Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 20, Issue 2, 2021

Background: Body defenses and metabolic processes probably co-evolved in such a way that rapid, energy-intensive acute inflammatory repair is functionally integrated with energy allocation in a starvation/ infection / injury-prone primitive environment. Disruptive metabolic surplus, aggravated by sedentary lifestyle induces chronic under-activation of AMPK, the master regulator of intracellular energy homeostasis. Sudden increase in chronic, dysregulated ‘sterile’ inflammatory disorders probably results from a shift towards calorie rich, sanitized, cushioned, injury/ infection free environment, repositioning inflammatory repair pathways towards chronic, non-microbial, ‘sterile’, ‘low grade’, and ‘parainflammation’. AMPK, (at the helm of energy provisioning) supervises the metabolic regulation of inflammasome activation, a common denominator in lifestyle disorders. Discussion: In this review, we discuss various pathways linking AMPK under-activation and inflammasome activation. AMPK under-activation, the possible norm in energy-rich sedentary lifestyle, could be the central agency that stimulates inflammasome activation by multiple pathways such as 1: decreasing autophagy, and accumulation of intracellular DAMPs, (particulate crystalline molecules, advanced glycation end-products, oxidized lipids, etc.) 2: stimulating a glycolytic shift (pro-inflammatory) in metabolism, 3: promoting NF-kB activation and decreasing Nrf2 activation, 4: increasing reactive oxygen species (ROS) formation, Unfolded Protein Response (UPR) and Endoplasmic Reticulum (ER) stress. Conclusion: The ‘inverse energy crisis’ associated with calorie-rich, sedentary lifestyle, advocates dietary and pharmacological interventions for treating chronic metabolic disorders by overcoming / reversing AMPK under-activation.

Novel Corona Virus 2019 (COVID-19) is a new virus spread rapidly all over the world. It has specific respiratory or gastrointestinal tract symptoms. Its reported complications include respiratory distress, systemic inflammatory response syndrome, and septic shock. Due to heavy cytokines released by the virus; corticosteroids (40-120 mg / day) were given to severe cases to reduce pneumonia. It’s a difficult task to control the spread of SARS-CoV-2, and to invent proper vaccines and treatments. In this review, the existing understanding of fatal, pandemic human coronavirus SARS-Cov2 (COVID-19), with special reference to its diagnosis, origin, transmission, and different approaches to develop its therapeutics, will be discussed.

Inflammation is an acute adaptive response to injury. However, if the initial inflammatory response to an injury is not completely healed, it becomes chronic low-level inflammation that is strongly associated with many chronic disease states, including metabolic (obesity and diabetes), cardiovascular, auto-immune, and neurogenerative disorders as well as cancer. The healing process is far more complex than the initiation of inflammation. Within that complexity of healing is a sequence of events that are under profound dietary control and can be defined by specific blood markers. Those molecular events of the healing process that are under significant dietary control are termed as the Resolution Response. The purpose of this review is to describe the molecular components of the Resolution Response and how different dietary factors can either optimize or inhibit their actions. In particular, those dietary components that optimize the Resolution Response include a calorie-restricted, protein-adequate, moderate-carbohydrate, low-fat diet referred to as the Zone diet, omega-3 fatty acids, and polyphenols. The appropriate combination of these dietary interventions constitutes the foundation of Pro-Resolution Nutrition. The effect of these dietary components the actions of NF-ΚB, AMPK, eicosanoids, and resolvins are described in this review, as well as ranges of appropriate blood markers that indicate success in optimizing the Resolution Response by dietary interventions.

Introduction: Newborn screening (NBS) by quantifying T cell receptor excision circles (TRECs) and Kappa receptor excision circles in neonatal dried blood spots (DBS) enables early diagnosis of different types of primary immune deficiencies. Global newborn screening for PID, using an assay to detect T-cell receptor excision circles (TREC) in dried blood spots (DBS), is now being performed in all states in the United States. In this review, we discuss the development and outcomes of TREC, TREC/KREC combines screening, and continued challenges to implementation. Objective: To review the diagnostic performance of published articles for TREC and TREC/ KREC based NBS for PID and its different types. Methods: Different research resources were used to get an approach for the published data of TREС and KREC based NBS for PID like PubMed, Scopus, Google Scholar, Research gate EMBASE. We extracted TREC and KREC screening Publisher with years of publication, content and cut-off values, and a number of retests, repeat DBS, and referrals from the different published pilot, pilot cohort, Case series, and cohort studies. Results: We included the results of TREC, combined TREC/KREC system based NBS screening from different research articles, and divided these results between the Pilot studies, case series, and cohort. For each of these studies, different parameter data are excluded from different articles. Thirteen studies were included, re-confirming 89 known SCID cases in case series and reporting 53 new SCID cases in 3.15 million newborns. Individual TREC contents in all SCID patients were <25 TRECs/μl (except in those evaluated with the New York State assay). Conclusion: TREC and KREC sensitivity for typical SCID and other types of PID was 100 %. It shows its importance and anticipating the significance of implementation in different undeveloped and developed countries in the NBS program in upcoming years. Data adapting the screening algorithm for pre-term/ill infants reduce the amount of false-positive test results.

Background: Burns induce a boost in local and systemic complement levels as well as immune cell infiltration in the burn wound, which may negatively affect wound healing. Objective: In this study, the effects of long-term treatment with complement inhibitor C1 esterase inhibitor (C1inh) on post-burn inflammation and wound healing parameters were analyzed in time up to 60 days post-burn. Methods: Burned pigs were treated either with or without C1inh up to 15 days post-burn. Burn wound biopsies and blood were collected at different time points up to 60 days post-burn. Thereafter, complement in blood as well as complement and immune cells in the wound, capillary leakage, necrosis, reepithelialization and wound contraction were quantified. Results: No significant differences in complement C3 blood levels were observed at any time point between C1inh-treated and control pigs. In the wound, complement C4 levels were significantly lower in the C1inh group than in controls at day 3-6 and 21-30 post-burn. Similarly, C3 levels, neutrophil and macrophage infiltration in the wound were, although not statistically significant, reduced in C1inh-treated pigs at day 9-14 post-burn. No differences in lymphocyte infiltration in the wound were found between C1inh and control pigs. C1inh-treated pigs also showed reduced capillary leakage. Despite these effects, no significant differences in the long-term wound healing parameters necrosis, reepithelialization and wound contraction were observed between C1inh and control pigs. Conclusion: In pigs, 15 days of C1inh treatment after burn, leads to a reduction in local inflammation and capillary leakage in the burn wound without affecting long-term wound healing parameters.

Background and Aims: Following a fat-rich diet, alterations in gut microbiota contribute to enhanced gut permeability, metabolic endotoxemia, and low grade inflammation–associated metabolic disorders. To better understand whether commensal bifidobacteria influence the expression of key metaflammation-related biomarkers (chemerin, MCP-1, PEDF) and modulate the pro-inflammatory bacteria- and lipid–coupled intracellular signaling pathways, we aimed at i) investigating the influence of the establishment of microbial signaling molecules-based cell-cell contacts on the involved intercellular communication between enterocytes, immune cells, and adipocytes, and ii) assessing their inflammatory mediators’ expression profiles within an inflamed adipose tissue model. Material and Methods: Bifidobacterium animalis R101-8 and Escherichia coli TG1, respectively, were added to the apical side of a triple co-culture model consisting of intestinal epithelial HT-29/B6 cell line, human monocyte-derived macrophage cells, and adipose-derived stem cell line in the absence or presence of LPS or palmitic acid. mRNA expression levels of key lipid metabolism genes HILPDA, MCP-1/CCL2, RARRES2, SCD, SFRP2 and TLR4 were determined using TaqMan qRT-PCR. Protein expression levels of cytokines (IL-1β, IL-6, and TNF-α), key metaflammation-related biomarkers including adipokines (chemerin and PEDF), chemokine (MCP- 1) as well as cellular triglycerides were assessed by cell-based ELISA, while those of p-ERK, p-JNK, p-p38, NF-ΚB, p-IΚBα, pc-Fos, pc-Jun, and TLR4 were assessed by Western blotting. Results: B. animalis R101-8 inhibited LPS- and palmitic acid-induced protein expression of inflammatory cytokines IL-1β, IL-6, TNF-α concomitant with decreases in chemerin, MCP-1, PEDF, and cellular triglycerides, and blocked NF-kB and AP-1 activation pathway through inhibition of p- IΚBα, pc-Jun, and pc-Fos phosphorylation. B. animalis R101-8 downregulated mRNA and protein levels of HILPDA, MCP-1/CCL2, RARRES2, SCD and SFRP2 and TLR4 following exposure to LPS and palmitic acid. Conclusion: B. animalis R101-8 improves biomarkers of metaflammation through at least two molecular/signaling mechanisms triggered by pro-inflammatory bacteria/lipids. First, B. animalis R101-8 modulates the coupled intracellular signaling pathways via metabolizing saturated fatty acids and reducing available bioactive palmitic acid. Second, it inhibits NF-kB’s and AP-1’s transcriptional activities, resulting in the reduction of pro-inflammatory markers. Thus, the molecular basis may be formed by which commensal bifidobacteria improve intrinsic cellular tolerance against excess pro-inflammatory lipids and participate in homeostatic regulation of metabolic processes in vivo.

Background: Due to the presence of both five-membered heterocyclics like pyrrole and thiophene in one molecule considerable attention was made for their enormous pharmacological activities out of which include anti-inflammatory and anti-ulcer activities. Objective: Chalcones with toluenesulfonylmethyl isocyanide (TosMIC) undergo synthesis to form some new aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives. Molecular docking of synthesized compounds with protein receptors of anti-inflammatory COX-1(3N8Y), COX-2 (1PXX) along with anti-ulcer H+/K+ATPase enzyme (2XZB) followed with drug-likeness, and in silico ADMET properties. Materials and Methods: The multicomponent reaction was carried out by the intermediate formation of α, β-unsaturated ketone from carbonyl compounds which on sequential addition undergoes [3+2] cycloaddition reaction in same medium affords aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives by addition of TosMIC in basic medium had resulted in series of compounds PY1 to PY12. All the new synthesized compounds were screened for their in-vitro anti-inflammatory activity by bovine serum albumin method followe with COX assay, and in-vivo by using carrageenan-induced rat paw edema method of the selected compounds PY1, PY5 and PY12 which is also screened for anti-ulcer activity by pylorus ligation method, respectively. Molecular docking was performed using autodock tools, drug-likeness by OSIRIS property explorer and admetSAR properties. Results and Discussion: From the synthesized compounds of aryl (4-aryl-1H-pyrrol-3-yl) (thiophen- 2-yl) methanone derivatives PY5 showed decent in-vitro and in-vivo anti-inflammatory along selectivity index of 6.2 for COX-1 with IC50(μM) value of 9.54 over diclofenac with 8.74 and PY1 showed decent in-vivo anti-ulcer activities along with drug-likeness and in silico ADMET predictions revealed that all the synthesized compounds have minimal toxic effects with good absorption as well as solubility characteristics. The selected compounds may serve as potential lead compounds for developing new anti-inflammatory and anti-ulcer drugs. Conclusion: From the newly synthesized molecules PY5 was found to be effective for anti-inflammatory and PY1 was found to be effective for anti-ulcer activities further derivitization and designed of modification to achieve more compounds with potent anti-inflammatory and anti-ulcer activities.

Background: Spontaneous bacterial peritonitis is a common bacterial infection of ascitic fluid, mainly in ascites due to liver cirrhosis. Mannose-binding lectin (MBL) can activate phagocytosis and the complement system. Spontaneous bacterial peritonitis was detected to be higher in MBL deficiency. This study aimed to assess ascitic fluid MBL in liver cirrhosis and spontaneous bacterial peritonitis. Methods: Ninety patients with cirrhotic ascites were included. Forty five of them had SBP. Child- Pugh score, Model for End Stage Liver Disease (MELD) and its update (uMELD) scores were used to assess the severity of liver cirrhosis. Ascitic fluid samples were obtained for differentiation of leucocytic count, estimation of albumin, protein, glucose, and serum-ascitic albumin gradient. Ascitic fluid levels of MBL were measured for all patients. SBP was documented if polymorphonuclear leucocytic count ≥250/mm in ascitic fluid. Results: Ascitic fluid MBL level was significantly lower in patients with SBP. MBL had a significant negative correlation with ascitic total leukocytic count (TLC), also with serum creatinine, bilirubin, PT, INR and MELD score among SBP patients. However, it had a significant positive correlation with ascitic protein and with platelets. According to multivariate analysis, fever, TLC, platelets, creatinine, MBL, glucose and polymorphs were independent predictors for SBP development. Conclusion: Ascitic fluid MBL could be a good predictive and prognostic marker in patients with cirrhosis and spontaneous bacterial peritonitis.

Background: Macrophages are the main players involved in inflammation. Intercellular adhesion molecule-1 (ICAM-1) facilitates macrophage polarization prior to extravasation into inflamed tissue. Piperine, a natural product derived from black pepper, possesses useful biological and pharmacological activities. In the current study, the possible anti-inflammatory effect of piperine on the expression of ICAM-1 on J774.1 murine macrophage cell line was investigated. Methods: Lipopolysaccharide (LPS)-stimulated J774.1 cells were cultured in the presence of different concentrations of piperine to examine the changes in ICAM-1 expression by real-time PCR and flow cytometry. Results: We found that piperine decreased ICAM-1 gene expression level from 2.4 ± 0.25 RFC (relative fold change) in LPS-only treated cells to 0.85 ± 0.525 RFC at 1μg/ml (p<0.05), 0.43 ± 0.27 RFC at 10μg/ml (p<0.01), and 0.26 ± 0.25 RFC at 20μg/ml (p<0.01). In flow cytometry, piperine at all concentrations significantly decreased ICAM-1 surface expressions (P<0.05). The geometric mean fluorescence intensity (g-MFI) in LPS-only treated cells (792 ± 57.3) decreased to 482±70 g-MFI at 20 μg/ml piperine. Conclusion: According to the results of this study, by decreasing the expression of ICAM-1, piperine has been suggested to reduce inflammation and have the potential to provide therapeutic benefits for immune-mediated diseases.

Objective: This study investigated the antinociceptive and anti-inflammatory activities of the aqueous extract of Ficus capensis (AEFC) by bio-guided fractionation. Methods: The anti-nociceptive and anti-inflammatory effects of AEFC (250, 500, 1000 mg/kg, i.p) were assessed using acetic acid-induced writhing, hot plate, tail-flick, formalin tests, and carrageenan- induced paw edema, respectively. The AEFC was fractionated base on polarity difference into butanol, ethyl acetate, and n-hexane fractions. The fractions (500 mg/kg) obtained were subjected to the same experimental procedures mentioned above. The EAF, which exerted the most productive activities, was further subjected to fractionation procedures that yielded six fractions (labeled CF1-CF6). These fractions (200 mg/kg) were tested for potential antinociceptive and anti-inflammatory activities. Notable antagonists (Naloxone and atropine) of the nociceptive pathway were used to evaluate the mechanism of the antinociceptive action of F. capensis. Results and Discussion: The AEFC, BF, EAF, and CF4 caused a significant (p<0.05) reduction in the number of abdominal writhes, an increase in reaction time against the hot plate, tail-flick tests, and a significant (p<0.05) inhibition in both phases of formalin test. The AEFC, BF, EAF, CF4, and CF6 caused a significant (p<0.05) inhibition of paw edema development due to carrageenan. Atropine significantly reversed the antinociceptive effect of CF4 in both phases of the formalin test. The results obtained revealed that CF4 produced central and peripheral antinociceptive effects, while CF6 is peripherally mediated. Conclusion: The results support the traditional uses of F. capensis in the treatment of various diseases associated with pain and inflammation. The column fraction CF4 exhibited muscarinic receptor- mediated antinociceptive activity.

Background: Pneumonia is an acute or chronic inflammatory disorder of the lungs, affecting the mucosal areas of the lung. It can be caused by bacteria, viruses or fungi. In some cases, it may be caused by physical or chemical irritants. Kolaviron, a natural bioflavonoid extract from Garcinia kola seeds, has been shown to possess anti-inflammatory properties in Flu-like conditions which are associated with cough. There has been a paucity of information on the likelihood of the effectiveness of kolaviron against pneumonia infections. Objective: To evaluate the antibacterial and anti-inflammatory effects of kolaviron on albino Wistar rats induced with pneumonia using Klebsiella pneumonia. Materials and Methods: Powdered Garcinia kola seeds were extracted with n-hexane and 100% methanol as solvents by using Soxhlet extractor. A standard method was used to obtain kolaviron from the seed extracts. A total of 24 albino Wistar rats were randomly divided into six groups A to F, each comprising four rats. The rats were allowed to acclimatize for 1 hour in very cold environments using ice packs. A standardized 1.0 x10 ^-5 mg/ml culture suspension was intranasally inoculated to the rats for 10 days to induce pneumonia-like symptoms. Thereafter, the kolaviron was administered to the rats such that a 500mg/kg kolaviron extract was given once daily to groups A (male rats) and B (female rats). Groups C (male rats) and D (female rats) received 250mg/kg of kolaviron extract once daily, while group E rats were given 0.5 ml of dimethyl sulfoxide (DMSO) once daily, which served as the negative control. The rats in Group F received 2.86 mg/kg of ofloxacin once daily and served as the positive control. All the treatments were done for a period of 5 days. Then 10 days after the treatments, the animals were sacrificed and the lungs were harvested for hydrostatic lung test and histopathological examination. An overnight broth culture of Klebsiella pneumonia was streaked in sterile molten nutrient agar maintained at 37°C for 24hrs. Later, a stock of 500mg/ml of kolaviron was prepared in DMSO. Two-fold dilutions were performed to obtain the following concentrations of 100%, 50%, 25%, 12.5%, 6.25%, 3.125%, and 1.565% with the stock. The anti-Klebsiella pneumonia activity of the kolaviron extract was determined using agar well diffusion methods and incubation was done at 37 o C for 24 hrs. Student t-test and Oneway Analysis of variance (ANOVA) were used for comparison of mean differences between and among the groups. Results and Discussion: The sensitivity of Klebsiella pneumonia to kolaviron was concentration- dependent. There was an increase in anti-Klebsiella pneumonia activity with a decrease in kolaviron concentration. Kolaviron (KV), at 500mg/kg concentration, was efficacious and showed significant anti-inflammatory effects (P<0.0001). This was also confirmed in the histopathological examinations. The 3.125% concentration of the kolaviron gave IZDs that ranged from 25.68±3.33 mm on day 1 to 27.33±2.78 mm on day 5. Treatment with kolaviron showed to be sex-dependent with a significant difference (p<0.0001), when pre-treatment and post-treatment effects were compared between male and female rats. Conclusion: Kolaviron can be used as an agent in the treatment of pneumonia as it possesses anti- inflammatory and anti-Klebsiella pneumonia activities.