Functional Activity Research Articles

Striking a balance: the Goldilocks effect of CD8α expression on NK cells.

NK cells are cytotoxic innate immune cells involved in antitumor immunity, and they provide a treatment option for patients with acute myeloid leukemia (AML). In this issue of the JCI, Cubitt et al. investigated the role of CD8α, a coreceptor present on approximately 40% of human NK cells. IL-15 stimulation of CD8α- NK cells induced CD8α expression via the RUNX3 transcription factor, driving formation of a unique induced CD8α (iCD8α+) population. iCD8α+ NK cells displayed higher proliferation, metabolic activity, and antitumor cytotoxic function compared with preexisting CD8α+ and CD8α- subsets. Therefore, CD8α expression can be used to define a potential dynamic spectrum of NK cell expansion and function. Because these cells exhibit enhanced tumor control, they may be used to improve in NK cell therapies for patients with AML.

The effect of exercise referral schemes and self-management strategies on use of prescription analgesics among community-dwelling older adults: registry linkage with randomised controlled trials

Background and objectiveExercise referral schemes and self-management strategies have shown positive effects on patient-reported and objectively measured outcomes, such as increased functional capacity and physical activity level. However, the impact of these interventions on analgesic use remains uncertain. We hypothesised that exercise referral schemes, either utilised alone or in combination with self-management strategies, is more effective in reducing use of prescription analgesics compared with a self-management strategy only.Subjects and methodsWe utilised data from two completed randomised controlled trials, namely The Welfare Innovation in Primary Prevention (n = 121) and The SITLESS project (n = 338), and information from the national Danish health registries, including the National Prescription Registry. The two trials have investigated the effectiveness of interventions, which include exercise referral schemes and self-management strategies, on various aspects such as physical function and levels of physical activity among community-dwelling older adults. The studies were conducted in the period 2015–2020 and comprised older adults aged 65+ years, living in three different Danish municipalities. Participants were recruited through nationally regulated preventive home-visits. To estimate changes in use of prescription analgesics over time, a linear fixed effects regression model was applied. The outcome measure was the mean total yearly defined daily dose of analgesics.ResultsAll intervention groups showed a within-group increase in overall analgesic use, though not statistically significantly different from zero. There were no differences in estimated changes in mean total yearly defined daily dose when comparing the intervention groups to the group receiving the least extensive intervention (self-management strategies/control). The findings indicated that exercise referral schemes and self-management strategies, whether administrated individually or in combination, did not result in a reduction in analgesic use over time.

The SRC family kinase inhibitor NXP900 demonstrates potent antitumor activity in squamous cell carcinomas

NXP900 is a selective and potent SRC family kinase (SFK) inhibitor, currently being dosed in a phase 1 clinical trial, that locks SRC in the “closed” conformation, thereby inhibiting both kinase-dependent catalytic activity and kinase-independent functions. In contrast, several multi-targeted kinase inhibitors that inhibit SRC, including dasatinib and bosutinib, bind their target in the active “open” conformation, allowing SRC and other SFKs to act as a scaffold to promote tumorigenesis through non-catalytic functions. NXP900 exhibits a unique target selectivity profile with sub-nanomolar activity against SFK members over other kinases. This results in highly potent and specific SFK pathway inhibition. Here, we demonstrate that esophageal squamous cell carcinomas (ESCC) and head and neck squamous cell carcinomas (HNSCC) are exquisitely sensitive to NXP900 treatment in cell culture and in vivo, and we identify a patient population that could benefit from treatment with NXP900.

Association Between Physical Activity Levels and Cognitive Function in Older Adults: A Replication Cohort Analysis Using the Brazilian Longitudinal Study of Aging

Introduction: Few studies address the complex relationship between physical activity and cognitive function in aging individuals. This topic has gained significant attention in recent years, as cognitive decline poses a substantial public health challenge. There is a lack of research focusing on the effect of physical activity on cognitive function in the Brazilian population. Purpose: Our study aims to replicate the findings of Lautenschlager et al. using a Brazilian cohort from the ELSI study, a comprehensive longitudinal study capturing aging processes and determinants among individuals in Brazil. Method: In line with the reference study, our analysis focused on individuals aged 50 and older without depression and dementia. The primary outcome was cognitive function, assessed using a summary score obtained from the ELSI study to replicate the ADAS-Cog, as in the original study. Participants were categorized into two groups: those engaging in moderate to vigorous exercise (exercise) and those who did not meet this exercise threshold (no exercise). To evaluate the relationship between exercise and cognitive function, we performed three linear regression models: one without adjustments for covariates, a second model adjusting for sex, education, and race (main model), and a third model with multiple adjustments. A sensitivity analysis using Cohen's D was also conducted. Results: In this study from the ELSI cohort, data from 7,292 individuals were available, and 6,147 met the inclusion criteria for analysis. A total of 935 individuals were excluded due to depression, and 98 were excluded due to dementia. Baseline characteristics were not well balanced between groups. The mean age in the exercise group was 64 years compared to 67 years in the no exercise group, with a higher percentage of males (48% vs. 39%) and a higher education level (12% with university education vs. 6%). In the unadjusted linear regression, there was a positive correlation between exercise and cognitive function (2.19, 95% CI 1.89-2.48, p<0.001). In the second model, which emulated the reference trial by including sex, race, and educational status, the positive correlation persisted, though with a lower effect size (1.53, 95% CI 1.25-1.82, p<0.001). A third model with additional adjustments was employed to assess the consistency of the association, which was maintained (1.92, 95% CI 1.62-2.23, p<0.001). Conclusion: Our study reaffirms the potential benefits of moderate to vigorous exercise on cognitive function in older adults with mild cognitive impairment.

A multifunctional injectable, self-healing, and adhesive hydrogel-based wound dressing stimulated diabetic wound healing with combined reactive oxygen species scavenging, hyperglycemia reducing, and bacteria-killing abilities

The proficient handling of diabetic wounds, a rising issue coinciding with the global escalation of diabetes cases, poses significant clinical difficulties. A range of biofunctional dressings have been engineered and produced to expedite the healing process of diabetic wounds. This study proposes a multifunctional hydrogel dressing for diabetic wound healing, which is composed of Polyvinyl Alcohol (PVA) and N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-teramethylpropane-1, 3-diaminium (TSPBA), and a dual-drug loaded Gelatin methacryloyl (GM) microgel. The GM microgel is loaded with sodium fusidate (SF) and nanoliposomes (LP) that contain metformin hydrochloride (MH). Notably, adhesive and self-healing properties the hydrogel enhance their therapeutic potential and ease of application. In vitro assessments indicate that SF-infused hydrogel can eliminate more than 98% of bacteria within 24 h and maintain a sustained release over 15 days. Additionally, MH incorporated within the hydrogel has demonstrated effective glucose level regulation for a duration exceeding 15 days. The hydrogel demonstrates a sustained ability to neutralize ROS throughout the entire healing process, predominantly by electron donation and sequestration. This multifunctional hydrogel dressing, which integrated biological functions of efficient bactericidal activity against both MSSA and MRSA strains, blood glucose modulation, and control of active oxygen levels, has successfully promoted the healing of diabetic wounds in rats in 14 days. The hydrogel dressing exhibited significant effectiveness in facilitating the healing process of diabetic wounds, highlighting its considerable promise for clinical translation.Graphical

Anti-angiogenic activity of a novel angiostatin-like plasminogen fragment produced by a bacterial metalloproteinase

Tumor growth depends on angiogenesis, a process by which new blood vessel are formed from pre-existing normal blood vessels. Proteolytic fragments of plasminogen, containing varying numbers of plasminogen kringle domains, collectively known as angiostatin, are a naturally occurring inhibitor of angiogenesis and inhibit tumor growth. We have developed an “affinity-capture reactor” that enables a single-step method for the production/purification of an angiostatin-like plasminogen fragment from human plasma using an immobilized bacterial metalloproteinase. The resulting fragment, named BL-angiostatin, contains one or two glycosyl chains and the N-terminal PAN module, which are not present in canonical angiostatins tested for cancer treatment. BL-angiostatin inhibited angiogenesis in vitro at 20 nM and the growth of both allograft and human xenograft tumors as well as lung metastasis of primary tumors mice at 0.3–10 mg kg−1. Derivatives of BL angiostatin lacking the PAN module or the terminal sialic acids in the glycosyl chains showed reduced anti-angiogenic activity in vivo, suggesting a role for these functions in activity, possibly via conferring a pharmacokinetic advantage to BL angiostatin compared to recombinant angiostatin lacking both features. These results highlight the potential of BL-angiostatin for therapeutic applications.

Computational stabilization of a non-heme iron enzyme enables efficient evolution of new function.

Directed evolution has emerged as a powerful tool for engineering new biocatalysts. However, introducing new catalytic residues can be destabilizing, and it is generally beneficial to start with a stable enzyme parent. Here we show that the deep learning-based tool ProteinMPNN can be used to redesign Fe(II)/αKG superfamily enzymes for greater stability, solubility, and expression while retaining both native activity and industrially-relevant non-native functions. For the Fe(II)/αKG enzyme tP4H, we performed site-saturation mutagenesis with both the wild-type and stabilized design variant and screened for activity increases in a non-native C-H hydroxylation reaction. We observed substantially larger increases in non-native activity for variants obtained from the stabilized scaffold compared to those from the wild-type enzyme. ProteinMPNN is user-friendly and widely-accessible, and straightforward structural criteria were sufficient to obtain stabilized, catalytically-functional variants of the Fe(II)/αKG enzymes tP4H and GriE. Our work suggests that stabilization by computational sequence redesign could be routinely implemented as a first step in directed evolution campaigns for novel biocatalysts.

Relationship between domain-specific physical activity and cognitive function in older adults - findings from NHANES 2011-2014.

To determine the relationship between domain-specific physical activity (PA) (e.g., occupational PA [OPA], transport-related PA [TPA], and recreational PA [RPA]) and cognitive function in older adults. The data was obtained from the 2011-2014 cycle of the NHANES. We utilized weighted multivariate linear regression models among the included 2,924 people aged 60 years or older for our purposes. RPA and total PA according to WHO guidelines were associated with verbal fluency (RPA β: 1.400, 95% CI: 0.776, 2.024, p = 0.002; total PA β: 1.115, 95% CI: 0.571, 1.659, p = 0.001), processing speed and executive function (RPA β: 2.912, 95% CI. 1.291, 4.534, p = 0.005; total PA β: 2.974, 95% CI: 1.683, 4.265, p < 0.001) were positively correlated, and total PA was correlated with delayed memory performance (β: 0.254, 95% CI: 0.058, 0.449, p = 0.019). No significant association was observed between OPA, TPA, and various aspects of cognitive function among individuals over 60 years. There was no noteworthy correlation discovered between OPA and TPA in relation to cognitive function. However, RPA and total PA exhibited significant associations with verbal fluency, processing speed, and executive function. Additionally, maintaining PA levels ranging from 600 to 1,200 MET-min/week would yield the most favorable outcomes for cognitive function.

MicroRNAs role in telomere length maintenance and telomerase activity in tumor cells.

MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of thehuman telomerase reverse transcriptase(hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells.Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.

Short-Term Effects of Cold Therapy and Kinesio Taping on Pain Relief and Upper Extremity Functionality in Individuals with Rotator Cuff Tendonitis: A Randomized Study.

Background and Objectives: Rotator cuff tendonitis (RCT) is one of the most common shoulder pathologies. It causes pain, limits shoulder joint movements, and impairs function. Despite various treatment methods, there are currently no specific guidelines regarding the most effective intervention for RCT. To the best of our knowledge, no studies have compared the effects of Kinesio taping (KT) and cold therapy (CT) on individuals with RCT. To this end, this study aimed to investigate and compare the short-term effects of KT and CT on pain relief and upper extremity functionality in individuals with RCT. Materials and Methods: One hundred and fourteen individuals were assessed for eligibility. Fifty-two individuals with RCT who met the inclusion criteria and agreed to participate were randomly allocated into either the KT or the CT group. A standardized home exercise program was given to all the participants. Their pain intensity, upper extremity function, shoulder range of motion (ROM), and grip strength were evaluated initially and after the three days of KT or CT applications. Results: All the assessment values significantly improved in the KT group. In the CT group, only the pain scores (except for the numerical rating scale (NRS) pain score during activity) were significantly improved in the CT group at the end of the third day of application compared to the initial values (p < 0.05). For all the measurement outcomes, the effects of time × group interactions were statistically significant (p < 0.05) in favor of the KT group, except for the resting pain (p = 0.688). Conclusions: The findings suggest that KT and CT could be used as adjunctive modalities to exercise for resting and night pain relief in patients with RCT. KT also had positive effects on the activity pain, function, ROM, and grip strength. The use of KT along with an exercise program could be a more effective therapeutic choice than the use of CT for improving night pain, activity pain, and upper extremity function during the short-term rehabilitation of RCT patients.

Revolutionizing the probiotic functionality, biochemical activity, antibiotic resistance and specialty genes of Pediococcus acidilactici BCB1H via in-vitro and in-silico approaches.

This study presents a comprehensive genomic exploration, biochemical characterization, and the identification of antibiotic resistance and specialty genes of Pediococcus acidilactici BCB1H strain. The functional characterization, genetic makeup, biological activities, and other considerable parameters have been investigated in this study with a prime focus on antibiotic resistance and specialty gene profiles. The results of this study revealed the unique susceptibility patterns for antibiotic resistance and specialty genes. BCB1H had good invitro probiotic properties, which survived well in simulated artificial gastrointestinal fluid, and exhibited acid and bile salt resistance. BCB1H didn't produce hemolysis and had certain antibiotic sensitivity, making it a relatively safe LAB strain. Simultaneously, it had good self-coagulation characteristics and antioxidant activity. The EPS produced by BCB1H also had certain antioxidant activity and hypoglycemic function. Moreover, the genome with a 42.4 % GC content and a size of roughly 1.92 million base pairs was analyzed in the genomic investigations. The genome annotation identified 192 subsystems and 1,895 genes, offering light on the metabolic pathways and functional categories found in BCB1H. The identification of specialty genes linked to the metabolism of carbohydrates, stress response, pathogenicity, and amino acids highlighted the strain's versatility and possible uses. This study establishes the groundwork for future investigations by highlighting the significance of using multiple strains to investigate genetic diversity and experimental validation of predicted genes. The results provide a roadmap for utilizing P.acidilactici BCB1H's genetic traits for industrial and medical applications, opening the door to real-world uses in industries including food technology and medicine.

TransPhoM-DS Study Grant Report: Rationale and Protocol for Investigating the Efficacy of Low-Power Transcranial Photobiomodulation on Language, Executive Function, Attention, and Memory in Down Syndrome

Down syndrome (DS) is the leading genetic cause of intellectual disability globally, affecting about 1 in every 800 births. Individuals with DS often face various neuropsychiatric conditions alongside intellectual disabilities due to altered brain development. Despite the diverse phenotypic expressions of DS, typical physical characteristics frequently influence language development and acquisition. EEG studies have identified abnormal oscillatory patterns in individuals with DS. Emerging interventions targeting the enhancement of gamma (40 Hz) neuronal oscillations show potential for improving brain electrical activity and cognitive functions in this population. However, effective cognitive interventions for DS remain scarce. Extensive research indicates that transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light can penetrate deeply into the cerebral cortex, modulate cortical excitability, and enhance cerebral perfusion and oxygenation. Furthermore, t-PBM has been shown to improve cognitive functions such as language, attention, inhibition, learning, and memory, including working memory. This study presents the rationale and design of an ongoing randomized, sham-controlled clinical trial aimed at assessing the effectiveness of t-PBM using NIR light in enhancing the language abilities of individuals with DS.

Imbalance of Th17 cells, Treg cells and associated cytokines in patients with systemic lupus erythematosus: a meta-analysis.

This article aims to investigate the changes of T helper 17 (Th17) cells, regulatory T (Treg) cells and their associated cytokines in patients with systemic lupus erythematosus (SLE). Multiple databases were investigated to identify articles that explored Th17 cells, Treg cells and relevant cytokines in SLE patients. A random effects model was used for calculating pooled standardized mean differences. Stata version 15.0 was utilized to conduct the meta-analysis. The levels of Th17 cells, IL-17, IL-6, IL-21 and IL-10 were higher in SLE patients than in healthy controls (HCs), but the TGF-β levels were lower. The percentage of Treg cells was lower than HCs in SLE individuals older than 33. Among studies that had 93% or lower females, the percentage of Th17 cells was greater in patients than in HCs. However, the percentage of Treg cells was lower when the proportion of females was less than 90%. Patients with lupus nephritis or active SLE had an increased proportion of Th17 cells and a decreased proportion of Treg cells. The increased level of Th17 cells and related cytokines could be the main reason for the elevated Th17/Treg ratio in SLE. The percentages of Th17 and Treg cells were associated with gender, age, disease activity and kidney function. Furthermore, the reduced proportions of Treg cells may primarily result in a rise in the Th17/Treg ratio in older or active SLE patients. https://www.crd.york.ac.uk/prospero, identifier CRD42023454937.

Myeloid-derived suppressor cells-induced exhaustion of CD8 + T-cell participates in rejection after liver transplantation

Liver transplantation (LT) rejection remains the most pervasive problem associated with this procedure, while the mechanism involved is still complicated and undefined. One promising solution may involve the use of myeloid-derived suppressor cells (MDSC). However, the immunological mechanisms underlying the effects of MDSC after LT remain unclear. This study is meant to clarify the role MDSCs play after liver transplantation. In this study, we collected liver tissue and peripheral blood mononuclear cells (PBMC) from LT patients showing varying degrees of rejection, as well as liver and spleen tissue samples from mice LT models. These samples were then analyzed using flow cytometry, immunohistochemistry and multiple immunofluorescence. M-MDSCs and CD8 + T-cells extracted from C57/BL6 mice were enriched and cocultured for in vitro experiments. Results, as obtained in both LT patients and LT mice model, revealed that the proportion and frequency of M-MDSC and PD-1 + T-cells increased significantly under conditions associated with a high degree of LT rejection. Within the LT rejection group, our immunofluorescence results showed that a close spatial contiguity was present between PD-1 + T-cells and M-MDSCs in these liver tissue samples and the proportion of CD84/PD-L1 double-positive M-MDSC was greater than that of G-MDSC. There was a positive correlation between the activity of CD84 and immunosuppressive function of M-MDSCs including PD-L1 expression and reactive oxygen species (ROS) production, as demonstrated in our in vitro model. M-MDSCs treated with CD84 protein were able to induce co-cultured CD8 + T-cells to express high levels of exhaustion markers. We found that CD84 regulated M-MDSC function via expression of PD-L1 through activation of the Akt/Stat3 pathway. These results suggest that the capacity for CD84 to regulate M-MDSC induction of CD8 + T-cell exhaustion may play a key role in LT rejection. Such findings provide important, new insights into the mechanisms of tolerance induction in LT.

A SMARTR workflow for multi-ensemble atlas mapping and brain-wide network analysis.

In the last decade, activity-dependent strategies for labelling multiple immediate early gene (IEG) ensembles in mice have generated unprecedented insight into the mechanisms of memory encoding, storage, and retrieval. However, few strategies exist for brain-wide mapping of multiple ensembles, including their overlapping population, and none incorporate capabilities for downstream network analysis. Here, we introduce a scalable workflow to analyze traditionally coronally-sectioned datasets produced by activity-dependent tagging systems. Intrinsic to this pipeline is simple multi-ensemble atlas registration and statistical testing in R (SMARTR), an R package which wraps mapping capabilities with functions for statistical analysis and network visualization. We demonstrate the versatility of SMARTR by mapping the ensembles underlying the acquisition and expression of learned helplessness (LH), a robust stress model. Applying network analysis, we find that exposure to inescapable shock (IS), compared to context training (CT), results in decreased centrality of regions engaged in spatial and contextual processing and higher influence of regions involved in somatosensory and affective processing. During LH expression, the substantia nigra emerges as a highly influential region which shows a functional reversal following IS, indicating a possible regulatory function of motor activity during helplessness. We also report that IS results in a robust decrease in reactivation activity across a number of cortical, hippocampal, and amygdalar regions, indicating suppression of ensemble reactivation may be a neurobiological signature of LH. These results highlight the emergent insights uniquely garnered by applying our analysis approach to multiple ensemble datasets and demonstrate the strength of our workflow as a hypothesis-generating toolkit.

Predictive modelling of freeway space utilising clinical history, normalised muscle activity, dental occlusion, and mandibular movement analysis

This study aimed to predict dental freeway space by examining the clinical history, habits, occlusal parameters, mandibular hard tissue movement, soft tissue motion, muscle activity, and temporomandibular joint function of 66 participants. Data collection involved video-based facial landmark tracking, mandibular electrognathography, surface electromyography of mandibular range of motion, freeway space, chewing tasks, phonetic expressions, joint vibration analysis, and 3D jaw scans of occlusion. This resulted in a dataset of 121 predictor features, with freeway space as the target variable. Six models were trained on synthetic data ranging from 500 to 25,000 observations, with 65 original observations reserved for testing: Linear Regression, Random Forest, CatBoost Regressor, XGBoost Regressor, Multilayer Perceptron Neural Network (MPNN), and TabNet. Explainable AI indicated that key predictors of freeway space included phonetics, resting temporalis muscle activity, mandibular muscle activity during clenching, body weight, mandibular hard tissue lateral displacements, and dental arch parameters. CatBoost excelled with a test error of 0.65 mm using 5000 synthetic data points, while a refined MPNN achieved the best performance with 25,000 synthetic data points and 121 unique predictors, yielding an absolute error of 0.43 mm on the 65 original observations.

Differential inducibility of transmembrane peptidoglycan recognition proteins (PGRPs) by bacterial challenges in the earthworm, Eisenia andrei

Peptidoglycan recognition proteins (PGRPs) and Toll-like receptors (TLRs) are highly conserved pattern recognition receptors (PRRs). Earthworms possess genes encoding TLRs that specifically respond to Gram-positive bacteria. In addition, several PGRPs have been recently identified, which are predicted to exhibit amidase activity but lack receptor function. In lophotrochozoans, a membrane-bound PRR responsible for detecting Gram-negative bacteria remains unidentified. This study reveals several novel transmembrane peptidoglycan recognition proteins (Ean-PGRPLs) in earthworms, whose mRNA expression increases in response to Gram-negative but not Gram-positive bacteria. This indicates that Ean-PGRPLs may serve as a PRR associated with intracellular signaling for Gram-negative bacteria.

Genetic deletion or pharmacologic inhibition of histone deacetylase 6 protects the heart against ischaemia/reperfusion injury by limiting tumour necrosis factor alpha-induced mitochondrial injury in experimental diabetes.

The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-α) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-α production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI. HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNF-α, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-α levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNF-α levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNF-α-induced mitochondrial injury in experimental diabetes.

Relationship between quantitative physical activity and deterioration of locomotive function: a cross-sectional study using baseline data from a cohort

BackgroundIn aged society, health policies aimed at extending healthy life expectancy are critical. Maintaining physical activity is essential to prevent the deterioration of body functions. Therefore, it is important to understand the physical activity levels of the target age group and to know the content and intensity of the required physical activity quantitatively. Especially we focused the role of non-exercise activity thermogenesis and sedentary time, which are emphasized more than the introduction of exercise in cases of obesity or diabetes.MethodsA total of 193 patients from 25 institutions were included. Participants underwent a locomotive syndrome risk test (stand-up test, 2-step test, and Geriatric Locomotive Function Scale-25 questionnaire) and were classified into three stages. Physical activity was quantitatively monitored for one week with 3-axial accelerometer. Physical activity was classified into three categories; (1) Sedentary behavior (0 ∼ ≤ 1.5 metabolic equivalents (METs)), (2) Light physical activity (LPA:1.6 ∼ 2.9 METs), and (3) Moderate to vigorous physical activity (MVPA: ≥3 METs). We investigated the relationship between physical activity, including the number of steps, and the stages after gender- and age- adjustment. We also investigated the relationship between social isolation using Lubben’s Social Network Scale (LSNS), as social isolation would lead to fewer opportunities to go out and less outdoor walking.ResultsComparison among the three stages showed significant difference for age (p = 0.007) and Body Mass Index (p < 0.001). After gender-and age-adjustment, there was a significant relation with a decrease in the number of steps (p = 0.002) and with MVPA. However, no relation was observed in sedentary time and LPA. LSNS did not show any statistically significant difference. Moderate to high-intensity physical activity and the number of steps is required for musculoskeletal disorders. The walking, not sedentary time, was associated to the locomotive stages, and this finding indicated the importance of lower extremity exercise.ConclusionsAdjusting for age and gender, the number of steps and moderate to vigorous activity levels were necessary to prevent worsening, and there was no effect of sedentary behavior. Merely reducing sedentary time may be inadequate for locomotive disorders. It is necessary to engage in work or exercise that moves lower extremities more actively.

HIPK2 in Colon Cancer: A Potential Biomarker for Tumor Progression and Response to Therapies.

Colon cancer, one of the most common and fatal cancers worldwide, is characterized by stepwise accumulation of specific genetic alterations in tumor suppressor genes or oncogenes, leading to tumor growth and metastasis. HIPK2 (homeodomain-interacting protein kinase 2) is a serine/threonine protein kinase and a "bona fide" oncosuppressor protein. Its activation inhibits tumor growth mainly by promoting apoptosis, while its inactivation increases tumorigenicity and resistance to therapies of many different cancer types, including colon cancer. HIPK2 interacts with many molecular pathways by means of its kinase activity or transcriptional co-repressor function modulating cell growth and apoptosis, invasion, angiogenesis, inflammation and hypoxia. HIPK2 has been shown to participate in several molecular pathways involved in colon cancer including p53, Wnt/β-catenin and the newly identified nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2). HIPK2 also plays a role in tumor-host interaction in the tumor microenvironment (TME) by inducing angiogenesis and cancer-associated fibroblast (CAF) differentiation. The aim of this review is to assess the role of HIPK2 in colon cancer and the underlying molecular pathways for a better understanding of its involvement in colon cancer carcinogenesis and response to therapies, which will likely pave the way for novel colon cancer therapies.