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AbstractPolycystic ovarian syndrome (PCOS) is a common endocrine disorder that primarily affects women of reproductive age. It is particularly prevalent among adolescent females who receive an insufficient diagnosis despite having potentially adverse consequences. The use of PCOS screening questionnaires has the potential to aid in the early detection of symptoms. The goal of this study is to observe if a self-administered questionnaire may be useful for a clear cognizance of the associated conditions like mental stress and menstrual characteristics correlated to polycystic ovary syndrome. In this study, we selected women within an age group of 17–40 with and without PCOS based on the modified Rotterdam criteria to fill out a self-administrated questionnaire based on the signs and symptoms of PCOS majorly focusing on mental stress and menstrual characteristics. SPSS software, univariate analyses were employed to elucidate the associations among the components of PCOS, demographic factors, and lifestyle characteristics, hence providing insights into the interrelationships among those variables. 64 women with PCOS and 141 women without PCOS participated in the present study. The present study revealed PCOS is greatly influenced by age at menarche (p-value= .043), typical cycle length (p-value = .000) mental health problems during menstruation (p-value = .032), and body mass index (p-value = .001). Multivariate hierarchical logistic regression analysis showed only 2 variables BMI (a-OR 1.156,95% CI (1.067–1.242), p-value = .000), and typical cycle length (a-OR 2.278, 95% CI (1.079–4.809), p-value = .003) were significant. The present study showed that BMI and menstrual cycle length were most closely associated with the incidence of PCOS, which is important in diagnosing and treating the condition. Considering the high incidence of PCOS among women of reproductive age and its potential for significant health implications, it would be prudent to incorporate inquiries regarding mental health concerns and menstrual patterns into routine medical assessments for this demographic analysis. This approach aims to ascertain whether additional diagnostic evaluations and screenings for PCOS are warranted.

Objective: Psychostimulant use induces oxidative stress and alters redox imbalance, influencing epigenetic signatures in the central nervous system (CNS). Among the various epigenetic changes, DNA methylation is directly linked to oxidative stress metabolism via critical redox intermediates such as NAD+, S-adenosylmethionine (SAM), and 2-oxoglutarate. Fluctuations in these intermediates directly influence epigenetic signatures, which leads to detectable alterations in gene expression and protein modification. This review focuses on recent advances in the impact of psychostimulant use on redox-imbalance-induced DNA methylation to develop novel epigenetics-based early interventions. Methods: This review is based on collective research data obtained from the PubMed, Science Direct, and Medline databases. The keywords used in the electronic search in these databases were redox, substance use disorder, psychostimulants, DNA methylation, and neurological diseases. Results: Instability in DNA methylation levels and redox expression effects are reported in various behavioral models stimulated by psychostimulants and opioids, indicating the widespread involvement of epigenetic changes in DNA methylation signatures in neurological disorders. Discussion: This review summarizes the need for more studies and experimental evaluations of DNA-methylation-based strategies that may help to understand the association between psychostimulant use and oxidative stress or redox-linked metabolic recalibration influencing neuronal impairments.

Background: Previous studies have indicated a close link between the inflammatory response, exacerbated by circadian disruption and psychostimulants such as cocaine and methamphetamine (METH). Indicators of this inflammation include cortisol and acute-phase proteins (APPs) like C-reactive protein (CRP), complement C3 (C3), and serum amyloid A (SAA). The connection between these inflammation markers and circulating mitochondrial DNA (mtDNA) has been gaining attention. However, the specific influence of cocaine and METH on APP, cortisol, and mtDNA levels in mice with disturbed circadian rhythm has yet to be explored, which is the main aim of this research. Methods: In our study, we employed 10–12-week-old male C57BL/6J mice, which underwent an imposed 6-h phase advance every six days for a total of eight cycles. This process led to the formation of mice with disrupted circadian rhythm and sleep disorders (CRSD). We administered 11 dosages of cocaine and METH 15 mg/kg and 20 mg/kg, respectively to these CRSD mice over the course of 22 days. Quantitative assessments of CRP, C3, SAA, cortisol, and cell-free circulating mtDNA were conducted using enzyme-linked immunosorbent assay (ELISA), Western Blot, and quantitative real-time polymerase chain reaction (qRT-PCR) techniques. Results: The experiment revealed that disruption in circadian rhythm alone or cocaine or METH on their own increased CRP, C3, SAA, and cortisol levels in comparison with the control group. CRSD mice, exposed to cocaine and METH, showed a significant rise in CRP, C3, and SAA, while those without exposure remained stable. We also found a reduction in circulating cell-free mtDNA in all CRSD mice, regardless of cocaine and METH exposure. Conclusions: The findings of our study affirm that the levels of CRP, C3, SAA, and cortisol, which reflect inflammation, are enhanced by circadian disruption, cocaine, and METH, and these levels show a strong correlation with the content of circulating cell-free mtDNA. Furthermore, it also shows the potential link between the disruption of the circadian clock and the inflammatory response triggered by cocaine and METH.

The chronic irreversible regression of cognitive ability and memory function in human immunodeficiency virus (HIV)-associated dementia (HAND) is linked with late-stage HIV infection in the brain. The molecular-level signatures of neuroinflammation and neurodegeneration are linked with dysfunction in HAND patients. Protein expression changes and posttranslational modification are epigenetic cues for dementia and neurodegenerative disease. In this study quantitative proteome analysis was performed to comprehensively elucidate changes in protein profiles in HIV-positive (HIV+) human brains. Frontal and temporal lobes of normal and HIV+ brains were subjected to label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the data-independent acquisition method. Comprehensive proteomic identification and quantification analysis revealed that 3294 total proteins and 251 proteins were differentially expressed in HIV+ brains; specifically, HIV+ frontal and temporal lobes had 132 and 119 differentially expressed proteins, respectively. Proteomic and bioinformatic analyses revealed protein alterations predominantly in the HIV+ frontal lobe region. The expression of GOLPH3, IMPDH2, DYNLL1, RPL11, and GPNMB proteins was significantly altered in HIV+ frontal lobes compared to that in normal brains. These proteins are associated with metabolic pathways, neurodegenerative disorders, and dementia. These proteomic-level changes may be potential biological markers and therapeutic targets to relieve the dementia-associated symptoms in individuals with HAND.

The human biological clock is the 24-h internal molecular network of circadian genes in synchronization with other cells in response to external stimuli. The rhythmicity of the clock genes is maintained by positive and negative transcriptional feedback loops coordinating the 24-h oscillation in different tissues. The superchiasmatic nucleus, the central pacemaker of the biological clock diminishes with aging causing alterations in the clock rhythmicity leading to the onset of neurodegenerative diseases mainly Alzheimer's disease, Parkinson's disease, and Huntington's disease. Studies have shown that brain and muscle Arnt -like 1 (Bmal1) and Circadian Locomotor Output Cycles Kaput (Clock) gene expression is altered in the onset of neurodegeneration. One of the major symptoms of neurodegeneration is changes in the sleep/wake cycle. Moreover, variations in circadian clock oscillations can happen due to lifestyle changes, addiction to alcohol, cocaine, drugs, smoking, food habits and most importantly eating and sleep/awake cycle patterns which can significantly impact the expression of circadian genes. Recent studies have focused on the molecular function of clock genes affected due to environmental cues. Epigenetic modifications are influenced by the external environmental factors. This review aims to focus on the principal mechanism of epigenetics influencing circadian rhythm disruption leading to neurodegeneration and as well as targeting the epigenetic modulators could be a novel therapeutic approach to combat neurodegenerative disorders., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Ru(II)-complexes have been recognised as promising in treating cancer. However, targeted delivery is an important facet to augment the efficiency of drugs. Consequently, this article portrays the construction of biotinylated-MWCNTs as an SMVT-guided nano-platform for the precise delivery of our previously-developed potent Ru(II)-scaffold, making it more effective against MCF-7 cells.

Alcohol, or ethanol, is a major contributor to detrimental diseases and comorbidities worldwide. Alcohol use during pregnancy intervenes the developing embryos leading to morphological changes, neurocognitive defects, and behavioral changes known as fetal alcohol spectrum disorder (FASD). Zebrafish have been used as a model to study FASD; however, the mechanism and the impact of ethanol on oxidative stress and inflammation in the zebrafish FASD model remain unexplored. Hence, we exposed zebrafish embryos to different concentrations of ethanol (0 %, 0.5 %, 1.0 %, 1.25 %, and 1.5 % ethanol (v/v)) at 4-96 hours post-fertilization (hpf) to study and characterize the ethanol concentration for the FASD model to induce oxidative stress and inflammation. Here, we studied the survival rate and developmental toxicity parameters at different time points and measured oxidative stress, reactive oxygen species (ROS) generation, apoptosis, and pro-inflammatory gene expression in zebrafish larvae. Our findings indicate that ethanol causes various developmental abnormalities, including decreased survival rate, spontaneous tail coiling, hatching rate, heart rate, and body length, associated with increased malformation. Further, ethanol exposure induced oxidative stress by increasing lipid peroxidation and nitric oxide production and decreasing glutathione levels. Subsequently, ethanol increased ROS generation, apoptosis, and pro-inflammatory gene (TNF-α and IL-1β) expression in ethanol exposed larvae. 1.25 % and 1.5 % ethanol had significant impacts on zebrafish larvae in all studied parameters. However, 1.5 % ethanol showed decreased survival rate and increased malformations. Overall, 1.25 % ethanol is the ideal concentration to study the oxidative stress and inflammation in the zebrafish FASD model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alcohol ingestion is a widespread habituation that evolved along with a growing population, altering physiological conditions through immunomodulatory function. There is much research that has reported that consumption of alcohol at low and heavy levels causes different biological impacts, including cellular injury, leading to systemic dysfunction and increased inflammatory markers. In the fate of professional phagocytic cells, efferocytosis is an inevitable mechanism activated by the apoptotic cells, thus eliminating them and preventing the accumulation of cell corpses/debris in the microenvironment. Subsequently, it promotes the tissue repair mechanism and maintains cellular homeostasis. Unfortunately, defective efferocytosis is widely found in several inflammatory and age-related diseases such as atherosclerosis, autoimmune diseases, lung injury, fatty liver disease, and neurodegenerative diseases. Alcohol abuse is one of the factors that provoke an immune response that increases the rate of morbidity and mortality in parallel in systemic disease patients. Information regarding the emergence of immunomodulation during alcoholic pathogenesis and its association with efferocytosis impairment remain elusive. Hence, here in this review, we discussed the mechanism of efferocytosis, the role of defective efferocytosis in inflammatory diseases, and the role of alcohol on efferocytosis impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Brahadeeswaran and Tamizhselvi.)

In recent years, mitochondria have gained significant interest in the field of biomedical research due to their impact on human health and ageing. As mitochondrial dynamics are strongly controlled by clock genes, misalignment of the circadian rhythm leads to adverse metabolic health effects. In this review, by exploring various aspects of research and potential links, we hope to update the current understanding of the intricate relationship between DRP1-mediated mitochondrial dynamics and changes in circadian rhythmicity leading to health issues. Thus, this review addresses the potential bidirectional relationships between DRP1-linked mitochondrial function and circadian rhythm misalignment, their impact on different metabolic pathways, and the potential therapeutics for metabolic and systemic disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Infections caused by Pseudomonas aeruginosa are becoming increasingly difficult to treat due to the emergence of strains that have acquired multidrug resistance. Therefore, phage therapy has gained attention as an alternative to the treatment of pseudomonal infections. Phages are not only bactericidal but occasionally show activity against biofilm as well. In this study, we describe the Pseudomonas phage Motto, a T1-like phage that can clear P. aeruginosa infections in an animal model and also exhibits biofilm-degrading properties. The phage has a substantial anti-biofilm activity against strong biofilm-producing isolates ( n  = 10), with at least a twofold reduction within 24 h. To demonstrate the safety of using phage Motto, cytotoxicity studies were conducted with human cell lines (HEK 293 and RAW 264.7 macrophages). Using a previously established in vivo model, we demonstrated the efficacy of Motto in Caenorhabditis elegans, with a 90% survival rate when treated with the phage at a multiplicity of infection of 10., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Manohar, Loh, Turner, Tamizhselvi, Mathankumar, Elangovan, Nachimuthu and Leptihn.)

A newly synthesized Schiff's base 2-(2-([2,2'-bithiophen]-5-ylmethylene)hydrazinyl)benzothiazole ( BT ) was obtained from the condensation reaction between 2-hydrazinobenzothiazole and 2,2-bithiophene-5-carboxaldehyde. The prepared probe BT was subjected to a confirmation of the structural arrangement through NMR, FTIR, ESI-HRMS, and single-crystal XRD spectral analysis. The BT colorimetric sensor showed selectivity and sensitivity toward the cyanide (CN - ) ion over other common anions such as ClO 4 - , Cl - , Br - , F - , I - , NO 2 - , OH - , HSO 4 - , and H 2 PO 4 - in a partial aqueous system CH 3 CN/H 2 O (8:2, v/v). The probe BT detects CN - with the lowest detection range as low as 1.33 × 10 -8 M (3.59 ppm); in comparison to that given by WHO guidelines, it is significantly lower. The stoichiometric interaction between the probe BT and analyte CN - was found to be 1:1 (BT/CN - ) binding mode using Jobs plot, and further association binding affinity was calculated to be 6.64 × 10 -3 M -1 . Additionally, these results were further supported by the FTIR and DFT calculations, as well as the 1 H NMR titration analysis, which complemented the binding data. The sensor probe BT was successfully employed in a cotton swab test kit approach and also in smartphone-assisted applications for the determination of CN - ions. Finally, the outstanding sensing properties of probe BT aided the quantitative detection of CN - ions, and it could be further applied to a variety of food samples, including apple seeds, sprouting potatoes, and cassava., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Protein N-terminal (Nt) acetylation is an essential post-translational process catalysed by N-acetyltransferases or N-terminal acetyltransferases (NATs). Over the past several decades, several types of NATs (NatA- NatH) have been identified along with their substrates, explaining their significance in eukaryotes. It affects protein stability, protein degradation, protein translocation, and protein-protein interaction. NATs have recently drawn attention as they are associated with the pathogenesis of human diseases. In particular, NAT-induced epigenetic modifications play an important role in the control of mitochondrial function, which may lead to inflammatory diseases. NatC knockdown causes a marked reduction in mitochondrial membrane proteins, impairing their functions, and NatA affects mitophagy via reduced phosphorylation and transcription of the autophagy receptor. However, the NAT-mediated mitochondrial epigenetic mechanisms involved in the inflammatory process remain unexplored. The current review will impart an overview of the biological functions and aberrations of various NAT, which may provide a novel therapeutic strategy for inflammatory disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The liver is in charge of a wide range of critical physiological processes and it plays an important role in activating the innate immune system which elicits the inflammatory events. Chronic ethanol exposure disrupts hepatic inflammatory mechanism and leads to the release of proinflammatory mediators such as chemokines, cytokines and activation of inflammasomes. The mechanism of liver fibrosis/cirrhosis involve activation of NLRP3 inflammasome, leading to the destruction of hepatocytes and subsequent metabolic dysregulation in humans. In addition, increasing evidence suggests that alcohol intake significantly modifies liver epigenetics, promoting the development of alcoholic liver disease (ALD). Epigenetic changes including histone modification, microRNA-induced genetic modulation, and DNA methylation are crucial in alcohol-evoked cell signaling that affects gene expression in the hepatic system. Though we are at the beginning stage without having the entire print of epigenetic signature, it is time to focus more on NLRP3 inflammasome and epigenetic modifications. Here we review the novel aspect of ALD pathology linking to inflammation and highlighting the role of epigenetic modification associated with NLRP3 inflammasome and how it could be a therapeutic target in ALD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brahadeeswaran, Dasgupta, Manickam, Saraswathi and Tamizhselvi.)

Acute Pancreatitis (AP) refers to the inflammatory state of the pancreatic mass caused by an abnormal release of digestive enzymes characterized by pancreatic acinar cell injury. It is mainly caused by gallstones, which primarily block sphincter of Oddi opening into the duodenum, heavyalcohol use, systemic diseases, etc. Stimulator of interferon genes known as STING uniquely senses the apoptotic and necrotic DNA fragments. Through the expression of TMEM173 (transmembrane protein 173) or STING protein in macrophages, downstream signaling pathways are activated in AP and are responsible for promoting inflammation. STING elicits a cascade of downstream signaling events such as activation of TBK1, IRF-3 phosphorylation, and IFN-β production along with other cytokines, which result in the excessive manufacture of the type-I IFNs and different kinds of proinflammatory cytokines that take part in the immune defense system of the host. Research findings suggest that STING regulates an array of innate immunity pathways, and the absence of proper treatment measures for AP provides the opportunity of evaluating STING as a striking therapeutic target for AP associated inflammation. Although the understanding of STING hyperactivation and its association with inflammation is relative of recent interest among researchers, extensive studies are going on to identify inhibitors that can directly target STING and inhibits the downstream signaling in AP. Therefore, this review aims to collectively compile the available pieces of evidence, which could help to better understand the role of STING signaling in AP and its promising role as a therapeutic target., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cyclin-dependent kinases (CDKs) belong to the serine/threonine kinase family, and their unique interactions with a variety of cyclin complexes influence its catalytic activity to ensure unimpaired cell cycle progression. In addition to their cell cycle regulatory roles, it is becoming increasingly clear that the CDKs can have multiple functional roles like transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions, and in spermatogenesis. Further in addition, recent reports suggest that CDKs have a remarkable regulatory role in influencing the pro-inflammatory functions of various cytokines during the clinical inflammatory responses. CDKs initiate the inflammatory responses by triggering the activity of prominent pro-inflammatory transcription factors such as nuclear factor kappa B (NF-kB), signal transducer and activator of transcription 3 (STAT3), and activator protein 1 (AP-1). The transcriptional CDKs (tCDKs) is crucial for organizing various transcription events and associated processes such as RNA capping, splicing, 3' end formation, and chromatin remodeling. Although the in-depth mechanism of certain mammalian CDKs is explored with respect to inflammation, the role of other tCDKs or any synergistic play among the members still remains unexplored. Until today, there is only supportive and palliative care available most of the inflammatory disorders, and thus it is the right time to explore novel pharmacological targets. In this regard, we focus on the pathophysiological role of CDK7, CDK8 and CDK9 and their impact on the development of inflammatory disorders within the mammals. Additionally, we discuss the potential trends of having tCDKs as a therapeutic target for fine-tuning inflammatory disorders., (Copyright © 2020. Published by Elsevier B.V.)

Background: Acute pancreatitis (AP), an inflammatory condition of pancreas, destructs the exocrine cells by releasing various pro-inflammatory cytokines that activates the stellate cells. However, the underlying molecular mechanism remains unclear. The present study investigated the role of retinoblastoma (Rb), hydrogen sulphide and nuclear factor-κB (NF-κB) in the regulation of exocrine cell proliferation under inflammatory condition., Methods: The randomly grouped male swiss mice were administered with 6 consecutive hourly i.p injections of caerulein to induce AP. Palbociclib (PD) (25 mg/kg body weight), a CDK4/6 inhibitor, was administered 1 h after the first cerulein injection intraperitoneally to block the RB pathway by inhibiting the activity of the CDK4/6 complexes and DL propargylglycine (PAG) which blocks the endogenous H 2 S production., Results: Pharmacological inhibition of CDK4/6 and H 2 S significantly improved pancreas and lung histopathological changes, decreased serum amylase level, both lung and pancreas myeloperoxidase (MPO) activity, TNFα expression and elevated IL10 expression. Furthermore, inhibition of RB pathway reduced cerulein-induced H 2 S level by reducing the expression of cystathionine gamma lyase (CSE) and NF-κB activation in pancreas and lungs. Also, blocking the RB signalling reduced the α-SMA expression in pancreas preventing the risk for pancreatic fibrosis. Whereas administration of H 2 S inhibitor PAG resulted in a decrease in CDK4/6-Rb expression in cerulein-induced AP., Conclusion: These results reveal a novel link between H 2 S/RB/NF-κB pathways, in AP and provide insight into possible mechanism that can be targeted in prevention of inflammation to cancer development., Competing Interests: Declaration of competing interest The authors declare that there are no potential conflicts of interest., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Garlic (Allium sativum) - derived organosulfur compound diallyl disulfide (DADS) possesses antioxidant, anti-inflammatory and anti-cancer effects. This study was aimed to investigate the anti-inflammatory role and the underlying molecular mechanisms of DADS in cerulein-induced acute pancreatitis (AP) and associated lung injury. Administration of DADS significantly attenuated the severity of pancreatic and pulmonary inflammation by inhibiting cerulein induced serum amylase, myeloperoxidase activity (MPO) and histological changes in pancreas and lung. Furthermore, the anti-inflammatory effect of DADS was associated with the decrease in tumor necrosis factor (TNF)-α,cystathionine-γ-lyase (CSE), preprotachykinin A (PPTA), neurokinin-1-receptor (NK1R) expression and hydrogen sulfide (H 2 S) production in both pancreas and lung. In addition, DADS reduced caerulein-induced I-κB degradation and subsequent translocation of NF-κB in the pancreas and lung. These results show for the first time that in AP, DADS exhibits an anti-inflammatory effect by inhibiting CSE/H 2 S and SP/NK1R signaling and NF-кB pathway., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Human immunodeficiency virus type 1 protease is essential for virus replication and maturation and has been considered as one of the important drug target for the antiretroviral treatment of HIV infection. The majority of HIV infections are caused due to non-B subtypes in developing countries. Subtype AE is spreading rapidly and infecting huge population worldwide. Understanding the interdependence of active and non-active site mutations in conferring drug resistance is crucial for the development effective inhibitors in subtype AE protease. In this work, we have investigated the mechanism of resistance against indinavir (IDV) due to therapy selected active site mutation V82F, non-active site mutations PF82V and their cooperative effects PV82F in subtype AE-protease using molecular dynamics simulations and binding free energy calculations. The simulations suggested all the three complexes lead to decrease in binding affinity of IDV, whereas the PF82V complex resulted in an enhanced binding affinity compared to V82F and PV82F complexes. Large positional deviation of IDV was observed in V82F complex. The preservation of hydrogen bonds of IDV with active site Asp25/Asp25' and flap residue Ile50/50' via a water molecule is crucial for effective binding. Owing to the close contact of 80s loop with Ile50' and Asp25, the alteration between residues Thr80 and Val82, further induces conformational change thereby resulting in loss of interactions between IDV and the residues in the active site cavity, leading to drug resistance. Our present study shed light on the effect of active, non-active site mutations and their cooperative effects in AE protease. Communicated by Ramaswamy H. Sarma.

Objective: We aim to study the protective effect of menadione on caerulein-induced acute pancreatitis (AP) and associated lung injury and to explore the possible mechanism., Methods: Male Swiss mice randomized into control and different experimental groups. AP was induced in mice by six hourly intraperitoneal (i.p) injections of caerulein (50 μg/kg at 1 h interval). Menadione (10 mg/kg) was administered one hour (i.p, 10 mg/kg) after the first caerulein injection and control animals were given hourly intraperitoneal (i.p) injection of isotonic sodium chloride solution for 6 hours., Results: Administration of menadione attenuated the severity of AP and associated lung injury as shown by the histopathology, reduced MPO and serum amylase activity. Further, the anti-inflammatory effect of menadione was associated with a reduction of pancreatic and pulmonary proinflammatory cytokine interleukin 1β (IL-1β) and hydrogen sulfide (H 2 S). Moreover, menadione inhibited caerulein-induced cystathionine-γ-lyase, preprotachykinin-A (PPTA) and neurokinin-1 receptor (NK-1R) expression in pancreas and lungs. Also menadione further enhances the beneficial effect by reducing caerulein-induced nuclear factor (NF) -κB activation in both pancreas and lung., Conclusion: The present findings show for the first time that in AP, menadione may exhibit an anti-inflammatory effect by down-regulating substance-P and H 2 S signaling via the NF-кB pathway., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objectives: In the present study, we have elaborated the anti-inflammatory mechanism of MSM through homing of CD34 + stem cells towards an inflamed region by regulating hydrogen sulfide (H 2 S) in an in vivo model of caerulein-induced acute pancreatitis (AP) and associated lung injury., Methods: Male Swiss mice were treated with hourly intraperitoneal injections of caerulein (50 μg/kg) for 6 h. MSM (500 mg/kg) was administered intraperitoneally 1 h after the first caerulein injection (therapeutic). The serum amylase activity and myeloperoxidase (MPO) activity in lung and pancreas were measured. The levels of H 2 S and interleukin (IL)-1β, cystathionine-γ-lyase (CSE) and CD34 + expressions in pancreas and lungs were determined by RT-PCR and ELISA., Key Findings: Methylsulfonylmethane significantly ameliorated pancreas and lung histopathological changes, decreased serum amylase, MPO activity and inhibited caerulein-induced IL-1β expression. Furthermore, MSM reduced caerulein-induced H 2 S levels by alleviating the expression of CSE in pancreas and lungs and increased CD34 expression and inhibited nuclear factor (NF)-κB translocation in caerulein-induced AP and associated lung injury., Conclusions: These findings indicate that MSM can effectively reduce inflammatory responses and induce the homing of CD34 + cells to the injured tissues., (© 2018 Royal Pharmaceutical Society.)

Objective: The present study aimed to evaluate the protective effects of scopoletin (SC) on cerulein-induced acute pancreatitis (AP) and associated lung injury in mice., Methods: Acute pancreatitis was induced in male Swiss mice by 6 consecutive hourly intraperitoneal injections of cerulein (50 μg/kg). Scopoletin was administered 1 hour (intraperitoneal, 10 mg/kg) after the first cerulein injection., Results: Administration of SC attenuated the severity of AP and associated lung injury as shown by histology, reduced myeloperoxidase, and serum amylase activity. Further, the anti-inflammatory effect of SC was associated with a reduction of pancreatic and pulmonary proinflammatory cytokines (interleukin 1β and tumor necrosis factor α) and hydrogen sulfide. Moreover, SC inhibited cerulein-induced nuclear factor κB activation in both pancreas and lung. Also, SC treatment further enhances the beneficial effect by reducing cerulein-induced mast cell activation as shown by reduced monocyte chemoattractant protein 1, interleukin 33, and preprotachykinin A expression (encodes neuropeptide substance P) in the pancreas and lungs., Conclusions: The present findings show for the first time that in AP SC may exhibit an anti-inflammatory effect by down-regulating substance P and hydrogen sulfide signaling via nuclear factor κB pathway.

HIV-1 protease plays a crucial role in viral replication and maturation, which makes it one of the most attractive targets for anti-retroviral therapy. The majority of HIV infections in developing countries are due to non-B subtype. Subtype AE is spreading rapidly and infecting huge population worldwide. The mutations in the active site of subtype AE directly impair the interactions with the inhibitor. The non-active site mutations influence the binding of the inhibitor indirectly and their resistance mechanism is not well understood. It is important to design new effective inhibitors that combat drug resistance in subtype AE protease. In this work, we examined the effect of non active site mutations L10F, L10F/N88S and L90M with nelfinavir using molecular dynamics simulation and binding free energy calculations. The simulations suggested that the L10F and L10F/N88S mutants decrease the binding affinity of nelfinavir, whereas the L90M mutant increases the binding affinity. The formation of hydrogen bonds between nelfinavir and Asp30 is crucial for effective binding. The benzamide moiety of nelfinavir shows large positional deviation in L10F and L10F/N88S complexes and the L10F/N88S mutation changes the hydrogen bond between the side chain atoms of 30th residue and the 88th residue. Consequently the hydrogen bond interaction between Asp30 and nelfinavir are destroyed leading to drug resistance. Our present study shed light on the resistance mechanism of the strongly linked mutation L10F/N88S observed experimentally in AE subtype., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Objectives: Morinda citrifolia (Noni), an important traditional medicinal plant still used in patients with bone fractures or dislocation to promote connective tissue repair and to reduce inflammation. However, the effects of Noni on bone metabolism and whether it influences the osteogenic differentiation is yet to be clarified. In this study, we investigated the effect of Morinda citrifolia (Noni) juice on the proliferation rate of rat bone marrow derived mesenchymal stem cells (BMSC) and the osteoblastic differentiation as shown by alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) mRNA expression in vitro ., Methods and Results: Treatment with 200 μg/ml Noni juice enhanced the proliferation rate of the BMSC and also upregulated the osteogenic differentiation marker genes ALP and OCN, and Runx2 measured by RTPCR. Consistent with these results collagen scaffolds implanted in vivo , which were loaded with BMSC pre-exposed to Noni, showed increased bone density measured by computed tomography and histological analysis revealed neo-angiogenesis for bone formation., Conclusions: These results suggest that Noni stimulates osteoblastogenesis and can be used as adjuvant natural medicine for bone diseases such as osteoporosis.

Objective: The main objective of this preliminary study is to confirm the synergistic anticarcinogenic potential of Vitex trifolia and Triticum aestivum ethanolic extracts., Materials and Methods: Rat hepatic microsomal degranulation is a short - term technique that has been used for the detection of potential chemical carcinogens, in vitro. The present study has been carried out to study the inhibition of ribosome- membrane disruption against 3, 8-Diamino-5-ethyl-6-pheylphenanthridinium bromide (EB), as the degranulating agent, by measuring the RNA/protein ratios of microsomal membranes in the presence or absence of V.trifolia and T. aestivum extracts. These two extracts were further evaluated for cytotoxic effect in HCT 116 and A549 cell lines., Results: V. trifolia and T. aestivum protects hepatic microsomes against the degranulatory attack by the carcinogen EB showed a significant reduction in the proliferation of the HCT 116 and A549 cancer cell lines., Conclusion: The ethanolic extracts of the plants, V. trifolia and T. aestivum individually possessed anti-degranulatory potential. Importantly they act synergistically, possess appreciable anticarcinogenic properties, based on their ability to inhibit EB induced liver microsomal degranulation. Further these extracts inhibit cell proliferation of cancer cell lines.

Substance P (SP) is involved in the pathophysiology of acute pancreatitis (AP) via binding to its high-affinity receptor, neurokinin-1-receptor (NK1R). An up-regulation of SP and NK1R expression was observed in experimental AP and in caerulein-stimulated pancreatic acinar cells. However, the mechanisms that lead to this up-regulation are not fully understood. In this study, we showed the role of protein kinase C (PKC) in caerulein-induced SP and NK1R production in isolated mouse pancreatic acinar cells. Caerulein (10(-7) M) stimulation rapidly activated the conventional PKC-α and novel PKC-δ as observed by the phosphorylation of these molecules. Pre-treatment of pancreatic acinar cells with Gö6976 (1-10 nM) and rottlerin (1-10 μM) inhibited PKC-α and PKC-δ phosphorylation, respectively, but not the other way round. At these concentrations used, PKC-α and PKC-δ inhibition reversed the caerulein-induced up-regulation of SP and NK1R, indicating an important role of PKCs in the modulation of SP and NK1R expression. Further experiments looking into signalling mechanisms showed that treatment of pancreatic acinar cells with both Gö6976 and rottlerin inhibited the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Inhibition of PKC-α or PKC-δ also affected caerulein-induced transcription factor activation, as represented by nuclear factor-κB and AP-1 DNA-binding activity. The findings in this study suggested that PKC is upstream of the mitogen-activated protein kinases and transcription factors, which then lead to the up-regulation of SP/NK1R expression in caerulein-treated mouse pancreatic acinar cells., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Objective: This study aimed to determine the effect of hydrogen sulfide (H2S) on Toll-like receptor 4 (TLR4)-mediated innate immune signaling in acute pancreatitis (AP) via substance P., Methods: Male Swiss mice were treated with hourly intraperitoneal injections of cerulein (50 μg/kg) for 10 hours. dl-propargylglycine ([PAG] 100 mg/kg, intraperitoneally), an inhibitor of H2S formation, was administered 1 hour after the induction of AP. Pancreatic acinar cells from male preprotachykinin-A gene-knockout mice (PPTA) and their wild-type counterparts were incubated with or without cerulein (10 M for 60 minutes). To better understand the effect of H2S in inflammation, acinar cells were stimulated with cerulein after addition of H2S donor, sodium hydrosulfide. In addition, cerulein-treated pancreatic acinar cells were pretreated with PAG (30 μM) for 1 hour., Results: The H2S inhibitor PAG eliminated TLR4, interleukin 1 receptor-associated kinase 4, tumor necrosis factor receptor-associated factor 6, and nuclear factor-κB (NF-κB) levels in in vitro and in vivo models of cerulein-induced AP. PPTA gene deletion reduced TLR4, myeloid differentiation factor 88, interleukin 1 receptor-associated kinase 4, tumor necrosis factor receptor-associated factor 6, and NF-κB in cerulein-treated pancreatic acinar cells, whereas administration of sodium hydrosulfide resulted in a further rise in TLR4 and NF-κB levels in cerulein-treated pancreatic acinar cells., Conclusion: The present findings show for the first time that in AP, H2S may up-regulate the TLR4 pathway and NF-κB via substance P.

We have earlier shown that mouse pancreatic acinar cells produce hydrogen sulfide (H(2)S), which plays a key role in the pathogenesis of acute pancreatitis (AP). H(2)S-dependent induction of inflammation is mediated by the activation of transcription factor NF-kappaB. We now provide evidence that activation of Src family kinases (SFKs) is crucial in signaling H(2)S-induced intracellular adhesion molecule (ICAM)-1 expression via NF-kappaB. Stimulation of acini with H(2)S resulted in a time-dependent activation of SFKs. In order to better understand this effect of H(2)S, acinar cells were stimulated with caerulein after addition of H(2)S donor, NaHS. Inhibition of SFKs impaired H(2)S-induced NF-kappaB activity and ICAM-1 expression in caerulein treated acinar cells. We also observed that H(2)S-induced up-regulation of ICAM-1 enhanced the adhesion of neutrophils onto acinar cells. Analysis of NF-kappaB pathway revealed that the effect of SFKs inhibition correlated with IkappaBalpha degradation and NF-kappaB DNA binding function. Interestingly, H(2)S-induced association of SFKs with translocation of NF-kappaB, and inhibition of SFKs prevented this response, indicating that this interaction may depend on activation of SFKs. These data suggest that H(2)S, by activating the phosphorylation of SFKs, may promote the transcriptional activity of NF-kappaB and eventually lead to an upregulation of ICAM-1 expression., (Copyright 2010 Elsevier Inc. All rights reserved.)

Deletion of mouse preprotachykinin-A (PPTA), which encodes mainly for neuropeptide substance P, has been shown to protect against lung injury and mortality in sepsis. This study explored microarray-based differential gene expression profiles in mouse lung tissue 8 h after inducing microbial sepsis and the effect of PPTA gene deletion. A range of genes differentially expressed (more than two-fold) in microarray analysis was assessed, comparing wild-type and PPTA-knockout septic mice with their respective sham controls, and the data were further validated. Genetic deletion of substance P resulted in a significantly different expression profile of genes involved in inflammation and immunomodulation after the induction of sepsis, compared with wild-type mice. Interestingly, apart from the various proinflammatory mediators, the antiinflammatory cytokine interleukin-1 receptor antagonist gene (IL1RN) was also elevated much more in PPTA(-/-) septic mice. In addition, semiquantitative RT-PCR analysis supported the microarray data. The microarray data imply that the elevated levels of inflammatory gene expression in the early stages of sepsis in PPTA-knockout mice are possibly aimed to resolve the infection without excessive immunosuppression. As scientists are divided over the effects of pro- and antiinflammatory mediators in sepsis, it seems prudent to define the status depending on a complete genome profile. This is the first report exploring pulmonary gene expression profiles using microarray analysis in PPTA-knockout mice subjected to cecal ligation and puncture-induced sepsis and providing additional biological insight into the protection received against lung injury and mortality.

The neuropeptide substance P (SP) has emerged to be an important proinflammatory mediator in acute pancreatitis (AP). The presence of substance P and its receptor, neurokinin-1 receptor (NK1R) has been shown in the pancreas and the pancreatic acinar cells. In this study, we investigated the unexplored mechanisms that mediate SP and NK1R expression using an in vitro AP model. Pancreatic acinar cells were obtained from pancreas of male Swiss mice. Isolated cells were treated with caerulein to mimic secretagogue pancreatitis. A concentration-dependent study that subjected the cells to 60 min of stimulation by caerulein showed that SP and the transcript from its gene preprotachykinin-A (PPT-A), and NK1R were up-regulated at a supraphysiological concentration of 10(-7) M. A concentration-dependent study on intracellular kinases, extracellular signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK) and also transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) showed that they were activated when the caerulein concentration was 10(-7) M. Inhibition of JNK reversed the up-regulation of PPT-A, SP, and NK1R. However, inhibition of ERK1/2 reversed the up-regulation of NK1R but not of PPT-A and SP. Furthermore, we found that specific ERK1/2 and JNK inhibitors reduce NF-kappaB and AP-1 activity. Taken together, our results suggest that supraphysiological concentrations of caerulein up-regulate the expression of SP and NK1R in pancreatic acinar cells, and the signaling molecules that are involved in this up-regulation include ERK1/2, JNK, NF-kappaB, and AP-1.

We have shown earlier that mouse pancreatic acinar cells produce hydrogen sulfide (H(2)S) and play a role in the pathogenesis of acute pancreatitis. It is noteworthy that recent evidence indicates that H(2)S has anti-inflammatory effects. To date, the mechanism by which H(2)S directly reduces inflammation has not been elucidated. In the present study, we hypothesized that H(2)S inhibits the production of proinflammatory cytokines by activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Pancreatic acinar cells were treated with the H(2)S donor, sodium hydrogen sulfide (NaHS) (5, 10, and 30 microM). To better understand the effect of H(2)S in inflammation, pancreatic acinar cells were stimulated with caerulein after the addition of NaHS (5, 10, and 30 microM). We observed that H(2)S at the 5 microM concentration down-regulates the activation of NF-kappaB and degradation of IkappaB alpha. However, H(2)S (5 microM) activates PI3K as reflected by AKT phosphorylation. We found that H(2)S-mediated activation of PI3K in caerulein-treated acinar cells correlated with the down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas phosphorylation of p38 and c-Jun NH(2)-terminal kinase and mitogen-activated protein kinases was unchanged. The PI3K inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] abolished the H(2)S-mediated activation of AKT and increases tumor necrosis factor alpha and interleukin 1beta levels in caerulein-treated acinar cells. These findings indicate that the phosphatidylinositol 3-kinase plays a negative role in NaHS-treated pancreatic acinar cells and suggest a role for H(2)S in the PI3K/AKT pathway in acute pancreatitis.

Neuropeptide modulation of immune cell function is an important mechanism of neuro-immune intersystem crosstalk. Substance P (SP) is one such key neuropeptide involved. In this study, we investigated the yet unexplored cellular mechanisms of SP-mediated inflammatory responses in macrophages using a mouse macrophage-like cell line RAW 264.7 and isolated peritoneal macrophages. We found that the conventional PKCalpha and novel PKCdelta and epsilon were selectively activated by SP via its primary neurokinin-1 receptor (NK-1R) on the cells. Activation of these PKC isoforms mediated the activation of downstream extracellular signal-regulated kinase-1/2 (ERK1/2) and the transcription factor NF-kappaB, which drove the transcription of inducible chemokines in macrophages. Additionally, phosphoinositide 3-kinase (PI3K)-Akt was also activated by SP/NK-1R in macrophages. Inhibition of PI3K-Akt pathway attenuated ERK1/2 and NF-kappaB activation, suggesting it also played a part in SP-induced cellular inflammatory response. Kinetic analysis indicated that PKC isoforms induced early ERK1/2 activation, while PI3K-Akt contributed to the pathway at later time points. It was further demonstrated that PKC and PI3K-Akt were activated independent of each other. Collectively, our results suggest that SP/NK-1R activates two convergent proinflammatory signaling pathways, PKCs and PI3K-Akt, resulting in ERK1/2 and NF-kappaB activation and chemokine production in mouse macrophages.

Neurokinin A (NKA) belongs to the tachykinin neuropeptide family. Its biological functions are primarily mediated by the neurokinin (NK)-2 receptor. NKA has been implicated in several inflammatory conditions. However, there are limited data about the mechanism of its pathogenetic action. Here, we investigated proinflammatory effects of NKA on peripheral immune cells using the mouse macrophage/monocyte cell line RAW 264.7 and primary peritoneal macrophages. The signaling mechanistic pathways involved were also studied. In mouse macrophages with no detectable NK-2 receptors, NKA induces the upregulation of NK-1 but not NK-2 receptor expression. Furthermore, NKA engages this NK-1 receptor, resulting in inflammatory-like responses involving activation of the transcription factor nuclear factor (NF)-kappaB and induction of NF-kappaB-responsive proinflammatory chemokine expression. NKA activates NF-kappaB as evidenced by induced phosphorylation (leading to degradation) of its inhibitory protein IkappaBalpha, increased cellular levels of the transactivation-active phospho(Ser(276))-p65 and its nuclear translocation, as well as enhanced DNA-binding activity of NF-kappaB. These responses are specifically inhibited by selective NK-1 receptor antagonists but not NK-2 receptor antagonists, thereby excluding the role of NK-2 receptor. Further investigation on the upstream signaling mechanisms suggests that two NF-kappaB-activating pathways (extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase/protein kinase B) are activated by NKA. Specific inhibitors of the two pathways block NF-kappaB-dependent chemokine expression. The inhibitory effects are mediated through regulation of nuclear translocation, DNA-binding activity, and/or transactivation activity of NF-kappaB. Together, we provide novel evidence that NKA engages NK-1 receptors on mouse macrophages to elicit NF-kappaB-dependent cellular responses. The findings reveal cellular mechanisms that may underlie NKA-mediated inflammatory and immunological conditions.

The neuropeptide substance P (SP), as a major mediator of neuroimmunomodulatory activity, modulates diverse functions of immune cells, including macrophages. In the current study, we focused on the yet uncertain role of SP in enhancing the inducible/inflammatory chemokine response of macrophages and the signaling mechanism involved. We studied the effect on the murine monocyte/macrophage cell line RAW 264.7 as well as isolated primary macrophages. Our data show that SP, at nanomolar concentrations, elicited selective chemokine production from murine macrophages. Among the chemokines examined, macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 are two major chemokines that were synthesized by macrophages in response to SP. Furthermore, SP treatment strongly induced the classic pathway of IkappaB-dependent NF-kappaB activation and enhanced DNA binding as well as transactivation activity of the transcription factor. SP-evoked transcriptional induction of chemokines was specific, since it was blocked by treatment with selective neurokinin-1 receptor antagonists. Moreover, SP stimulation of macrophages activated the ERK1/2 and p38 MAPK but not JNKs. Blockade of these two MAPK pathways with specific inhibitors abolished SP-elicited nuclear translocation of phosphorylated NF-kappaB p65 and NF-kappaB-driven chemokine production, suggesting that the two MAPKs lie in the signaling pathways leading to the chemokine response. Collectively, our data demonstrate that SP enhances selective inflammatory chemokine production by murine macrophages via ERK/p38 MAPK-mediated NF-kappaB activation.

Objectives: The present study investigated whether chemokines are involved in hydrogen sulfide (H2S)-associated pathogenesis of acute pancreatitis and associated lung injury., Methods: We have examined the effect of DL-propargylglycine, a cystathionine gamma-lyase inhibitor, on the synthesis of CC chemokine monocyte chemotactic protein 1, Regulated upon Activation, Normal T-cell Expressed, and Secreted, and macrophage inflammatory protein-1alpha (MIP-1alpha), and CXC chemokine MIP-2 in an in vitro and in vivo model of cerulein-induced acute pancreatitis and associated lung injury. In addition, the pancreatic acinar cells were treated with H2S donor drug, sodium hydrosulfide. The expression of these chemokines in the pancreatic acini, pancreas, and lungs was determined by quantitative real-time reverse transcriptase polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry., Results: After treatment with DL-propargylglycine, reverse transcriptase polymerase chain reaction, and enzyme-linked immunosorbent assay demonstrated down-regulation of cerulein-induced increase in monocyte chemotactic protein 1, MIP-1alpha, and MIP-2 expression but had no apparent effect on Regulated upon Activation, Normal T-cell Expressed, and Secreted expression., Conclusions: These results suggest that the proinflammatory effect of H2S may be mediated by chemokines.

Hydrogen sulphide (H(2)S), a novel gasotransmitter, has been recognized to play an important role in inflammation. Cystathionine-gamma-lyase (CSE) is a major H(2)S synthesizing enzyme in the cardiovascular system and DL-propargylglycine (PAG) is an irreversible inhibitor of CSE. Substance P (SP), a product of preprotachykinin-A (PPT-A) gene, is a well-known pro-inflammatory mediator which acts principally through the neurokinin-1 receptor (NK-1R). We have shown an association between H(2)S and SP in pulmonary inflammation as well as a pro-inflammatory role of H(2)S and SP in acute pancreatitis. The present study was aimed to investigate the interplay between pro-inflammatory effects of H(2)S and SP in a murine model of caerulein-induced acute pancreatitis. Acute pancreatitis was induced in mice by 10 hourly intraperitoneal injections of caerulein (50 (g/kg). PAG (100 mg/kg, i.p.) was administered either 1 hr before (prophylactic) or 1 hr after (therapeutic) the first caerulein injection. PAG, given prophylactically as well as therapeutically, significantly reduced plasma H(2)S levels and pancreatic H(2)S synthesizing activities as well as SP concentrations in plasma, pancreas and lung compared with caerulein-induced acute pancreatitis. Furthermore, prophylactic as well as therapeutic administration of PAG significantly reduced PPT-A mRNA expression and NK-1R mRNA expression in both pancreas and lung when compared with caerulein-induced acute pancreatitis. These results suggest that the pro-inflammatory effects of H(2)S may be mediated by SP-NK-1R pathway in acute pancreatitis.

Hydrogen sulphide (H(2)S) is synthesized from L-cysteine via the action of cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase (CBS). We have earlier shown that H(2)S acts as a mediator of inflammation. However the mechanism remains unclear. In this study, we investigated the presence of H(2)S and the expression of H(2)S synthesizing enzymes, CSE and CBS, in isolated mouse pancreatic acini. Pancreatic acinar cells from mice were incubated with or without caerulein (10(-7) M for 30 and 60 min). Caerulein increased the levels of H(2)S and CSE mRNA expression while CBS mRNA expression was decreased. In addition, cells pre-treated with DL-propargylglycine (PAG, 3 mM), a CSE inhibitor, reduced the formation of H(2)S in caerulein treated cells, suggesting that CSE may be the main enzyme involved in H(2)S formation in mouse acinar cells. Furthermore, substance P (SP) concentration in the acini and expression of SP gene (preprotachykinin-A, PPT-A) and neurokinin-1 receptor (NK-1R), the primary receptor for SP, are increased in secretagogue caerulein-treated acinar cells. Inhibition of endogenous production of H(2)S by PAG significantly suppressed SP concentration, PPT-A expression and NK1-R expression in the acini. To determine whether H(2)S itself provoked inflammation in acinar cells, the cells were treated with H(2)S donor drug, sodium hydrosulphide (NaHS), (10, 50 and 100 muM), that resulted in a significant increase in SP concentration and expression of PPT-A and NK1-R in acinar cells. These results suggest that the pro-inflammatory effect of H(2)S may be mediated by SP-NK-1R related pathway in mouse pancreatic acinar cells.

Butylated hydroxy toluene (BHT), 800 mg/kg body weight, dissolved in corn oil and administered (ip) in a single injection to male rats, damaged the lung as indicated by an increase in lavage ACE, protein and LDH and caused a significant increase in phospholipid, particularly, phosphatidyl choline (PC) in lung lavage and extracellular surfactant. The plasma lecithin cholesterol acyl transferase (LCAT) activity was inhibited leading to an increase in serum phospholipids and phosphatidyl choline. The results indicate that BHT-induced lung phospholipidosis may be attributed to an increase in surfactant phospholipids and/or due to the leakage of plasma phospholipids through damaged capillary membrane.