot analysis. RESULTS: PV dose-dependently relaxed PE-induced contractions in endothelial-intact but not -denuded aorta. The concentration to produce 50% relaxation was 22.04±1.77 µg/ml. PV-induced vasorelaxation was markedly blocked by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), an NOS inhibitor, methylene blue (MB), a guanylyl cyclase inhibitor, and hemoglobin, an NO scavenger. PV increased cGMP formation; however, this effect was also suppressed by co-pretreatment with l-NAME, MB, hemoglobin, and Ca2+-free medium. In HUVECs, PV increased NO formation, which was greatly attenuated by NOS inhibitors (L-NAME and L-NMMA) and by removing extracellular Ca2+ and chelating intracellular Ca2+ with BAPTA-AM. In addition, PV promoted eNOS phosphorylation, Nrf2 degradation, and HO-1 protein expression according to a Western blot analysis. CONCLUSIONS: The results suggest that PV possesses vasorelaxing action in an endothelium-dependent manner and works through activating Ca2+/calmodulin- dependent NO synthesis; when NO is released and then transferred to smooth muscle cells, NO activates guanylyl cyclase and increases cGMP formation, ultimately resulting in vasorelaxation. Thus, PV can be considered for application as a potential therapeutic approach for vascular-associated disorders.

Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.

Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia.

Polygonum viviparum L. inhibits the lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages through haem oxygenase-1 induction and activation of the Nrf2 pathway.

BACKGROUND: Polygonum viviparum L. (PV) is a member of the family Polygonaceae and is widely distributed in high-elevation areas. It is used as a folk remedy to treat inflammation-related diseases. This study was focused on the anti-inflammatory response of PV against lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. RESULTS: Treatment with PV did not cause cytotoxicity at 0-50 µg mL(-1) in RAW264.7 macrophages, and the IC(50) value was 270 µg mL(-1). PV inhibited LPS-stimulated nitric oxide (NO), prostaglandin (PG)E(2) , interleukin (IL)-1ß and tumour necrosis factor (TNF)-α release and inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 protein expression. In addition, PV suppressed the LPS-induced p65 expression of nuclear factor (NF)-κB, which is associated with the inhibition of IκB-α degradation. These results suggest that, among mechanisms of the anti-inflammatory response, PV inhibits the production of NO and these cytokines by down-regulating iNOS and COX-2 gene expression. Furthermore, PV can induce haem oxygenase (HO)-1 protein expression through nuclear factor E2-related factor 2 (Nrf2) activation. A specific inhibitor of HO-1, zinc(II) protoporphyrin IX, inhibited the suppression of iNOS and COX-2 expression by PV. CONCLUSION: These results suggest that PV possesses anti-inflammatory actions in macrophages and works through a novel mechanism involving Nrf2 actions and HO-1. Thus PV could be considered for application as a potential therapeutic approach for inflammation-associated disorders.

Multi-omics analysis reveals copper-induced growth inhibition mechanisms of earthworm (Eisenia fetida).

Exposure to high concentrations of copper can cause toxic effects on the growth and development of organisms, but the relevant toxic mechanisms are far from fully understood. This study investigated the changes of metabolites, genes, and gut microorganisms in earthworms (Eisenia fetida) exposed to 0 (control), 67.58 (low), 168.96 (medium), and 337.92 (high) mg/kg of Cu in soil for 60 days. Differentially expressed genes (DEGs) and differential metabolites (DMs) at the low-, medium-, and high-level Cu exposure groups were identified and introduced into Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Integrated metabolomic and transcriptomic analysis revealed that amino acid metabolism, lipid metabolism, and carbohydrate metabolism are the major metabolic pathways disturbed by Cu exposure. Furthermore, Cu exposure significantly decreased the diversity of the intestinal bacterial community and affected the relative abundance (increased or decreased) of intestinal colonizing bacteria. This resulted in high energy expenditure, inhibited nutrient absorption and fatty acid synthesis, and weakened antioxidant and detoxification abilities, ultimately inhibiting the growth of E. fetida. These findings offer important clues and evidence for understanding the mechanism of Cu-induced growth and development toxicity in E. fetida and provide further data for risk assessment in terrestrial ecosystems.

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.

Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2.

Epigenetic regulation is involved in numerous physiological and pathogenic processes. Among the key regulators that orchestrate epigenetic signaling are over 50 human protein lysine methyltransferases (PKMTs). Interrogation of the functions of individual PKMTs can be facilitated by target-specific PKMT inhibitors. Given the emerging need for such small molecules, we envisioned an approach to identify target-specific methyltransferase inhibitors by screening privileged small-molecule scaffolds against diverse methyltransferases. In this work, we demonstrated the feasibility of such an approach by identifying the inhibitors of SETD2. N-propyl sinefungin (Pr-SNF) was shown to interact preferentially with SETD2 by matching the distinct transition-state features of SETD2's catalytically active conformer. With Pr-SNF as a structure probe, we further revealed the dual roles of SETD2's post-SET loop in regulating substrate access through a distinct topological reconfiguration. Privileged sinefungin scaffolds are expected to have broad use as structure and chemical probes of methyltransferases.