Rosmarinic acid attenuates hepatic steatosis by modulating ER stress and autophagy in oleic acid-induced HepG2 cells

Non-alcoholic fatty acid disease (NAFLD) has become an emerging entity of liver disorders worldwide. Oxidative stress and deranged autophagy-induced endoplasmic reticulum (ER) stress has recently been recognized as one of the prime factors involved in the pathological mechanism underlying NAFLD and progressive non-alcoholic steato-hepatitis (NASH). Epidemiological and experimental data reveal the potency of dietary polyphenols in averting NAFLD. In this line, to analyse and address the underlying pathogenic mechanisms, in the present study, oleic acid-induced HepG2 cells were treated with rosmarinic acid (RA), a dietary polyphenol with well-established cytoprotective properties. Treatment with rosmarinic acid (20 μg) was found to potently counter the elevated levels of total cholesterol (TC) and triglycerides (TG). Additionally, exposure of oleic acid-induced HepG2 cells to rosmarinic acid showed reduced levels of ROS and increased activity of enzymic and non-enzymic antioxidants. The steatotic HepG2 cells presented a pronounced increase in the expression of key ER stress markers such as p-PERK, p-IRE-1, ATF-6, p-eIF-α and CHOP, which was considerably reduced upon treatment with rosmarinic acid. Moreover, exposure to rosmarinic acid altered the deranged autophagic mechanism in oleic acid-induced HepG2 cells, which was observed via the protein expression of Beclin 1, LC31, ATG5 and ATG7. This study demonstrates that rosmarinic acid abrogates NAFLD via diminishing ER stress by nullifying oxidative stress and restoring deranged autophagy and can be used as a potent adjunct in the treatment of NAFLD, thus illustrating the valuable application of polyphenols in combating NAFLD.

Non-alcoholic fatty acid disease (NAFLD) has become an emerging entity of liver disorders worldwide.     

Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine

Journal of Neuro-Oncology - MYC-driven medulloblastomas are highly aggressive childhood tumors with dismal outcomes and a lack of new treatment paradigms. We identified that targeting replication...     

The combination of appetitive and aversive reinforcers and the nature of their interaction during auditory learning

Learned changes in behavior can be elicited by either appetitive or aversive reinforcers. It is, however, not clear whether the two types of motivation, (approaching appetitive stimuli and avoiding aversive stimuli) drive learning in the same or different ways, nor is their interaction understood in situations where the two types are combined in a single experiment. To investigate this question we have developed a novel learning paradigm for Mongolian gerbils, which not only allows rewards and punishments to be presented in isolation or in combination with each other, but also can use these opposite reinforcers to drive the same learned behavior. Specifically, we studied learning of tone-conditioned hurdle crossing in a shuttle box driven by either an appetitive reinforcer (brain stimulation reward) or an aversive reinforcer (electrical footshock), or by a combination of both. Combination of the two reinforcers potentiated speed of acquisition, led to maximum possible performance, and delayed extinction as compared to either reinforcer alone. Additional experiments, using partial reinforcement protocols and experiments in which one of the reinforcers was omitted after the animals had been previously trained with the combination of both reinforcers, indicated that appetitive and aversive reinforcers operated together but acted in different ways: in this particular experimental context, punishment appeared to be more effective for initial acquisition and reward more effective to maintain a high level of conditioned responses (CRs). The results imply that learning mechanisms in problem solving were maximally effective when the initial punishment of mistakes was combined with the subsequent rewarding of correct performance.     

Spatial variation in the joint effect of extreme heat events and ozone on respiratory hospitalizations in California

Extreme heat and ozone are co-occurring exposures that independently and synergistically increase the risk of respiratory disease. To our knowledge, no joint warning systems consider both risks; understanding their interactive effect can warrant use of comprehensive warning systems to reduce their burden. We examined heterogeneity in joint effects (on the additive scale) between heat and ozone at small geographical scales. A within-community matched design with a Bayesian hierarchical model was applied to study this association at the zip code level. Spatially varying relative risks due to interaction (RERI) were quantified to consider joint effects. Determinants of the spatial variability of effects were assessed using a random effects metaregression to consider the role of demographic/neighborhood characteristics that are known effect modifiers. A total of 817,354 unscheduled respiratory hospitalizations occurred in California from 2004 to 2013 in the May to September period. RERIs revealed no additive interaction when considering overall joint effects. However, when considering the zip code level, certain areas observed strong joint effects. A lower median income, higher percentage of unemployed residents, and exposure to other air pollutants within a zip code drove stronger joint effects; a higher percentage of commuters who walk/bicycle, a marker for neighborhood wealth, showed decreased effects. Results indicate the importance of going beyond average measures to consider spatial variation in the health burden of these exposures and predictors of joint effects. This information can be used to inform early warning systems that consider both heat and ozone to protect populations from these deleterious effects in identified areas.

Early warning systems for air pollution (1, 2) and heat (3, 4) have been implemented in various areas to limit the health impact of these increasingly prevalent environmental stressors (5, 6). Extreme heat events and some air pollutants such as tropospheric ozone have similar meteorological drivers, as they result from chemical reactions between volatile organic compounds, nitrogen oxides (NOx), and sunlight, leading them to regularly coincide (7). However, no joint early warning systems have been implemented to combat the dual burden of these environmental health risks. An improved understanding of these risks and the interaction between these hazards is important to inform the development and use of early warning systems that consider these joint exposures.The adverse health effects of heat are well documented. For example, exposure to high ambient temperature has been shown to increase the risk of mortality and morbidity for a range of diseases (8, 9). High ambient temperature causes heat stress and decreases ability to thermoregulate efficiently, which can produce heat-related inflammation and cardiac stress (10). Several studies have found impacts of heat on respiratory hospital admissions, such as chronic obstructive pulmonary disease and an increase in respiratory infections leading to increased hospitalizations (11–14).Ozone is a reactive, oxidative gas that is absorbed by the upper respiratory tract; epidemiological studies show a robust relationship between acute exposure to ambient ozone and morbidity (15). Ozone pollution is associated with a range of adverse health effects induced by oxidative stress and increased risk of respiratory disease, such as acute respiratory illnesses and asthma (15–18). In 2015, it was reported that globally, 4.1 million disability-adjusted life years were attributable to ozone exposure alone (19).Ambient ozone increases under high ambient temperature and blazing sunlight, both of which are characteristics of extreme heat events (15). Due to the comparable meteorological patterns, heat and ozone are co-occurring risk factors, and a number of studies have considered the potential concurrent risks and interaction of these exposures in driving the health burden (20–22). Studies in Brisbane, Australia, and in the Netherlands suggested that both ozone and heat play a role in increasing excess deaths during a heat wave (23, 24). Interaction between both exposures suggests that the effect of both ozone and heat drive an increased burden compared to each exposure individually. Findings differ between these studies, some revealing a strong relative interaction (20, 25, 26), while others demonstrate a weaker signal (27, 28) or no joint effect (29). For example, high temperature enhanced the effects of ozone on all-cause mortality in France (20) and cardiovascular and respiratory deaths in China (22). In contrast, no relative interaction between ozone and heat was observed in all but one city in England (23).Although several studies have considered the joint effects of temperature and ozone (20, 26, 27), few have considered the fine spatial variation in these effects (30). The consideration of fine spatial variation is important because it can provide location-specific thresholds that are most effective in revealing this health burden. Studying spatial variation across diverse regions is vital because it can reveal the heterogeneity of this interaction that can be used to inform warning systems. One study applied a spatial semiparametric model to estimate the joint effects of ozone and temperature risk in urban areas in the United States (30). Although that paper finds evidence of ozone–temperature interaction at high temperature thresholds and ozone concentrations, the study focused on urban areas and the relationship varied by city studied. Therefore, we were motivated to consider this interaction at the zip code level in various geographical and sociodemographic contexts.Some vulnerable groups are known to be especially susceptible to the effects of ozone and heat. For example, the ozone-related excess attributable risk was found to be almost two times higher for Black compared to White residents in California for air pollution exposure above federal standards (31). Racial discrimination plays a role, as decreased access to primary care, private insurance, and preventive medication of Black residents when compared to their White counterparts likely drive this health disparity (31). Furthermore, racial minorities and communities of a low socioeconomic status are also more susceptible to heat-related health effects; this is associated with poorer physical health, lower access to air conditioning, and greater neighborhood-level exposure that may increase risk (32). Green space, for example, has been shown to be a modifier of heat-related health effects (14). Although these contextual variables are known to play a role in the effect of these exposures, no study to our knowledge has considered the role of sociodemographics and neighborhood-level factors in driving the interactive effect between ozone and heat.We examined the potential heterogeneity in the joint effects between heat and ozone resolving fine geographical scales. The majority of studies considering joint effects have not used heat waves or extreme heat events as a binary variable to study temperature effects. We argue that studying the effects of temperature exceeding thresholds is a policy-relevant measure that can be used to activate early warning systems (9). Moreover, most studies focus on mortality, and very few have considered the burden on hospitalizations, a more moderate signal that could reveal broader health impacts. Lastly, the majority of studies investigated heat–ozone interactions based on the relative scale by including a product term in multiplicative models (33, 34). In this study, we investigate interaction on the additive scale that constitutes a more relevant public health measure (35, 36) since it directly quantifies the absolute number of hospital admission cases that could be prevented by a joint intervention on both heat and ozone exposures as compared to independent interventions. Focusing on the highly diverse state of California, we explore the role of sociodemographics and environment characteristics at the zip code level in predicting these joint effects to identify factors that can be used to prioritize areas for joint warning systems.     

Ethylenediamine: an effective reagent for deacetylation of natural products

The use of ethylenediamine in methanol is described for the selective cleavage of the acetate group in nimbin (1) to 6-deacetyl nimbin (1a) under microwave irradiation. This method enables to deacetylate without affecting other functional groups such as α,β-unsaturated ketone, ester, ether, etc. in certain tetranortriterpenoids and other acetate-containing natural compounds.     

Shrinkage Study and Strength Aspects of Concrete with Foundry Sand and Coconut Shell as a Partial Replacement for Coarse and Fine Aggregate

The demand for natural aggregates (river sand) is increasing day by day, leading to the destruction of the environment, a burden that will be passed on to young people. Further, wastes from various industries are being dumped in landfills, which poses serious environmental problems. In order to ensure sustainability, both the issues mentioned above can be solved by utilizing industrial waste as aggregate replacement in the concrete construction industry. This research is done to find out the results using two substances viz., waste foundry sand (WFS) and coconut shell (CS) substitute for river sand and coarse aggregate. Many researchers have found the maximum benefits of substituted substances used in cement, which has material consistency. This current observation explores these strong waste properties of waste-infused concrete and cement, which experience shrinkage from drying out. The replacement levels for waste foundry sand were varied, between 10%, 20%, and 30%, and for CS, it was 10% and 20%. The experimental outcomes are evident for the strength, which increases by using WFS, whereas the strength decreases by increasing the CS level. The concrete that experiences shrinkage from drying out is included in the waste material, showing a higher magnitude of drying shrinkage than conventional concrete.     

Pulmonary Function Assessment in Mild to Moderate Persistent Asthma Patients Receiving Montelukast,Doxofylline, and Tiotropium With Budesonide: A Randomized Controlled Study

Background

There is no comparative study among asthma patients receiving first-line versus various second-line treatment regimens for mild to moderate persistent asthma.

Objective

We assessed the pulmonary function in asthma patients receiving montelukast, doxofylline, and tiotropium with budesonide in a pilot group.

Methods

Patients were recruited as per the study criteria and randomly allocated to 4 groups to receive budesonide (400 µg) with formoterol (12 µg), doxofylline (400 mg), montelukast (10 mg), or tiotropium (18 µg) for a period of 3 months. Outcomes included forced expiratory volume in 1 second (FEV₁) and rescue medication use.

Results

A total of 167 patients were recruited; among them, 123 patients completed the study. At baseline, no significant difference (P > 0.05) was observed in any of the outcome measures. Significant within-group improvement in FEV₁ was observed in all the groups. At day 90, between-group difference revealed that improvement in FEV₁ was significantly (P < 0.05) high for budesonide plus formoterol followed by budesonide plus doxofylline, budesonide plus montelukast, and, lastly, budesonide plus tiotropium. Similarly, within-group comparison revealed a significant (P < 0.05) reduction in rescue medication use in all the groups. The intensity in decrease was more in budesonide plus formoterol group followed by budesonide plus doxofylline, budesonide plus montelukast, and budesonide plus tiotropium groups.

Conclusion

On the basis of our findings, among the second-line treatment regimens, budesonide plus doxofylline and budesonide plus montelukast was found to be better than budesonide plus tiotropium in patients with mild to moderate persistent asthma. Further studies with a larger sample size are likely to be useful.