Enhancing physical function and activity level in malnourished older adults through oral nutrition supplements: a randomized controlled trial.

BACKGROUND: Malnutrition of older individuals, leads to significant functional decline, reducing their quality of life. Lifestyle interventions; dietary improvements and supplementation are explored to enhance the physical function of older adults. The current study aimed to assess the impact of oral nutritional supplements (ONS) on the functional and activity levels of Sri Lankan older adults. METHODS: This randomized controlled trial included; an intervention group (IG) receiving 200 mL of ONS providing 247 kcal per serving, for 12 weeks and a control group (CG) receiving an equivalent volume of water. Changes in handgrip strength, knee extension strength, gait speed, functional and activity levels were assessed. RESULTS: The IG showed significant improvements in handgrip strength (43.96 ± 18.61 kg vs. 32.81 ± 17.92 kg; p < 0.001) and knee extension strength (23.45 ± 2.29 kg vs. 16.41 ± 2.09 kg; p < 0.001) following 12 weeks compared to the CG. The IG also exhibited significant improvements in gait speed (1.31 ± 0.52 m/s vs. 0.87 ± 0.26 m/s), Barthel index score, (0.30 ± 0.47 vs. -0.18 ± 0.66), PASE score (0.52 ± 17.79 vs. -1.60 ± 21.77) and IPAQ categories. CONCLUSIONS: ONS was found to be effective in improving the functional and physical activity levels of malnourished older adults. TRIAL REGISTRATION: Sri Lanka Clinical Trial Registry SLCTR/2022/021. Registered on 06/10/2022.

Perceptions of the importance of sports nutrition knowledge and barriers in implementing them: a qualitative study among track and field stakeholders in Sri Lanka.

BACKGROUND: Integrating the core aspects of sports nutrition knowledge [SNK] into the multidisciplinary team is critical to improving an athlete's performance and well-being. Conducting in-depth interviews with members of the sports-related team is a comprehensive method of gathering information on various aspects of SNK. This qualitative study aimed to examine the opinions and beliefs of stakeholders in athletics regarding the importance of SNK. METHODS: Fifteen professional track and field athletes and stakeholders were recruited into the study. Separate in-depth interviews were conducted to collect information within four key themes. Practical difficulties in getting an appropriate meal were included in an additional theme. Thematic analysis was performed using NVIVO v10.0. RESULTS: All participants were mindful of the importance of proper food habits for overall athletic outcomes and reported different opinions on meal timing and composition. The opinions on supplements were heterogeneous and both positive and negative claims were reported. Beliefs regarding hydration demonstrated that the cohort was well aware of the significance of adequate hydration plus the signs and consequences of dehydration with many reporting experiences of the negative consequences of dehydration. All respondents reported that both alcohol and smoking may have an adverse impact on performance and health. CONCLUSIONS: All respondents emphasized the importance of proper food habits for sports performance and well-being, but also identified barriers to optimizing nutrition.

Strategies to Improve Physical Activity and Nutrition Behaviours in Children and Adolescents: A Review.

Despite widespread acknowledgement of the multifarious health benefits of physical activity (PA), including prevention and control of obesity, an overwhelming majority of children and adolescents are not sufficiently active to realise such benefits. Concurrently, young people are significantly impacted by the rapid global rise of sedentarism, and suboptimal dietary patterns during key phases of development. Regrettably, the cumulative effects of unhealthy behaviours during the growing years predisposes young people to the early stages of several chronic conditions, including obesity. Clear and consistent approaches are urgently needed to improve eating and activity behaviours of children and adolescents. Based on existing evidence of "best bets" to prevent and control obesity and its comorbidities, we present a set of non-negotiable strategies as a 'road map' to achieving prevention and improving the health of children and adolescents.

Trends and associations between maternal characteristics and infant birthweight among Indigenous and non-Indigenous people in Tasmania, Australia: a population-based study.

OBJECTIVE: This study aimed to investigate the trends and associations of maternal characteristics and birthweight among Indigenous and non-Indigenous infants. STUDY DESIGN: This was a retrospective population-based study. METHODS: Fourteen years (2005-2018) of birthweight and perinatal health data of live-born singletons and their mothers obtained from the Tasmanian Data Linkage Unit were used to assess the trends and associations between maternal characteristics and infant birthweight using regression modelling. RESULTS: Compared with non-Indigenous mothers (n = 76,750), Indigenous mothers (n = 3805) had a significantly higher prevalence of risk factors during the 14-year period. Although the prevalence of prepregnancy obesity and gestational diabetes mellitus (GDM) markedly increased in both groups, the rate of increase was higher (P < 0.001) for Indigenous than non-Indigenous mothers. Smoking, alcohol consumption and illegal drug use during pregnancy reduced over the years, and there was no significant difference in the rate of reduction between the groups. Large-for-gestational-age (LGA) births increased while small-for-gestational-age (SGA) births decreased in both groups over time. In addition, high birthweight (HBW) births decreased while low birthweight (LBW) births increased. The rates of increase in LGA and LBW births and the rates of decrease in SGA and HBW births were significantly higher in Indigenous mothers compared with non-Indigenous mothers (P < 0.001 for all). The association between Indigenous ethnicity and LBW and SGA births weakened after adjusting for other confounding maternal and perinatal variables. LBW and SGA were positively associated with Indigenous ethnicity, age <18 years, smoking, alcohol consumption and illegal drug use, pre-eclampsia, underweight prepregnancy body mass index and low socio-economic status. Women with higher parity, pre-existing diabetes and prepregnancy overweight or obesity were more likely to give birth to an infant with HBW or LGA. CONCLUSIONS: The prevalence of risk factors for abnormal birthweight is higher among Tasmanian Indigenous mothers, contributing to a gap in birthweight outcomes between Indigenous and non-Indigenous infants. The dramatic increase in prepregnancy obesity and GDM in both groups highlight the importance of screening and management of GDM during pregnancy. Comprehensive programmes co-designed and co-managed in consultation with Indigenous people are needed to support healthy lifestyle choices among Indigenous women to address the barriers to individuals adopting behaviour change and to help close the health outcomes-related gap between Indigenous and non-Indigenous mothers and infants.

Coconut oil consumption and bodyweight reduction: a systematic review and meta-analysis.

INTRODUCTION: Due to the composition and biological properties of coconut oil, there is still considerable debate regarding potential benefits for the management of obesity, including the specific impact on body weight (BW) reduction. This systematic review and meta-analysis of clinical trials aims to assess the impact of coconut oil on BW reduction in comparison to other oils and fats. EVIDENCE ACQUISITION: The databases, PubMed®, Web of Science®, EMBASE®, and SciVerse Scopus® were systematically searched. A combination of medical subject headings and words linked to coconut oil and obesity parameters were utilized. Any clinical trials comparing coconut oil to any other form of oil or fat, with more than one month feeding period among adults were considered. EVIDENCE SYNTHESIS: From the 540 potentially relevant papers, 9 were included. The period of coconut oil intake varied from four to twelve weeks, apart from one long-term trial where coconut oil was consumed for two years. When compared to other oils and fats, coconut oil substantially decreased BW (N.=546), Body Mass Index (BMI) (N.=551), and percentage of fat mass (FM%) (N.=491) by 0.75 kg (P=0.04), 0.28 kg/m2 (P=0.03), and 0.35% (P=0.008), respectively. Coconut oil consumption did not result in any significant alteration in waist circumference (WC) (N.=385) (-0.61 cm; P=0.30), waist-to-hip ratio (WHR) (N.=330) (-0.01; P=0.39) and FM (N.=86) (-0.25 kg; P=0.29). CONCLUSIONS: Results indicate a small statistically significant reduction in BW, BMI, and FM% in the coconut oil group. In contrast, consumption of coconut oil had no statistically significant effect on WC, WHR, or FM.

Physical Activity and Food Environments in and around Schools: A Case Study in Regional North-West Tasmania.

A better understanding of the physical activity (PA) infrastructure in schools, the walkability of neighborhoods close to schools, and the food environments around schools, particularly in rural, socioeconomically challenged areas such as the North-West (NW) of Tasmania, could be important in the wider effort to improve the health of school-age children. Accordingly, this research aimed to assess PA resources, walkability, and food environments in and around schools in three socioeconomically disadvantaged, regional/rural Local Government Areas (LGAs) of Tasmania, Australia. A census of schools (including assessment of the PA infrastructure quality within school grounds), a walkability assessment, and a census of food outlets surrounding schools (through geospatial mapping) were executed. Most of the schools in the study region had access to an oval, basketball/volleyball/netball court, and free-standing exercise equipment. In all instances (i.e., regardless of school type), the quality of the available infrastructure was substantially higher than the number of incivilities observed. Most schools also had good (i.e., within the first four deciles) walkability. Numerous food outlets were within the walking zones of all schools in the study region, with an abundance of food outlets that predominantly sold processed unhealthy food.

A Spatial Analysis of Access to Physical Activity Infrastructure and Healthy Food in Regional Tasmania.

Prevalence of physical inactivity and obesity continues to increase in regional areas such as North-West (NW) Tasmania and show no signs of abating. It is possible that limited access to physical activity infrastructure (PAI) and healthier food options are exacerbating the low levels of habitual physical activity and obesity prevalence in these communities. Despite a burgeoning research base, concomitant exploration of both physical activity and food environments in rural and regional areas remain scarce. This research evaluated access (i.e., coverage, variety, density, and proximity) to physical activity resources and food outlets in relation to socioeconomic status (SES) in three NW Tasmanian communities. In all three study areas, the PAI and food outlets were largely concentrated in the main urban areas with most recreational tracks and natural amenities located along the coastline or river areas. Circular Head had the lowest total number of PAI (n = 43) but a greater proportion (30%) of free-to-access outdoor amenities. There was marked variation in accessibility to infrastructure across different areas of disadvantage within and between sites. For a considerable proportion of the population, free-to-access natural amenities/green spaces and recreational tracks (73 and 57%, respectively) were beyond 800 m from their households. In relation to food accessibility, only a small proportion of the food outlets across the region sells predominantly healthy (i.e., Tier 1) foods (~6, 13, and 10% in Burnie, Circular Head and Devonport, respectively). Similarly, only a small proportion of the residents are within a reasonable walking distance (i.e., 5-10 min walk) from outlets. In contrast, a much larger proportion of residents lived close to food outlets selling predominantly energy-dense, highly processed food (i.e., Tier 2 outlets). Circular Head had at least twice as many Tier 1 food stores per capita than Devonport and Burnie (0.23 vs. 0.10 and 0.06; respectively) despite recording the highest average distance (4.35 and 5.66 km to Tier 2/Tier 1 stores) to a food outlet. As such, it is possible that both food and physical activity environment layouts in each site are contributing to the obesogenic nature of each community.

Current Activities Centered on Healthy Living and Recommendations for the Future: A Position Statement from the HL-PIVOT Network.

We continue to increase our cognizance and recognition of the importance of healthy living (HL) behaviors and HL medicine (HLM) to prevent and treat chronic disease. The continually unfolding events precipitated by the coronavirus disease 2019 (COVID-19) pandemic have further highlighted the importance of HL behaviors, as indicated by the characteristics of those who have been hospitalized and died from this viral infection. There has already been recognition that leading a healthy lifestyle, prior to the COVID-19 pandemic, may have a substantial protective effect in those who become infected with the virus. Now more than ever, HL behaviors and HLM are essential and must be promoted with a renewed vigor across the globe. In response to the rapidly evolving world since the beginning of the COVID-19 pandemic, and the clear need to change lifestyle behaviors to promote human resilience and quality of life, the HL for Pandemic Event Protection (HL-PIVOT) network was established. The 4 major areas of focus for the network are: (1) knowledge discovery and dissemination; (2) education; (3) policy; (4) implementation. This HL-PIVOT network position statement provides a current synopsis of the major focus areas of the network, including leading research in the field of HL behaviors and HLM, examples of best practices in education, policy, and implementation, and recommendations for the future.

The current global state of movement and physical activity - the health and economic costs of the inactive phenotype.

Physical inactivity is one of the major contributing factors to the global pandemic of non-communicable diseases. Unfortunately, low levels of habitual movement and physical activity (PA) are seen in an increasing proportion of populations across low- and middle-income countries and high-income countries alike. This new normal - the inactive phenotype - is a significant contributor to multiple health and economic costs. Here we provide a brief historical overview of societal declines in PA, roughly consistent with major transitions in PA and nutrition in recent decades. This is followed by a synthesis of research evidence linking inactivity with poor health outcomes and prevention approaches needed to impact a perpetuation of poor lifestyle behaviors. A major focus of the paper is on the economic/health costs and the reduction of the inactive phenotype. In summary, we demonstrate that the consequences of insufficient PA are manifold, and if sustained, impact short and long-term health and quality of life, along with substantial economic costs.

Long-term sustainability of a physical activity and nutrition intervention for rural adults with or at risk of metabolic syndrome.

OBJECTIVE: To determine longer-term (18-month) sustainability of a six-month physical activity and nutrition intervention for 50-69-year-olds with or at risk of metabolic syndrome residing in a rural Australian community. METHODS: Participants (n=151) were followed-up at 12 and 18 months post-intervention. Changes in nutrition behaviours (fat and fibre barometer); physical activity behaviours (IPAQ); anthropometry (waist-hip ratio, weight, BMI), blood pressure, blood parameters (triglycerides, glucose, LDL-, HDL-, non-HDL, total-cholesterol) were analysed using t-tests and repeated measures ANOVA. RESULTS: Across three time points (6, 12 and 18 months) marginal decrease was observed for waist circumference (p=0.001), a modest increase was observed for diastolic blood pressure (p=0.010) and other outcome measures remained stable. CONCLUSION: Maintenance and ongoing improvement of health behaviours in the longer-term is challenging. Future studies must look for ways to embed interventions into communities so they are sustainable and investigate new approaches to reduce the risk of chronic disease. Implications for public health: Metabolic syndrome is a major health issue in Australia and worldwide. Early identification and management are required to prevent the progression to chronic disease. This 18-month follow-up showed that outcomes measures remained relatively stable; however, there is a need to investigate opportunities for embedded community interventions to support long-term health behaviour change.

The effect of workplace lifestyle programmes on diet, physical activity, and weight-related outcomes for working women: A systematic review using the TIDieR checklist.

Physical activity and healthy diets are essential for the prevention of obesity and chronic disease that disparately impact women compared with men. Given the number of women engaged in the workforce, workplace interventions could improve lifestyle behaviours and health outcomes for women. This systematic review aimed to identify intervention characteristics of lifestyle programmes or organizational policy changes in the workplace associated with improved diet, physical activity, or weight-related outcomes for working women using the template for intervention description and replication (TIDieR) checklist. Seven databases were searched for controlled studies published up to March 2019 that included a workplace diet and/or physical activity intervention. From 5,318 identified records, 20 studies (23 articles and 26 intervention arms) were included. Data were extracted on diet, physical activity, weight-related outcomes, and TIDieR components. Findings indicated that group delivery may improve physical activity outcomes, and a high number of sessions may benefit weight-related outcomes for physical activity interventions. Mixed interventions that included tailoring and input from non-healthcare professionals may also enhance physical activity. In contrast, the role of mixed interventions in improving diet and weight-related outcomes was less clear. Overall, workplace health programmes were effective at improving lifestyle behaviours for working women.

Akt1 signalling supports acinar proliferation and limits acinar-to-ductal metaplasia formation upon induction of acute pancreatitis.

Molecular signalling mediated by the phosphatidylinositol-3-kinase (PI3K)-Akt axis is a key regulator of cellular functions. Importantly, alteration of the PI3K-Akt signalling underlies the development of different human diseases, thus prompting the investigation of the pathway as a molecular target for pharmacologic intervention. In this regard, recent studies showed that small molecule inhibitors of PI3K, the upstream regulator of the pathway, reduced the development of inflammation during acute pancreatitis, a highly debilitating and potentially lethal disease. Here we investigated whether a specific reduction of Akt activity, by using either pharmacologic Akt inhibition, or genetic inactivation of the Akt1 isoform selectively in pancreatic acinar cells, is effective in ameliorating the onset and progression of the disease. We discovered that systemic reduction of Akt activity did not protect the pancreas from initial damage and only transiently delayed leukocyte recruitment. However, reduction of Akt activity decreased acinar proliferation and exacerbated acinar-to-ductal metaplasia (ADM) formation, two critical events in the progression of pancreatitis. These phenotypes were recapitulated upon conditional inactivation of Akt1 in acinar cells, which resulted in reduced expression of 4E-BP1, a multifunctional protein of key importance in cell proliferation and metaplasia formation. Collectively, our results highlight the critical role played by Akt1 during the development of acute pancreatitis in the control of acinar cell proliferation and ADM formation. In addition, these results harbour important translational implications as they raise the concern that inhibitors of PI3K-Akt signalling pathways may negatively affect the regeneration of the pancreas. Finally, this work provides the basis for further investigating the potential of Akt1 activators to boost pancreatic regeneration following inflammatory insults. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Local hyperthyroidism promotes pancreatic acinar cell proliferation during acute pancreatitis.

Proliferation of pancreatic acinar cells is a critical process in the pathophysiology of pancreatic diseases, because limited or defective proliferation is associated with organ dysfunction and patient morbidity. In this context, elucidating the signalling pathways that trigger and sustain acinar proliferation is pivotal to develop therapeutic interventions promoting the regenerative process of the organ. In this study we used genetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones to elucidate their role in acinar proliferation following caerulein-mediated acute pancreatitis in mice. In addition, molecular mechanisms mediating the effects of thyroid hormones were identified by genetic and pharmacological inactivation of selected signalling pathways.In this study we demonstrated that levels of the thyroid hormone 3,3',5-triiodo-l-thyronine (T3) transiently increased in the pancreas during acute pancreatitis. Moreover, by using genetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones, we showed that T3 was required to promote proliferation of pancreatic acinar cells, without affecting the extent of tissue damage or inflammatory infiltration.Finally, upon genetic and pharmacological inactivation of selected signalling pathways, we demonstrated that T3 exerted its mitogenic effect on acinar cells via a tightly controlled action on different molecular effectors, including histone deacetylase, AKT, and TGFß signalling.In conclusion, our data suggest that local availability of T3 in the pancreas is required to promote acinar cell proliferation and provide the rationale to exploit thyroid hormone signalling to enhance pancreatic regeneration. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Epidemiology and determinants of type 2 diabetes in south Asia.

Type 2 diabetes has rapidly developed into a major public health problem in south Asia (defined here as Bangladesh, Bhutan, India, Nepal, Pakistan, and Sri Lanka) in recent decades. During this period, major lifestyle changes associated with economic transition, industrialisation, urbanisation, and globalisation have been key determinants in the increasing burden of non-communicable diseases. A decline in nutrition quality, reduced physical activity, and increased sedentary behaviours are reflected in the increasing prevalence of type 2 diabetes and related risk factors in the region. The International Diabetes Federation 2017 estimates of the prevalence of diabetes in adults in the region range from 4·0% in Nepal to 8·8% in India. The prevalence of overweight ranges from 16·7% in Nepal to 26·1% in Sri Lanka, and the prevalence of obesity ranges from 2·9% in Nepal to 6·8% in Sri Lanka. An increasing proportion of children, adolescents, and women are overweight or obese, leading to a heightened risk of type 2 diabetes. Ethnic south Asians present with greater metabolic risk at lower levels of BMI compared with other ethnic groups (referred to as the south Asian phenotype), with type 2 diabetes often developing at a younger age, and with rapid progression of diabetic complications. Because of the presence of multiple risk factors and a body composition conducive to the development of type 2 diabetes, south Asians should be aggressively targeted for prevention. In this Series paper, we detail trends in the prevalence of diabetes in the region and address major determinants of the disease in the context of nutrition and physical activity transitions and the south Asian phenotype.

Clinical management of type 2 diabetes in south Asia.

Compared with other ethnic groups, south Asian people with type 2 diabetes tend to develop the disease at a younger age and manifest with higher glycaemia, dyslipidaemia, nephropathy, and cardiovascular diseases. Additionally, specific issues that can affect treatment of type 2 diabetes in south Asia include poor awareness of the disease, delay in diagnosis, inadequate treatment, the use of ineffective and often harmful alternative medicines, and frequent non-compliance with lifestyle recommendations and drug treatment. Disease development at younger ages, delayed diagnosis, and inadequate management result in early development of severe complications and premature mortality. In this Series paper, we describe the challenges associated with the increasing burden of type 2 diabetes in south Asia and discuss ways to improve clinical care of people with the disorder in the region (defined to include Bangladesh, Bhutan, India, Nepal, Pakistan, and Sri Lanka). Treatment of diabetes in south Asia needs to be individualised on the basis of diverse and heterogeneous lifestyle, phenotype, environmental, social, cultural, and economic factors. Aggressive management of risk factors from diagnosis is necessary to reduce the risk of microvascular and macrovascular complications, focusing on provision of basic treatments (eg, metformin, low-cost statins, and blood pressure-lowering drugs) and other interventions such as smoking cessation. Strengthening of the primary care model of care, better referral linkages, and implementation of rehabilitation services to care for patients with chronic complications will be important. Finally, improvement of physicians' skills, provision of relevant training to non-physician health-care workers, and the development and regular updating of national clinical management guidelines will also be crucial to improve diabetes care in the region.

Applying Precision Medicine to Healthy Living for the Prevention and Treatment of Cardiovascular Disease.

Healthy living medicine (HLM) is an emerging concept that recognizes the importance of: (1) Moving more and sitting less; (2) Consuming a healthy diet at the appropriate caloric load; (3) Maintaining a healthy body weight; and (4) Not smoking. Suffice to say, HLM should be practiced by all health professionals, prescribing a personalized healthy living polypill to individuals under their care while titrating the dosage for optimal adherence and therapeutic efficacy. Traditionally, HLM, particularly when practiced in the context of physical activity and diet, is commonly viewed as an all-or-none and one-size-fits-all paradigm. As an example, there has been a dichotomous perception to physical activity messaging, where achieving anything less than 150 minutes of moderate-intensity physical activity per day is not beneficial. The same holds true for the all-or-none perception of 5 servings of fruits and vegetables per day; anything less is not beneficial. While these are certainly desirable targets, healthy living practices at levels below current guidelines portend significant health benefits. Precision medicine is defined as "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person." Much of the focus in precision medicine has been directed toward genomics and only recently has the influence of environment and lifestyle been considered. This review will highlight the importance of HLM directed toward the prevention and treatment of chronic diseases in the context of precision medicine.

Retirement village physical activity and nutrition intervention process evaluation: Informing practice.

OBJECTIVE: This process evaluation aimed to determine participants' perceptions of the strategies utilised in a six-month intervention that set out to improve physical activity and nutrition in retirement village (RV) residents. METHODS: Qualitative and quantitative data were collected from intervention participants residing in 17 RVs located in Perth, Western Australia, via self-report questionnaires (n = 139) and semi-structured interviews (n = 16). RESULTS: Intervention resources were moderately useful and suitable. Program ambassadors were encouraging (86%), but more frequent, and more direct, contact were preferred. The main reason for withdrawing from the program was health-related conditions (aches, pains, injuries). CONCLUSION: This study provides evidence that the intervention was reasonably appropriate for older adults residing in RVs. Program ambassadors were well accepted, a successful strategy that should be considered for future interventions in RVs. Increased face-to-face engagement was preferred, but such an approach will require greater investment. The findings contribute to a small research base concerned with health behaviour interventions in RVs.

Enhanced proliferation of pancreatic acinar cells in MRL/MpJ mice is driven by severe acinar injury but independent of inflammation.

Adult pancreatic acinar cells have the ability to re-enter the cell cycle and proliferate upon injury or tissue loss. Despite this mitotic ability, the extent of acinar proliferation is often limited and unable to completely regenerate the injured tissue or restore the initial volume of the organ, thus leading to pancreatic dysfunction. Identifying molecular determinants of enhanced proliferation is critical to overcome this issue. In this study, we discovered that Murphy Roths Large (MRL/MpJ) mice can be exploited to identify molecular effectors promoting acinar proliferation upon injury, with the ultimate goal to develop therapeutic regimens to boost pancreatic regeneration. Our results show that, upon cerulein-induced acinar injury, cell proliferation was enhanced and cell cycle components up-regulated in the pancreas of MRL/MpJ mice compared to the control strain C57BL/6. Initial damage of acinar cells was exacerbated in these mice, manifested by increased serum levels of pancreatic enzymes, intra-pancreatic trypsinogen activation and acinar cell apoptosis. In addition, MRL/MpJ pancreata presented enhanced inflammation, de-differentiation of acinar cells and acinar-to-ductal metaplasia. Manipulation of inflammatory levels and mitogenic stimulation with the thyroid hormone 5,3-L-tri-iodothyronine revealed that factors derived from initial acinar injury rather than inflammatory injury promote the replicative advantage in MRL/MpJ mice.

Inhibition of Class I Histone Deacetylases Abrogates Tumor Growth Factor ß Expression and Development of Fibrosis during Chronic Pancreatitis.

Pancreatic fibrosis is the hallmark of chronic pancreatitis, a highly debilitating disease for which there is currently no cure. The key event at the basis of pancreatic fibrosis is the deposition of extracellular matrix proteins by activated pancreatic stellate cells (PSCs). Transforming growth factor ß (TGFß) is a potent profibrotic factor in the pancreas as it promotes the activation of PSC; thus, pharmacologic interventions that effectively reduce TGFß expression harbor considerable therapeutic potential in the treatment of chronic pancreatitis. In this study, we investigated whether TGFß expression is reduced by pharmacologic inhibition of the epigenetic modifiers histone deacetylases (HDACs). To address this aim, chronic pancreatitis was induced in C57BL/6 mice with serial injections of cerulein, and the selective class 1 HDAC inhibitor MS-275 was administered in vivo in a preventive and therapeutic manner. Both MS-275 regimens potently reduced deposition of extracellular matrix and development of fibrosis in the pancreas after 4 weeks of chronic pancreatitis. Reduced pancreatic fibrosis was concomitant with lower expression of pancreatic TGFß and consequent reduced PSC activation. In search of the cell types targeted by the inhibitor, we found that MS-275 treatment abrogated the expression of TGFß in acinar cells stimulated by cerulein treatment. Our study demonstrates that MS-275 is an effective antifibrotic agent in the context of experimental chronic pancreatitis and thus may constitute a valid therapeutic intervention for this severe disease.