SUMO2/3 promotes the progression and oxaliplatin resistance of colorectal cancer through facilitating the SUMOylation at Ku80‐K307

Posted on 20 June 2023 by

We describes the role for SUMO2/3 during oxaliplatin resistance in CRC and assessed the contribution of Ku80 SUMOylation in this process. Overexpression of SUMO2/3-promoted CRC cell proliferation, invasion, migration in vitro and in vivo. SUMOylation of K307 in Ku80 attenuated the DNA damage of CRC cells caused by oxaliplatin and was consistent with an antiapoptotic role for SUMO2/3.

Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and is typically treated with the FOLFOX regimen (folinic acid, 5-fluorouracil, and oxaliplatin). However, oxaliplatin resistance remains a serious clinical problem. In the present study, we found that SUMO2/3 was overexpressed in CRC tissues and exogenous overexpression of SUMO2/3 promoted CRC cell proliferation, extension, and invasion and positively regulated the cell cycle. In contrast, SUMO2/3 gene knockdowns inhibited migration and repressed cell viability in vitro and in vivo. In addition, we found that SUMO2/3 was recruited to the cell nucleus and suppressed oxaliplatin-induced apoptosis of CRC cells. Moreover, Ku80, a DNA-binding protein essential for the repair of DNA double-strand breaks, was confirmed to bind with SUMO2/3. Notably, Ku80 undergoes SUMOylation at K307 by SUMO2/3 and this correlated with apoptosis in CRC cells suffering oxaliplatin stress. Collectively, we found that SUMO2/3 plays a specific role in CRC tumorigenesis and acts through Ku80 SUMOylation which is linked with the development of CRC-oxaliplatin resistance.

The underestimated role of mitochondria in vitiligo: From oxidative stress to inflammation and cell death

Posted on 20 June 2023 by nYi Lin, nYuecen Ding, nYue Wu, nYiwen Yang, nZiqi Liu, nLeihong Xiang, nChengfeng Zhangn

Morphologically and functionally altered mitochondria may disrupt the redox balance, trigger inflammatory responses and cause various forms of melanocyte death, all of which jointly contribute to the onset and progression of vitiligo. The impairment of Nrf2 pathways in vitiligo is closely associated with mitochondria damage, rendering both mitochondria and Nrf2 promising targets in vitiligo treatment.

Abstract

Vitiligo is an acquired depigmentary disorder characterized by the depletion of melanocytes in the skin. Mitochondria shoulder multiple functions in cells, such as production of ATP, maintenance of redox balance, initiation of inflammation and regulation of cell death. Increasing evidence has implicated the involvement of mitochondria in the pathogenesis of vitiligo. Mitochondria alteration will cause the abnormalities of mitochondria functions mentioned above, ultimately leading to melanocyte loss through various cell death modes. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in mitochondrial homeostasis, and the downregulation of Nrf2 in vitiligo may correlate with mitochondria damage, making both mitochondria and Nrf2 promising targets in treatment of vitiligo. In this review, we aim to discuss the alterations of mitochondria and its role in the pathogenesis of vitiligo.

Association between infectious exposures in infancy and epigenetic age acceleration in young adulthood in metropolitan Cebu, Philippines

Posted on 20 June 2023 by

Abstract

Objectives

The drivers of human life expectancy gains over the past 200 years are not well-established, with a potential role for historical reductions in infectious disease. We investigate whether infectious exposures in infancy predict biological aging using DNA methylation-based markers that forecast patterns of morbidity and mortality later in life.

Methods

N = 1450 participants from the Cebu Longitudinal Health and Nutrition Survey—a prospective birth cohort initiated in 1983—provided complete data for the analyses. Mean chronological age was 20.9 years when venous whole blood samples were drawn for DNA extraction and methylation analysis, with subsequent calculation of three epigenetic age markers: Horvath, GrimAge, and DunedinPACE. Unadjusted and adjusted least squares regression models were evaluated to test the hypothesis that infectious exposures in infancy are associated with epigenetic age.

Results

Birth in the dry season, a proxy measure for increased infectious exposure in the first year of life, as well as the number of symptomatic infections in the first year of infancy, predicted lower epigenetic age. Infectious exposures were associated with the distribution of white blood cells in adulthood, which were also associated with measures of epigenetic age.

Conclusions

We document negative associations between measures of infectious exposure in infancy and DNA methylation-based measures of aging. Additional research, across a wider range of epidemiological settings, is needed to clarify the role of infectious disease in shaping immunophenotypes and trajectories of biological aging and human life expectancy.

Fit‐Fat Index is better associated with heart rate variability compared to fitness and fatness alone as indicators of cardiometabolic human health

Posted on 20 June 2023 by

Abstract

Objectives

Cardiorespiratory fitness and fatness indicators have been related to heart rate variability (HRV) parameters. The Fit-Fat Index (FFI) is a single index combining cardiorespiratory fitness and fatness indicators. To the best of our knowledge, no studies have previously analyzed whether FFI are related to cardiac autonomic nervous system activity assessed through HRV parameters. This study aimed (i) to examine the association of cardiorespiratory fitness, fatness indicators, and FFI with HRV parameters; and (ii) to report what of the different fatness indicators included in FFI is better associated with HRV parameters in sedentary adults.

Methods

One hundred and fifty healthy adults (74 women; 76 men), aged between 18 and 65 years old, participated in this cross-sectional study. We measured cardiorespiratory fitness (maximal oxygen consumption) and fatness indicators (waist-to-height ratio [WHR], fat mass percentage [FM%] and visceral adipose tissue [VAT]). Three FFIs were calculated as the quotient between cardiorespiratory fitness and one out of three possible fatness indicators: Fit-Fat Index calculated waist-to-height ratio (FFI_WHR), Fit-Fat Index calculated with FM% (FFI_FM%), and Fit-Fat Index calculated with VAT (FFI_VAT). HRV parameters were measured in resting conditions using a Polar RS800CX.

Results

FFI_WTHR, FFI_FM% and FFI_VAT were related to different HRV parameters (β ranges between −0.507 and 0.529; R ² ranges between 0.096 and 0.275; all p < .001) and the association was stronger with HRV parameters than the isolated fitness or fatness indicators (β ranges between −0.483 and 0.518; R ² ranges between 0.071 and 0.263; all p < .001). FFI_VAT was the index more consistently associated with HRV parameters (β ranges between −0.507 and 0.529; R ² ranges between 0.235 and 0.275; all p < .001).

Conclusion

Our study suggests that compound FFIs are better predictors of HRV parameters than either cardiorespiratory fitness or fatness indicators alone. The FFI_VAT was the best index in terms of its association to HRV.

Autophagy in a Nutshell

Posted on 16 June 2023 by nOren Shatz, nZvulun Elazarn

Autophagy degrades or recycles cellular components through the formation of a double membrane vesicle, termed autophagosome, which fuses with the lysosome, where the degradation process takes place. In this Graphical Review we provide an updated and comprehensive overview on autophagosome biogenesis, a unique process consisting of three main phases: nucleation, expansion, and maturation, tightly regulated by lipid species and protein complexes.

Autophagy is an intracellular catabolic process that eliminates cytoplasmic constituents selectively by tight engulfment in an isolation membrane or recycles bulk cytoplasm by nonselective sequestration. Completion of the isolation membrane forms a double membrane vesicle, termed autophagosome, that proceeds to fusion with the lysosome, where the inner membrane and its cytoplasmic content are degraded. Autophagosome biogenesis is unique in that the newly-formed membrane, termed phagophore, is elongated by direct lipid flow from a proximal ER-associated donor membrane. Recent years mark a tremendous advancement in delineating the direct regulation of this process by different lipid species and associated protein complexes. Here we schematically summarize the current view of autophagy and autophagosome biogenesis.

Adipose tissue‐derived mesenchymal stem cells ameliorate cognitive impairment in Alzheimer’s disease rat model: Emerging role of SIRT1

Posted on 15 June 2023 by nMohamed Nabil, nDina H. Kassem, nAzza A. Ali, nHala O. El‐Mesallamyn

The present study aimed to investigate the therapeutic potential of adipose tissue-derived mesenchymal stem cells (Ad-MSCs) in Alzheimer's disease (AD) rat model, and to explore the possible implication of SIRT1. Our data demonstrated that transplantation of Ad-MSCs alleviated cognitive impairment in AD rats. Additionally, they exhibited anti-amyloidogenic, anti-apoptotic, anti-inflammatory, as well as neurogenic effects. Furthermore, Ad-MSCs were found to mediate their therapeutic effects, at least partially, via modulating both central and systemic SIRT1 levels. Hence, the current study portrays Ad-MSCs as an effective therapeutic approach for AD management and opens the door for future investigations to further elucidate the role of SIRT1 and its interrelated molecular mediators in AD.

Abstract

Alzheimer's disease (AD) is a complex form of neurodegenerative dementia. Growing body of evidence supports the cardinal role of sirtuin1 (SIRT1) in neurodegeneration and AD development. Recently, adipose tissue-derived mesenchymal stem cells (Ad-MSCs) have made their mark for a wide array of regenerative medicine applications, including neurodegenerative disorders. Therefore, the present study aimed to investigate the therapeutic potential of Ad-MSCs in AD rat model, and to explore the possible implication of SIRT1. Ad-MSCs were isolated from rat epididymal fat pads and properly characterized. Aluminum chloride was used to induce AD in rats, and afterward, a group of AD-induced rats received a single dose of Ad-MSCs (2 × 10⁶ cell, I.V per rat). One month after Ad-MSCs transplantation, behavioral tests were done, brain tissues were collected, then histopathological and biochemical assessments were performed. Amyloid beta and SIRT1 levels were determined by enzyme-linked immunosorbent assay. Whereas expression levels of neprilysin, BCL2 associated X protein, B-cell lymphoma-2, interleukin-1β, interleukin-6, and nerve growth factor in hippocampus and frontal cortex brain tissues were assessed using reverse transcriptase quantitative polymerase chain reaction. Our data demonstrated that transplantation of Ad-MSCs alleviated cognitive impairment in AD rats. Additionally, they exhibited anti-amyloidogenic, antiapoptotic, anti-inflammatory, as well as neurogenic effects. Furthermore, Ad-MSCs were found to possibly mediate their therapeutic effects, at least partially, via modulating both central and systemic SIRT1 levels. Hence, the current study portrays Ad-MSCs as an effective therapeutic approach for AD management and opens the door for future investigations to further elucidate the role of SIRT1 and its interrelated molecular mediators in AD.

Annual recruitment is correlated with reproductive success in a smallmouth bass population

Posted on 15 June 2023 by David P. Philipp

Canadian Journal of Zoology, Ahead of Print.
Annual recruitment in fish is undoubtedly impacted by a vast number of biotic and abiotic factors. That is especially the case for fish species such as the black bass (species in the genus Micropterus), where there is extended parental care. Although much focus has been given in the past on determining the roles that many of these factors (e.g., temperatures, wind, flow rates, and habitat change) play in determining recruitment among the back basses, little attention has been given to assessing what role reproductive success plays in that determination. To address this question, we conducted a long-term study on two adjacent smallmouth bass (SMB) Micropterus dolomieu Lacepède, 1802 populations in eastern ON to assess the relationship between annual fry cohort size (FCS) (i.e., population-wide reproductive success) and annual recruitment. To measure population-wide annual FCS, we used snorkel surveys to conduct a complete census of nesting SMB males during the spawn from 1990 to 2015. During those surveys, we quantified mating success, determined which nests were successful or not, and calculated the number of independent fry produced each year by summing those numbers across all successful nests. Summer snorkel surveys from 1991 to 2016 assessed annual recruitment through visual counts of age 1+ juveniles. Results demonstrated a highly significant, positive, linear relationship between annual FCS and annual recruitment.

Membrane association of the ATG8 conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis

Posted on 10 June 2023 by

During the formation of autophagosomes, the phagophore membrane expands rapidly and is decorated by lipidated ATG8s, LC3 and GABARAP. The amphipathic helix of ATG3, the ubiquitin-like E2 enzyme, has unique properties that catalyse the conjugation of ATG8 to phosphatidylethanolamine (PE). Further membrane expansion occurs by interaction in cis when the N-terminus of the lipidated ATG8 inserts into the membrane.

Autophagy is a highly conserved intracellular pathway that is essential for survival in all eukaryotes. In healthy cells, autophagy is used to remove damaged intracellular components, which can be as simple as unfolded proteins or as complex as whole mitochondria. Once the damaged component is captured, the autophagosome engulfs it and closes, isolating the content from the cytoplasm. The autophagosome then fuses with the late endosome and/or lysosome to deliver its content to the lysosome for degradation. Formation of the autophagosome, sequestration or capture of content, and closure all require the ATG proteins, which constitute the essential core autophagy protein machinery. This brief ‘nutshell’ will highlight recent data revealing the importance of small membrane-associated domains in the ATG proteins. In particular, recent findings from two parallel studies reveal the unexpected key role of α-helical structures in the ATG8 conjugation machinery and ATG8s. These studies illustrate how unique membrane association modules can control the formation of autophagosomes.

Spatiotemporal variation in pup abundance and preweaning survival of harbour seals (Phoca vitulina) in the St. Lawrence Estuary, Canada

Posted on 10 June 2023 by Limoilou-Amélie Renaud

Canadian Journal of Zoology, Ahead of Print.
Marine mammal populations worldwide greatly benefitted from conservation measures put in place since the 1970s following overexploitation, and many pinniped populations have recovered. However, threats due to bycatch, interspecific interactions or climate change remain, and detailed knowledge on vital rates, population dynamics, and their responses to environmental changes is essential for efficient management and conservation of wild populations. In this study, we quantified pup abundance and survival of individually marked harbour seal (Phoca vitulina Linnaeus, 1758) pups during the preweaning period at Bic Island and Métis sites in the St. Lawrence Estuary from 1998 to 2019. We used mark-recapture models to evaluate competing hypotheses regarding variation in daily preweaning survival rates and capture probability during the pups’ first 30 days of life. Pup abundance increased from 76 [95% CI: 59, 101] to 323 [95% CI: 233, 338] in the past two decades at Bic Island and from 66 [95% CI: 47, 91] to 285 [95% CI: 204, 318] at Métis. Preweaning survival was generally higher at Bic (0.73 [95% CI: 0.58, 0.82]) than at Métis (0.68 [95% CI: 0.52, 0.79]). We hypothesize that differences between habitats and human disturbance contribute to lower preweaning survival at Métis, but behavioural studies are needed to understand the impacts of disturbance on mother–pup interactions during the nursing period.

Predator–prey interactions between gleaning bats and katydids

Posted on 10 June 2023 by Hannah M. ter Hofstede

Canadian Journal of Zoology, Ahead of Print.
Bats are voracious predators of insects, and many insects have ears sensitive to the high-frequency echolocation calls of bats. Eared insects show a variety of defences when they detect bat echolocation calls. Professor Brock Fenton was an early contributor to the field of bat–insect interactions, inspiring many students to pursue investigations that have advanced our understanding of the relationship between predators and prey. Reflecting on the integrative nature of Dr. Fenton's research, this review highlights research on the evolutionary arms race between gleaning insectivorous bats and katydid prey. Studies on this system have enhanced the field of sensory ecology by illuminating how animal auditory systems can encode and distinguish between signals that overlap in their acoustic properties but have very different consequences for the listener (sex or death). These studies also inform us about the ecological and evolutionary selection pressures on signalers and receivers that can shape mate attraction and predator avoidance behaviour. In particular, many Neotropical katydids rely on preventative instead of reactive defences against gleaning bats, likely due to the regular presence of echolocation calls from non-gleaning bats that reduce the information content of predator cues. We conclude with suggestions for future research on these fascinating animals.