Recent Advances in Inflammation & Allergy Drug Discovery最新文献

Anti-inflammatory therapies currently in use mainly include steroidal and non-steroidal drugs. Contrary to their side effects, the steroid hormones glucocorticoids, which are synthetic versions of natural cortisol, are nevertheless often employed to treat a variety of inflammatory disorders. Other drug class of choice is non-steroidal drugs which mainly target COX-2 and hence the synthesis of prostaglandins, particularly PGE2. To cure both the short-term effects of chronic inflammatory disorders and the long-term symptoms of acute inflammation, pharmaceutical chemists are in continuous search for more potent and less toxic agents. Apart from these two drug classes, phytochemicals are gaining the attention of researchers as source of alternative antiinflammatory agents. However, every drug class has its own advantages or disadvantages thus requiring intervention of newer approaches. Currently, drugs used for anti-inflammatory therapies are costly with low efficacy, high health risk, and socio-economic impact due to the concern issue of their toxicity. Recently, nano-drug delivery system has been experiencing main interest as a new approach for targeting therapeutic agents to the target sites in a controlled, sustained manner and has various advantages as compared to the conventional drug delivery system like, increased solubility, bioavailability, improved pharmacokinetic profile of drugs, surface area and rate of dissolution and additionally, overcomes the problems related to hydrophobicity, toxicity. Present review summarized the intervention of nanotechnology to overcome the limitations/ risk associated with current anti-inflammatory drugs of different classes.

Nintedanib is a competitive inhibitor of non-receptor tyrosine kinase (nRTKs) and receptor tyrosine kinase (RTKs). Nintedanib is a substrate for the P-glycoprotein transporter, which returns ingested substances to the gastrointestinal lumen. At present, Nintedanib is being prescribed for individuals diagnosed with idiopathic pulmonary fibrosis (IPF). This assessment provides a concise overview of the latest patents pertaining to Nintedanib. The patents covered in this analysis are categorized into sections, including patents related to the active ingredient, polymorph, formulation, and treatment method. The purpose of this compilation is to offer researchers convenient access to all the relevant patents in a single resource. Information was collected from diverse web databases, including both paid and free sources. Paid databases, such as Orbit® and SciFinder® were utilized as examples. On the other hand, free databases, such as the European Patent Office's Espacenet®, WIPO Patentscope® the Indian patent database, and Google Patents, were also accessed for data gathering purposes. The orange-book listed patents for Nintedanib are set to expire in July 2029. These patents explore various excipients to address the solubility issue in the long-term storage of the formulation. However, despite these efforts, there is still a need for further research to enhance the properties of the Nintedanib formulation. Extensive research has been conducted on multiple methods for manufacturing Nintedanib and its formulations. This dynamic study has the potential to create opportunities for numerous generic companies to enter the United States market. This, in turn, will improve healthcare accessibility by lowering costs.

Background: Inflammation plays a significant role in the pathophysiology of Acute Coronary Syndrome (ACS) but is not included in current risk stratification.

Objective: To determine the association between Thrombolysis in Myocardial Infarction (TIMI) risk score and inflammatory biomarkers in the ACS, including unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). We hypothesized that including inflammatory biomarkers could add prognostic value to the TIMI risk score.

Methods: In this cross-sectional study, serum levels of interleukins (IL)-6 and IL-1β and MDA (malondialdehyde) were quantified by ELISA and colorimetry, respectively , patients with ACS (n = 48; 31.3% with UA, 33.3% with NSTEMI, and 35.4% with STEMI) and healthy controls (n = 43). We assessed the TIMI scores in the first 24 h after symptom onset.

Results: The results showed that patients with ACS had significantly higher levels (p<0.05) of the inflammatory biomarkers IL-6, IL-1β, and MDA compared to the control group. However, we found no significant differences in IL-6, IL-1β, and MDA levels among the patients with ACS according to their classification as UA, NSTEMI, and STEMI. Positive correlations were observed between TIMI and IL-6 (r=0.68), IL-1β (r= 0.53), and MDA (r=0.58) in patients with UA and between TIMI and IL-1β (r= 0.62) in STEMI patients.

Conclusion: These data suggest the presence of a pro-inflammatory profile in patients with ACS as well as positive correlations between TIMI scores and the inflammatory biomarkers IL-6, IL-1β, and MDA in patients with UA and between TIMI scores and IL-1β in patients with STEMI. Combining inflammatory biomarkers with the TIMI risk score could provide better insight into the processes involved in ACS.

Purpose: To prepare solid lipid nanopaticles (SLNs) of Ketoprofen (KP) using microwave method. Ketoprofen (KP) is 2-(3-benzolphenyl) propionic acid with anti-inflammatory, analgesic and antipyretic property. The drug has short half-life of 120 mins. It belongs to BCS Class II drug. Gastric irritation is a major limitation for delivery because of acidic nature of the drug. Development of solid lipid nanoparticles with its transdermal drug delivery was the aim of present work.

Methods: Microwave-assisted microemulsion technique was used for the development of solid lipid nanoparticles. Stearic acid was used as lipid and tween 80 was used as surfactant. By varying the type of lipid and input energy watt, batches were formulated. SLNs were evaluated for zeta potential, drug entrapment, particle size and in-vitro drug release. Crystallinity behaviour was determined by differential scanning calorimetry and powder X-ray diffraction. Anti-inflammatory activity was evaluated for batch M4 of SLNs. The gel was prepared for M4 batch. It was evaluated for viscosity, pH, drug content, in-vitro and ex-vivo diffusion study.

Results: SLN were developed successfully. Based on the size, entrapment efficiency, stability and drug release, batch M4 was selected. SLNs showed 74.8% entrapment efficiency. Forty-fold improvement was observed in the solubility. The particle size was of 682.9 nm and average size of 1047 nm. PDI was 0.685. Zeta potential was -29.5 mV. M4 SLNs batch of gel showed burst release followed by a controlled release for 8 hrs in in-vitro drug release.

Conclusion: SLNs were successfully prepared by Microwave-assisted microemulsion technique. SLNs with anti-inflammatory activity was successfully developed with its transdermal delivery.

Background: The organism's defense against aggressive agents is performed by the innate immune system, via activation of pattern-recognition receptors (PRRs). Initially, these agents are recognized by the immune system, resulting in the inflammatory response that activates the pathogen elimination and tissue repair. Inflammasomes are macromolecules related to the host's response to endo or exogenous aggressive agents. Thus, inflammation mediated by inflammasomes plays an important role in the pathogenesis of diseases, such as neurodegenerative disorders, autoimmune diseases, and type 2 diabetes, justifying their attractiveness as drug targets. One of the most important tasks remains in the ATPase nucleotide-binding oligomerization domain nucleotide-binding domain leucine-rich repeat-containing receptors protein 3 (NLRP3), in which the blocking of its oligomerization is related to the functional inhibition of inflammasomes. Here, we performed molecular docking and dynamics simulations for NP3-146, an analog of MCC950, and to obtain information about the complex stability and main interactions with amino acid residues from NLRP3.

Methods: Using the crystalized structure recently deposited in the protein data bank (7alv), molecular docking in GOLD software and Molecular dynamics simulations in GROMACS software were performed, to generate the RMSD, RMSF, Rg, SASA, and H-bond plots.

Results: The results of RMSD, RMSF, Rg, SASA, and H-bond plots of both complexes confirmed the stability at the active site. Besides, the analyses of the most stable conformation showed that the main interactions are performed with Ala227, Ala228, Pro352, Ile411, Phe575, and Arg578 residues.

Conclusion: This report confirmed the stability of NP3-146, similar to the know inhibitor MCC950, and provides various information useful to design NLRP3 inhibitors.

Background: Inflammation is the response to the reaction of any type of bodily injury by elevating cellular metabolism and releasing soluble mediators. It is also a contributing factor of pain. Predimenol, which has previously been known as DLBS1442, is a bioactive extract from Phaleria macrocarpa (Scheff.) Boerl (Thymelaceae). It can be an alternative treatment for pain relief, especially for long-term use.

Objective: The objective of this study is to evaluate the anti-inflammatory activities of predimenol through the evaluation of several parameters involved in the inflammatory pathway.

Methods: Cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-  (TNF-), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), and nuclear factor B (NF-B) were observed after 24 h exposure of predimenol (0-180 µg/mL) to lipopolysaccharides (LPS)-activated RAW 264.7 cell. The inflammatory markers were measured using nitric oxide (NO) assay and enzyme-linked immunosorbent assay (ELISA) for COX-2 inhibitor assay. The gene expressions of TNF-α, IL-1β, IL-2 and IL-6 were quantified using the polymerase chain reaction (PCR) method. Western blotting was applied to detect phosphorylated IB kinase (IKK) protein to confirm the activation of NF-κB.

Results: Our study showed a similar mechanism with most non-steroidal anti-inflammatory drugs (NSAIDs). Predimenol consistently downregulated the expression of iNOS and inhibited COX-2 activity. Moreover, predimenol significantly inhibited the LPS-induced production of NO, TNF-α, IL-1β, IL-2 and IL-6. Down-regulation of these markers was suggested due to the reduction of NF-κB transcription level and activation by predimenol.

Conclusion: Predimenol exhibits anti-inflammatory activities through NF-kB inactivation-mediated COX-2 suppression, which may suggest that predimenol is a potential analgesic and anti-inflammatory agent.

Advancements in stem cell research have enabled the establishment of three-dimensional (3D) primary cell cultures, known as organoids. These culture systems follow the organization of an in vivo organ, as they enclose the different epithelial cell lines of which it is normally composed. Generation of these 3D cultures has bridged the gap between in vitro models, made up by two-dimensional (2D) cancer cell lines cultures, and in vivo animal models, that have major differences with human diseases. Organoids are increasingly used as a model to study colonization of gastric mucosa by infectious agents and to better understand host-microbe interactions and the molecular events that lead to infection, pathogen-epithelial cells interactions and mechanisms of gastric mucosal injury. In this review we will focus on the role of organoids as a tool to investigate molecular interactions of Helicobacter (H.) pylori and Epstein Barr Virus (EBV) and gastric mucosa and how these infections, that affect ≈ 45% of the world population, might progress to gastric cancer, a highly prevalent cancer and the third leading cause of cancer death.

The main objectives of the present work are to determine the clinical effect of niranthin on visceral or somatic inflammatory pain. The study was performed to determine the effects of niranthin on visceral or somatic inflammatory hypersensitivity of adult Swiss albino mice by using complete Freund's adjuvant (CFA) induced pain model. The effect of CFA injection was determined after 24 hours of injection by using an aesthesiometer such as Von Frey filaments to evaluate tactile acetone-evoked cooling and thermal sensitivity. We used a digital Plethysmometer to measure paw edema. Single dose of niranthin intraperitoneal injection (5 & 10 mg/kg) was injected into mice having CFA-induced mechanical hypersensitivity and after 30 minutes of administration, reduced mechanical hypersensitivity was observed. In addition, niranthin also reduced acetone-evoked hypersensitivity within 4 hours. Compared to DMSO, niranthin was most highly active to reduce CFA-induced paw edema. To reduce mechanical hypersensitivity, multiple doses of niranthin (bis in die (b.i.d.)) from 1st - 5th day and b.i.d. day 9th and 10th) were given and remarkable results were observed such as did not cause tolerance in multiple dosing and significantly reduced in CFA induced hypersensitivity. This work reported niranthin having antinociceptive activity and indicated that niranthin is conventionally active in the management of persistent pain.

Background: Gastrointestinal (GI) cancer is associated with a group of cancers affecting the organs in the GI tract, with a high incidence and mortality rate. This type of cancer development involves a series of molecular events that arise by the dysregulation of gene expressions and microRNAs (miRNAs).

Objectives: This mini-review focuses on elucidating the mechanism of tumor suppressor miRNA-mediated oncogenic gene silencing, which may contribute to a better understanding of miRNA-mediated gene expression regulation of cell cycle, proliferation, invasion, and apoptosis in GI cancers. In this review, the biological significance of tumor suppressor miRNAs involved in gastrointestinal cancers is briefly explained.

Methods: The articles were searched with the keywords 'miRNA', 'gastrointestinal cancers', 'esophageal cancer', 'gastric cancer', 'colorectal cancer', 'pancreatic cancer', 'liver cancer', and 'gall bladder cancer' from the Google Scholar and PubMed databases. A total of 71 research and review articles have been collected and referred for this study.

Results: This review summarises recent research enhancing the effectiveness of miRNAs as novel prognostic, diagnostic, and therapeutic markers for GI cancer treatment strategies. The expression pattern of various miRNAs has been dysregulated in GI cancers, which are associated with proliferation, cell cycle regulation, apoptosis, migration, and invasion.

Conclusion: The role of tumor suppressor miRNAs in the negative regulation of oncogenic gene expression was thoroughly explained in this review. Its potential role as a microRNA therapeutic candidate is also discussed. Profiling and regulating tumor suppressor miRNA expression in gastrointestinal cancers using miRNA mimics could be used as a prognostic, diagnostic, and therapeutic marker, as well as an elucidating molecular therapeutic approach to tumor suppression.