Abstract1.     Climatic factors are known to mediate the expression of social behaviors. Likewise, variation in social behavior can dictate climate responses. Understanding interactions between climate and sociality is crucial for predicting impacts of climate change on animal populations.

At the beginning of the COVID-19 pandemic, Dr Tedros, Director-General of the World Health Organization (WHO) called for solidarity in our global response. While the call has echoed in various World Health Assembly (WHA) resolutions and other major public health commitments, many responses (local, national, and global) to the pandemic have seen shortfalls in solidarity. This viewpoint uses the COVID-19 pandemic to explore the roots of solidarity and trust and the political, economic, and social values and forces that shape it. The shortfall in our pandemic response exposes the limits and conditions of solidarity. However, we argue that solidary can be strengthened to contribute to global health security. Lastly, we reflect on the importance of solidarity in emergency preparedness, response, and recovery and the implications for public health practice.

Background: 18 years ago Porter and Teisberg published their landmark manuscript on “Redefining Health Care.” As part of the implementation of their Full Cycle of Care, instruments have been developed to achieve value-based medicine, such as consistent commitment to measurability (“benchmarking”). One of these instruments is the Balanced Scorecard (BSC). This is an organizational tool for implementing strategies in institutions, which is constantly being further developed and given new forms of application. The strength of BSCs lies in their ability to integrate multiple perspectives. Here we propose the first BSC for prostate cancer (PC) treatment. Methods: BSC are used to assess performance in healthcare organizations across four dimensions: financial, patient and referrer, process, and learning and development. This study aimed to identify key performance indicators (KPIs) for each perspective. A systematic literature search was conducted using multiple databases and specific search terms to identify KPIs for PC care, excluding case reports, conference abstracts, and editorials, and without assessing methodological quality due to the study’s nature. Results: In the present study, a PC-specific BSC and KPIs were defined for the four classic perspectives, as well as for a newly developed disease and outcome perspective of PC, including patient-related parameters from the German Cancer Society (DKG) and the International Consortium for Health Outcomes Measurement (ICHOM). Conclusions: The developed BSC provides a comprehensive set of perspectives for an Integrated Practice Unit or center in PC care, ensuring that the indicators remain manageable and applicable. The BSC facilitates value creation in line with Porter’s Full Cycle of Care by systematically collecting and providing economic, personnel, and medical results, actions, and indicators.

Abstract: This study delves into an often overlooked facet of animal relationships, shedding light on the intricacies that render these bonds distinct. The research centers on the mechanisms through which animals cultivate friendships, the benefits they derive from such connections, and the myriad manifestations of these relationships across three distinct regions in Bangladesh. Notably, this investigation extends beyond intraspecies interactions to encompass interspecies bonds, including those between humans and feline and ovine companions, the companionship shared between a young feline and a human, human-canine affiliations, and the human-goat relationships. By examining these varied connections, this research seeks to unveil the profound emotional ties that transcend species boundaries and underscore the transformative influence they exert on the well-being of animals.Keywords: Ethology, Zoology, Animal Behavior, Behavioral Diversity, Domestic AnimalsIntroduction: Animals are fascinating creatures that never cease to amaze us with their unique abilities and behaviors. One aspect of their lives that has been gaining attention in recent years is their ability to form deep and lasting friendships with members of their own species and even with members of other species. From unlikely pairings, such as a cat and a man, to more common partnerships, like a dog and a human, these bonds can be heartwarming and fascinating to observe. On the basis of three different regions of Bangladesh, I attempted to investigate some of the most fascinating instances of animal friendship, exploring the scientific underpinnings of these bonds and the priceless lessons they can impart about the relationships we develop with others. In the vast and diverse animal kingdom, friendships transcend species boundaries, defying conventional expectations and captivating the hearts of enthusiasts. It can be a source of protection, with individuals banding together to avoid potential threats. It can also serve as a means of survival, with different species depending on each other for food, shelter, or mutual defense. Perhaps the most significant aspect of animal friendship is the emotional bond that can develop between individuals, transcending the boundaries of instinct and biological necessity. Dolphins are known for forming complex social networks, with individuals often developing strong bonds that can endure throughout their lifetime. Elephants display remarkable empathy and solidarity, offering comfort and support to their fellow herd members in times of distress. Even seemingly solitary big cats have been observed to form social bonds, displaying moments of affection and dependence on one another. While friendships in some animals may have clear evolutionary advantages, others seem to defy any logical explanation. Consider the well-known story of Owen and Mazie, a young hippopotamus and an older turtle who became inseparable friends after meeting in a Kenyan wildlife sanctuary (Hatkoff 2006). Despite their stark differences in size, species, and behavior, their friendship blossomed, captivating the world and reminding us of the unexpected connections that arise in nature. In light of the fact that there had not been any research on this subject from a Bangladeshi perspective, I thought about conducting a study and gathering information to share with everyone, whether they love animals or not.

Phlebia genus is a relevant group of fungi with crucial role in numerous ecosystems. In tropical and subtropical areas this genus allows the efficient degradation of lignin and carbon recovery; however, the majority of these fungal species remains undiscovered. The main purpose of this work was to determine the enzymatic activity of extracellular proteins of a novel Phlebia floridensis strain isolated in Yucatan Peninsula, Mexico. The results that are reported here demonstrate that soluble protein extract of P. floridensis can degrade a broad spectrum of recalcitrant compounds. This induced protein extract is able to modify not only phenolic and non-phenolic compounds, but also anthroquinone dyes, even without addition of exogenous hydrogen peroxide. Using LC-MS/MS, we were able to identify a novel chloroperoxidase in enzymatic extract. As far as we know, this is the first report about the presence of this type of enzyme in Phlebia genus.

Salmonella Typhimurium (STM) is a facultative anaerobe of zoonotic importance and one of the causative agents of non-typhoidal salmonellosis (NTS). During infection, STM must adapt to the changes in oxygen concentration encountered in the crucial niches of host like gut lumen and intramacrophage environments. But being a chemo-organoheterotroph, STM is capable of obtaining its energy from organic sources via redox reactions. NarL, a transcription factor and the response regulator of the two-component regulatory system NarX/L, gets activated under nitrate rich anaerobic condition. Upon activation, it upregulates the nitrate reduction during anaerobic respiration. However, in this study, we observed a significant attenuation of virulence in the narL-knockout strain of STM, while the respective morphotypes got rescued upon genetic complementation. Along with motility and biofilm forming ability, the mutant strain displayed reduced intracellular replication in either intestinal epithelial cells or monocyte-derived macrophages of poultry origin. Further, in vivo competitive assay in the murine model showed that wild type STM significantly outcompeted its isogenic narL null mutant.

Abstract: Purpose: Fundus fluorescein angiography (FFA) is usually done when the patient is on an empty stomach. In case, if the patient is not, their FFA is rescheduled for the next day to avoid the risk of complications. The purpose of this study was to compare the complications in patients who had undergone an FFA procedure on an empty stomach to those who had breakfast immediately before the procedure. Methods: In this study, 210 participants underwent FFA, of which 104 were fasting, and 106 had breakfast just before their procedure. In these two populations, we compare the immediate and post-procedure complications. Result: Patients who had FFA on an empty stomach were more likely to experience nausea and vomiting (11.32% vs 7.69%), skin allergies (1.89% vs 1.92%), and unconsciousness (0.94% vs 2.88%). In either the fasting or control groups, no complications were statistically significant (P>0.05). Conclusion: FFA is generally a safe procedure, however, previous studies have observed increased adverse events with people on empty stomachs. In individuals with various systemic disorders and diets, our study found no increase in adverse effects. Consequently, FFA shouldn’t be postponed in these individuals who are not on a diet or who have systemic co-morbidities.

Seed water imbibition is critical to the seedling establishment in tropical forests. The neotropical tree Hymenaea ( Hymenaea courbaril) is a model system to study seed storage xyloglucan (XyG) mobilization after germination. Typical of many legumes, seed coats of Hymenaea are formed by a palisade of lignified cells, conferring imperviousness to water and the need for scarification to germinate. Below this fortified cell layer, a parenchyma layer, composed mainly of pectins, is juxtaposed on the surface of the cotyledon, whose cells contain thick cell walls containing mostly XyG. Here we used scanning electron and fluorescence microscopies, and NMRi spectroscopy to visualize water uptake and distribution in seeds of Hymenaea. An experiment with in vitro Hymenaea pectin or XyG composites with cellulose from the Whatman paper demonstrated the cell wall polymers’ functions during imbibition. We observed that water follows distinct pathways containing different cell wall compositions to varying speeds through the seed coat and cotyledons until embryo metabolism is activated synchronically with storage mobilization. We conclude that the dynamic interactions between water and wall polysaccharides (pectins and hemicellulose) of different seed tissues are central to determining water distribution and preparing the seedling for establishment.

Negative pressures of the industrial world have led to establishment of Brundtland Commission report stating importance of sustainable development for inter and intra generational equity in 1987. Since then sustainable development goals have been marked for poverty alleviation, clean and affordable water, energy security, environment, and agriculture sectors. The global concern of climate change, desertification, and degradation led threats, impact, and resilience for landuse and livelihood is incorporated in sustainable development goals. Sustainable development goals for climate action are met using multiple approaches. Transformative approaches are one such set of approaches for meeting environment challenges for landuse and ecological transient areas or ecotones of agriculture, grasslands, and wetlands affected by human and natural disturbances. Nature based solution falls under transformative approaches and matches the policy efforts on sustainable development goals on decade on restoration and climate positive action for land use and livelihoods. Regeneration potential of natural sites after anthropogenic or natural disturbances is reflected by vegetation health, soil health, and ecology of ecotones. The potential to regenerate is characteristic for ecosystems to revive against anthropogenic and ecological pressures. This facilitates to understand the restoration processes for land degradation and succession changes in an ecosystem. Ecotones are transient ecological regions between different ecosystems and are sensitive sites to study vegetation change due to pressures of globalized world. To detect the changes in vegetation due to climate, desertification, and land degradation on ecotones, we are using NDVI. We are using it for time series analysis for vegetation based changes. We are analyzing vegetation changes over a period of twenty years at a frequency of two weeks. We expect to see changes in the vegetation growth in the presence of anthropogenic and climate impacts.

Dissolved organic matter and nutrients released from forest leaf litter are important cross-ecosystem resources that support freshwater ecosystems. Dissolved organic matter released from leaf litter is one of the allochthonous sources for heterotrophic organisms in freshwater communities. However, the role of macro- and micronutrients released from leaf litter in producing autochthonous organic matter in aquatic ecosystems is not necessarily well understood. In this study, therefore, we investigated how dissolved nutrients released from leaf litter affect the algal growth, biomass production, and cell elemental quotas. Specifically, we focused on the responses of the green algae to TDN, TDP, and micronutrients released from the leaf litter of 11 temperate tree species. We found that the algal growth rate increased with TDP when micronutrients were amended. In contrast, the algal biomass production increased with TDN, regardless of micronutrient amendment. Micronutrient limitation of algal growth rate was found in the leaf litter leachates from oak, Japanese elm, and Japanese hemlock. However, algal biomass production was limited by micronutrients only in the leaf litter leachate from Japanese hemlock. More importantly, leaf litter leachates from different tree species altered algal cell quotas and C:N:P ratios, which would affect secondary production. These results suggest that forest vegetation change or succession affect the quantity and quality of autochthonous organic matter and thus the mass transfer efficiency in the aquatic community by changing the stoichiometry of nutrient input from the leaf litter.

The interaction of robotics along with artificial intelligence in healthcare has bring a transformative shift in medical practice and patient care. This commentary article delves into the realm of robotics applications in healthcare , exploring the multifaceted ways in which these technologies are revolutionizing the industry. By shedding light on latest advancements and breakthroughs , we provide insights into how robotics is enhancing precision , efficiency , and patient outcomes while redefining the boundaries of modern healthcare. Through this commentary , we aim to stimulate discussions on the challenges , ethical considerations, and potential future directions of robotics in healthcare.

Background and Aim: Respiratory distress is one of the most common underlying causes of Emergency Department visits in children, with a high morbidity and mortality rate which could raise a lot of concerns, acquiring early recognition of the underlying cause and appropriate treatment. The current study aimed to determine the prevalence and distribution of underlying causes of respiratory distress. Material and Methods: In this retrospective cohort study, demographic and clinical information of 154 patients older than one month who were referred to the Mofid Children’s Hospital emergency department in Tehran, Iran, from October 2018 to April 2019 were gathered from Hospital Information System (HIS) and analyzed with SPSS Statistics 23.0 version. Results: 154 participants were recruited with a mean age of 33.02±37.21 months, and 66% were male. The most common clinical symptom among these children was tachypnea (90.6%). Asthma (35.1%), pneumonia (31.8%), sepsis (8.4%), bronchiolitis and croup (7.8%), and foreign body (7.1%) were the most common causes of respiratory distress. When comparing clinical symptoms, nasal flaring was substantially more common in younger individuals than in older patients (P-value=0.04), but there were no significant differences between the sexes. In terms of underlying causes, patients with bronchiolitis and airway malformation were considerably younger than those without these disorders (P-value 0.001), whereas patients with chest wall deformity were more likely to be older (P-value=0.01), and it was more frequent among girls (P-value=0.03). Conclusion: Respiratory distress can be manifested with a variety of signs and symptoms and different underlying causes which may defer in different genders, ages, and regions. Among patients referred to a tertiary center in Tehran, tachypnea was the most common clinical symptom, and asthma was the most frequent cause of respiratory distress. Knowing the underlying causes of this emergent clinical status in pediatrics can help us in developing appropriate treatment approach.

The beak which is the feeding organ of cephalopods contains extremely rich ecological information. To understand its function in different species the research to the 3-D morphology is essential. In this article, a full workflow of 3-D model restoration of high-fidelity cephalopods beak, based on software-oriented techniques, was established. To begin with, take an upper beak of cuttlefish Sepia pharaonis for example, a group of isometic view from different orientations for modeling references could be obtained synchronously, in few images, with triangular prisms around it. The software Photoshop © was applied then to extract the contour of the beak hence to build the 2-D reference gallery. Thirdly, the software ZBrush 2020© was exerted to create the beaks in 3-D digital form as realistic as possible, based on reference gallery we built, and printed. These digital-twin models were compared with their prototype beaks and that of big fin reef squid to verify their accuracy. The aim of this study was to provide a feasible method for digital modeling of small organic objects like cephalopod beak that is accurate, and fast enough to support scientific research and popular communication.

Purpose: The aim of this study was to examine the current perceptions in prescription of systemic antibiotics for treating periodontal and peri-implant diseases. Methods: It was a descriptive, cross-sectional study involving an electronic survey of a sample of periodontists from Pakistan. A pre-validated questionnaire was disseminated to Pakistan Medical and Dental Council registered periodontists of Pakistan in order to ascertain their prescribing patterns of systemic antibiotics for various periodontal diseases. These included plaque-induced gingivitis, aggressive periodontitis, chronic periodontitis, acute gingival and periodontal conditions, conditions associated with dental implants, mucogingival surgery and periodontal regeneration. Results: From the 68 periodontists that responded to this study, 44 completed the questionnaire and their responses were analyzed. Prescribing trends of systemic antibiotics varied individually as well as for different periodontal conditions among the responding periodontists. Highest rate of antibiotics prescription was recorded for the management of aggressive periodontitis, which was 95.5%. Succeeding this were acute periodontal conditions, implant placement surgery, periodontal regeneration procedures and mucogingival surgery, having a prescription rate of 93.2%, 79.5%, 50% and 29.5%, respectively. Combination of amoxicillin and metronidazole, azithromycin, and amoxicillin were the three drugs of choice for various periodontal conditions. Conclusion: Based on the results from this survey, it was deduced that systemic antibiotics are widely prescribed by the periodontists in Pakistan, with varying rates and patterns for different periodontal and peri-implant diseases. These results highlight the need for guidelines and recommendations in the prescription of antibiotics for various periodontal diseases and peri-implant conditions.

Background Despite the limited evidence in immunocompromised populations, the U.S. Food and Drug Administration issued an Emergency Use Authorization in December 2021 for tixagevimab/cilgavimab (T/C) indicated for COVID-19 pre-exposure prophylaxis. T/C has been used widely at our center, therefore, we sought to determine the safety and effectiveness of T/C for this indication in a cohort of kidney transplant recipients. Methods This was a retrospective, single-center, Institutional Review Board-approved study evaluating the outcomes of 122 kidney transplant recipients who received tixagevimab/cilgavimab for pre-exposure prophylaxis of COVID-19. Adult patients who received T/C between January 1 st, 2022 and March 31 st, 2022 were reviewed for inclusion. The efficacy population (n= 115) comprised those who received two doses and the safety population (n=122) comprised those who received any amount of T/C. The primary outcome was the rate of hospitalization for COVID-19 infection within six months of the first dose of T/C. The secondary outcome was serious adverse events attributed to T/C. Results Within six months of administration, low rates of hospitalization (2%) and adverse events (2%) were found, with no incidence of heart failure, myocardial infarction, or anaphylaxis. Conclusion Overall, our study demonstrated that T/C in kidney transplant recipients was safe and associated with low rates of hospitalization for COVID-19 infection when susceptible Omicron subvariants were dominant.

Anaphylaxis after omalizumab in a patient with Hymenoptera venom allergy Esra Hazar, MDAssistant ProfessorAlanya Alaaddin Keykubat University Medical School, Pediatric Allergy and Immunology Unit, AntalyaShort title: Anaphylaxis with omalizumabCorresponding Author:Esra HazarAlanya Alaaddin Keykubat University Research and Training HospitalPediatric Allergy and Immunology UnitOba Mah Fidanlik Cad 07400 Alanya/AntalyaPhone: 02425134841/1294Cell Phone: 05339490874Word count: 1398The author declare no conflict of interest

Background: While risk of infection with SARS-CoV-2 is low to pregnant women and the fetus, there is increased risk of preterm birth and admission into ICU. The fetus is relatively protected against infection, with cases of vertical transmission being rare. Various receptors and accessory molecules which are known to regulate SARS-CoV-2 viral entry into host cells have soluble versions which could act as decoy traps. Following on from our previous findings regarding the abundance of some of these molecules in breast milk and amniotic fluid, we show the maternal-fetal interface is also rich in these molecules and how systemically they can be differentially expressed between males, non-pregnant females, pregnant females, and neonates. Methods: Archived placental samples from before the pandemic, and blood from participants in late 2020 who had not tested positive for COVID-19 were analysed for the presence of receptors by ELISA, immunohistochemistry, immunoblotting and flow cytometry. Results: We have confirmed that the placenta and membranes are particularly rich in CD26 and CD147 and gone on to consider if it is possible that shedding of these molecules into the maternal and fetal circulation occurs. However, except for sCD147 in umbilical cord plasma compared to all groups and sNRP-1 in pregnant women in comparison to men and neonates, the expression of soluble forms of these molecules is primarily consistent between the groups studied here. Conclusion: The maternal-fetal interface has potential mechanisms to protect the fetus from contracting SARS-CoV-2 by being rich with soluble versions of receptors involved in host cell entry of the virus, thereby limiting infection of host cells.

The role of neoadjuvant chemotherapy in advanced Ovarian Cancer (AOC): Avoiding ‘needless hurt’ or a Trojan horse?

Objective Investigate maternal and neonatal outcomes associated with breech presentation in planned community births in the United States Design Cohort analysis of a national perinatal data registry Setting Homes and birth centres, United States Sample Medical records of individuals with a term, singleton gestation (N=71,943) planning community birth at labour onset Methods Descriptive statistics to calculate associations between types of breech presentation and perinatal outcomes Main Outcome Measures Maternal: intrapartum/postpartum transfer, hospitalization, caesarean, haemorrhage, severe perineal laceration, duration of labour stages and membrane rupture Neonatal: transfer, hospitalization, NICU admission, congenital anomalies, umbilical cord prolapse, birth injury, intrapartum/neonatal death Results One percent (n=695) of individuals experienced breech birth, with most (57%) presenting frank breech (19% complete, 18% incomplete, 5% unknown breech type). Among all breech labours, there were high rates of intrapartum transfer and caesarean (OR 9.0, 95% CI 7.7-10.4 and OR 18.6, 95% CI 15.9-21.7, respectively), with no substantive difference based on parity, planned site of birth, or level of health system integration. Risk of nearly all assessed neonatal outcomes was higher for all breech presentation types, including hospital transfer, NICU admission, birth injury, and umbilical cord prolapse. Breech presentation was also associated with increased risk of intrapartum/neonatal death (OR 8.5, 95% CI 4.4-16.3), even after excluding congenital anomalies. Conclusions All types of breech presentation in community birth settings are associated with increased risk of adverse neonatal outcomes. Findings contribute to informed decision-making and reinforce the need for accessible, high-quality care for planned vaginal breech birth in hospitals.

Background:Angiomatoid fibrous histiocytoma (AFH) is a clinically rare low-grade malignant soft tissue tumor with occasional metastasis,It accounts for 0.3% of all soft tissue tumors, and it occurs most frequently in the extremities, followed by the trunk and head and neck.Primary angiomatoid fibrous histiocytoma of the pulmonary bronchus is rare, In this paper, the clinical and imaging data of a case of Primary angiomatoid fibrous histiocytoma of the pulmonary bronchus are reported and the literature is reviewed. Case description:A 57-year-old female patient developed cough without obvious inducement six months ago, with paroxyspasms of dry cough, chest tightness and shortness of breath, aggravating after activity.Laboratory tests showed:C-reactive protein 50.9mg/L, ferritin 346ng/ml, AFP<0.9ng/ml, CEA 3.45ng/mL,CA199 19.U/mL,CA125 10.50U/mL,CA50 10.60IU/ml,T-SPOT(-).Chest CT scan showed bronchial occlusion, attasis and soft tissue density in the right middle lobe of the lung. Enhanced scan showed uneven enhancement of endobronchial nodules. 18F-FDG PET/CT showed a density shadow of nodular soft tissue in the right lung bronchus. The density was even and the boundary was unclear. The size was about 2.2cm×2.5cm, and the uptake of 18F-FDG was higher than that of uniform uptake, the maximum standard uptake value (SUVmax) was 11.2.Bronchoscopy showed that the mass was nodular or polypoid, nodular, yellow and tough.The results of bronchoscopic biopsy showed:there were histocytes and dendritic cells in the background of lymphocytes and plasma cells, and no components of squamous cell carcinoma.According to the imaging diagnosis, the preoperative diagnosis was inclined to lung cancer. Due to the obvious symptoms of the patient, the family members and the patient requested surgery, and the postoperative pathological diagnosis was Primary angiomatoid fibrous histiocytoma of the pulmonary bronchus. Conclusion:The incidence of primary pulmonary AFH is very low, its clinical manifestations and imaging findings lack characteristics, and the final diagnosis still needs pathology.However, when middle-aged and elderly patients were found to have soft tissue shadows in the bronchus with clear boundaries and uneven density,the enhanced scan was moderately to significantly enhanced,and high FDG uptake on PET/CT scan,AFH should be considered,and surgical resection may be the best treatment.In conclusion, this case report further broadens the spectrum of lung and bronchial tumors.

INTRODUCTION Breast cancer is currently one of the most commonly diagnosed cancer and the fifth most common cause of cancer-related deaths with an estimated number of 2.3 million new cases worldwide according to the GLOBOCAN 2020 data.1 Breast cancer is detected early in recent years by screening, and have an advanced treatment options including surgery, radiotherapy and chemo-endocrine therapy. So, these patients have a better survival rate. But, some patients still present with locally advanced, metastatic or recurrent breast cancer. The resection of locally advanced or recurrent breast carcinomas frequently results in large chest-wall skin defects. Reconstruction of large defects following mastectomy remains a technical challenge for oncosurgeons and plastic surgeons.2 While skin grafts are non-aesthetic, other local fascio-cutaneous and pedicled flaps are often inadequate for full coverage. Free flaps are increasingly used for aesthetic breast reconstruction,2 but they often require expertise, equipment and time that are not frequently available in a setting like ours. Since, a large number of breast cancer patients often present in late stage with skin involvement, operability and outcome are often determined by whether negative margins could be achieved with satisfactory soft tissue reconstruction. As of late, we have used external oblique myocutaneous (EOM) flap as a means of closing such large defects with encouraging results.

Background and Purpose Inhibition of NLRP3 inflammasome plays a critical therapeutic potential in colonic inflammatory responses. The Timosaponin BⅡ (TBⅡ) isolated from the traditional Chinese medicine Anemarrhena asphodeloides has outstanding anti-inflammatory effects in various diseases. Here, we investigated the protective effects of TBⅡ against dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. Experimental Approach Wild-type (WT) and NLRP3 knockout (NLRP3-/-) mice were applied to evaluate the protective effects of TBⅡ in DSS-induced mice colitis. The role of TBⅡ in the LPS+ATP-induced cell model was evaluated by inhibiting or overexpressing NLRP3. RNA-seq, ELISA, western blots, immunofluorescence staining, and the expression analysis by qPCR were performed to examine the alterations of colonic NLRP3 expression in colon tissues and cells, respectively. Key Results TBⅡ treatment repaired the intestinal mucosal barrier and alleviated colonic inflammation In mice with DSS-induced ulcerative colitis. RNA-seq analysis and levels of protein expression demonstrated that TBⅡ could prominently inhibit NLRP3 signaling. TBⅡ-mediated NLRP3 inhibition was associated with the alleviation of intestinal permeability and the inflammatory response via blocking the communication between epithelial cells and macrophages. However, pharmacological inhibition of NLRP3 or NLRP3 overexpression significantly impaired TBⅡ-mediated the anti-inflammatory effect. Mechanistically, TBⅡ-mediated NLRP3 inhibition may be partially associated with the suppression of NF-κB. Conclusion and Implications TBⅡ exerted a prominent protective effect against colitis by impeding the crosstalk between epithelial cells and macrophages, partially in the NLRP3-mediated inhibitory mechanism. These beneficial effects could make TBⅡ a promising drug for relieving colitis.

Background and Purpose: Hepatic steatosis, which is triggered by dysregulation of lipid metabolism and redox equilibrium in the liver, is regarded as a risk factor in the initiating process of NAFLD. However, pharmacologic engagement of this process appears to be difficult. This study aims to identify the target of NSC48160, and investigate the mechanism by which NSC48160 exerts its liver protecting effect and ameliorate nonalcoholic steatohepatitis. Experimental Approach: We identified the small molecule NSC48160 as an effective agent against nonalcoholic steatohepatitis. We found that NSC48160 significantly lowered hepatic lipid levels in vitro and in vivo by activating the AMPK-dependent pathway. Key Results: Here, we found that activation of liver AMPK by NSC48160 can prevent HFD-induced liver steatosis. RNA-seq profiling and metabonomics analysis revealed that NSC48160-induced lipogenesis is modulated by lipid metabolism. Using in silico molecular docking combined with surface plasmon resonance and cellular thermal shift assay, we confirmed AMPKα as a direct molecular target of NSC48160. Activation of AMPK was further supported by the fact that the knockdown of AMPK blocked the hepatoprotective effect of the NSC48160 and regulated its downstream pathway involved in lipogenesis by SREBP1c-FASN pathway and fatty acid oxidation by CPT1A-PPARα pathway. Moreover, NSC48160 dramatically reduces ROS production, recovers the levels of the membrane potential and NAD+/NADH, and improves the mitochondrial respiration. Conclusion and Implications: These findings suggest that NSC48160 is a promising hit compound in the pursuit of a pharmacological approach to regulate the lipogenesis and fatty acid oxidation in the treatment of nonalcoholic steatohepatitis.

Background and Purpose: Although the amphiphilic nature of the widely used antithrombotic drug Ticagrelor is well known, it was never considered as a membranotropic agent, which is able to interact with lipid bilayer in a receptor-independent way. In this work we investigate the influence of Ticagrelor on plasma membrane lipid order in platelets and whether this could modulate affinity of P2Y12 receptor to Ticagrelor. Experimental Approach: Here, we combined fluorescent in situ, in vitro and in silico approaches to probe the interactions between the plasma membrane of platelets and Ticagrelor. The influence of Ticagrelor on the lipid order of the platelets’ plasma membrane and large unilamellar vesicles was studied using advanced fluorescent probe NR12S. Further, the properties of the model lipid bilayers in presence of Ticagrelor were characterized by molecular dynamics simulations. Finally, the influence of an increased lipid order on the dose response of platelets to Ticagrelor was studied. Key Results: Ticagrelor incorporates spontaneously into lipid bilayers and affects the lipid order of the membranes of model vesicles and isolated platelets in non-trivial composition and concentration-dependent manner. We showed that higher plasma membrane lipid order in platelets leads to the lower IC50 for Ticagrelor. It is shown that membrane incorporation of Ticagrelor increases the affinity of the drug to its own therapeutic target, the P2Y12 receptor, by means of increasing the order of the platelet’s plasma membrane. Conclusion and Implications: A novel dual mechanism of Ticagrelor action is suggested that combines direct binding to P2Y12 receptor with simultaneous modulation of receptor’s lipid microenvironment.