Anti-inflammatory Research Articles

Acute purulent otitis media: key features of pathogenetic therapy

Acute purulent otitis media is an inflammation of the mucous membrane of the middle ear, a disease often encountered both in pediatric practice and in adult patients. The prerequisite for the development of this pathology is a violation of the function of the auditory tube, often occurring in inflammatory diseases of the upper respiratory tract, as well as in conditions of hypertrophy of the pharyngeal tonsil. Bacterial microflora, represented in most clinical cases by S. pneumoniae and H. influenzae, traditionally acts as an etiological factor of acute purulent otitis media. The authors of the article discuss the features of the clinical course of the disease, the causes of frequent recurrent course and the risk of developing purulent complications. The article highlights current problems of diagnosis and treatment of acute otitis media at different stages, including rational and justified use of antibacterial drugs. The authors consider the possibility of using topical anti-inflammatory and analgesic drugs as an alternative to the systemic use of non-steroidal anti-inflammatory drugs (NSAIDs) for rapid relief of the main symptoms of the disease. The authors conclude that ear drops containing lidocaine and phenazone, due to their combined action, are effective as a symptomatic treatment for acute otitis media, including its recurrent course, help reduce the frequency of prescribing antibacterial drugs, effectively relieve pain, reduce the duration of the disease and significantly improve the patient’s quality of life. Due to the high safety profile and the possibility of using ear drops with phenazone and lidocaine from birth, this dosage form finds its successful application in pediatric practice.

Structure of Medication Therapy in Patients with Complex Hand Bone Fractures in Kyrgyz Republic

This article analyzes the structure of medication therapy in patients with complex hand bone fractures in the Kyrgyz Republic. Complex hand fractures are common injuries requiring a multi-stage treatment approach, including surgery, immobilization, and adequate medication therapy. The article examines various therapeutic regimens used at different stages of treatment: the first-line therapy includes analgesics and anti-inflammatory drugs, the second-line therapy adds hormonal medications and tissue regeneration stimulants, and alternative methods incorporate biologically active agents and physiotherapy. Effectiveness was evaluated based on clinical indicators such as pain level, bone healing rate, complication frequency, and restoration of hand function. The article also discusses gender-specific differences in therapeutic approaches, necessitating the consideration of pharmacokinetics and pharmacodynamics in men and women. This study highlights the need for the development of standardized treatment protocols adapted to local healthcare conditions to improve treatment efficacy and reduce complications.

Crystallinity of covalent organic frameworks controls immune responses

Biomaterials can act as pro- or anti-inflammatory agents. However, effects of biomaterials crystallinity on immune responses are poorly understood. We demonstrate that the adjuvant-like behaviour of covalent organic framework (COF) biomaterial is dependent on its crystallinity. COF crystallinity is inversely correlated with the activation of mouse and human dendritic cells (DC), but with antigen presentation by mouse DCs only. Amorphous COFs upregulates NFkB, TNF, and RIG-I signalling pathways, as well as the chemotaxis-associated gene Unc5c, when compared to crystalline COFs. Meanwhile, Unc5c inhibition disrupts the correlation between crystallinity and DC activation. Furthermore, COFs with the lowest crystallinity admixed with chicken ovalbumin (OVA) antigen prevent OVA-expressing B16F10 tumour growth in 60% of mice, with this protection associated with the induction of antigen-specific, pro-inflammatory T cell. The lowest crystalline COFs admixed with TRP2 antigen can also prevent non-immunogenic YUMM1.1 tumour growth in 50% of mice. These findings demonstrate that the crystallinity of biomaterials is an important aspect to consider when designing immunotherapy for pro- or anti-inflammatory applications.

Structure and Function of Sabinene Synthase, a Monoterpene Cyclase That Generates a Highly Strained [3.1.0] Bicyclic Product.

Sabinene is a plant natural product with a distinctive strained [3.1.0] bicyclic ring system that is used commercially as a spicy and pine-like fragrance with citrus undertones. This unusual monoterpene has also been studied as an antifungal and anti-inflammatory agent as well as a next-generation biofuel. In order to understand the molecular determinants of [3.1.0] bicyclic ring formation in sabinene biosynthesis, we now report three X-ray crystal structures of sabinene synthase from Western red cedar, Thuja plicata (TpSS), with open and partially closed active site conformations at 2.21-2.72 Å resolution. We additionally report the complete biochemical characterization of sabinene synthase, including steady-state kinetics, active site mutagenesis, and product array profiling. The catalytic metal ion requirement is unexpectedly broad for a class I terpene cyclase: optimal catalytic activity was measured using Mn2+ or Co2+, with more modest activity observed using Mg2+ or Ni2+. Kinetic parameters were determined for both full-length TpSS and a deletion variant lacking the putative N-terminal plastidial targeting sequence, designated ΔTpSS. Monoterpene product profiles for both indicated similar product arrays independent of the catalytic metal ion used, with sabinene comprising nearly 90% of the total products generated. Site-directed mutagenesis was utilized to probe the function of active site residues, and several mutants yielded altered product arrays. Most notably, the G458A substitution converted ΔTpSS into a high-activity α-pinene synthase. α-Pinene contains a bicyclic [3.1.1] ring system; structural and mechanistic analyses suggest a molecular rationale for the reprogrammed transannulation reaction, leading to the alternative bicyclic product.

On the local treatment of exacerbation of tonsillopharyngitis

Introduction. Anatomical and topographic features of abundant pharyngeal innervation, causing pronounced symptoms of exacerbations of tonsillopharyngitis and significantly reducing the well-being of patients, will determine the improvement of treatment.Aim. To evaluate the possibility of using a nonsteroidal anti-inflammatory drug with the flurbiprofen in complex exacerbations of chronic tonsillopharyngitis.Materials and methods. The clinical observation of 117 patients with exacerbation of chronic tonsillopharyngitis was carried out. By random sampling, all patients were divided into 2 groups, where persons of the main group (n = 61) for standard conservative therapy took a tableted nonsteroidal anti-inflammatory drug with the active substance flurbiprofen 1 tablet with a 3-6-hour time interval during.Results and discussion. On day 3 of the therapy, a more pronounced improvement in both the severity of clinical complaints and pharyngoscopy data was noted to a greater extent in patients of the main group: a decrease in the severity of edema of the palatine tonsils by 1.6 points, vascular injection by 1.8 points, edema of the palatine arches by 2.2 points, hyperemia of the mucous membrane by 3.7 points. In the Conrol group (n = 56), there was a decrease in the severity of edema of the palatine tonsils by 1.4 points, vascular injection by 1.2 points, edema of the palatine arches by 1.7 points, hyperemia of the mucous membrane by 2.4 points. During the 7-day course of treatment, psychological health was restored by 24.8 points in the control group and by 32.3 points in the main group. An increase in vital activity was noted by 18.7 points in the control group and by 34.2 points in the main group, a clear increase in physical activity by 19.6 points and 7.6 points in the main and control groups, respectively.Conclusions. Earlier relief of inflammatory symptoms of exacerbations of tonsillopharyngitis and restoration of patient well-being when a nonsteroidal anti-inflammatory drug was included in complex therapy confirmed its good efficacy and safety.

Benchtop 19F Nuclear Magnetic Resonance (NMR) Spectroscopy-Optimized Knorr Pyrazole Synthesis of Celecoxib and Mavacoxib, 3-(Trifluoromethyl) Pyrazolyl Benzenesulfonamides, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Fluorinated organic compounds have demonstrated remarkable utility in medicinal chemistry due to their enhanced metabolic stability and potent therapeutic efficacy. Several examples exist of fluorinated non-steroidal anti-inflammatory drugs (NSAIDs), including diflunisal, flurbiprofen, and trifluoromethylated pyrazoles celecoxib and mavacoxib. These trifluoromethylated pyrazoles, which are most commonly constructed through the cyclocondensation of a trifluorinated 1,3-dicarbonyl and an aryl hydrazine, are also found in numerous other drug candidates. Here, we interrogate the effects of solvents and the presence of Brønsted or Lewis acid catalysts on catalyzing this process. We highlight the utility of benchtop 19F NMR spectroscopy in enabling the real-time quantification of reaction progress and the identification of fluorinated species present in crude reaction mixtures without the need for cost-prohibitive deuterated solvents. Ultimately, we find that the reaction solvent has the greatest impact on the rate and product yield, and also found that the relationship between the keto-enol equilibrium of the dicarbonyl starting material pyrazole formation rate is highly solvent-dependent. More broadly, we describe the optimization of the yield and kinetics of trifluoromethylpyrazole formation in the synthesis of celecoxib and mavacoxib, which is made possible through high-throughput reaction screening on benchtop NMR.

Assessment of co-administration of Non-steroidal anti-inflammatory drug with proton pump inhibitors on hepatic-renal structure in vivo

Assessment of co-administration of Non-steroidal anti-inflammatory drug with proton pump inhibitors on hepatic-renal structure in vivo

Study of anti-inflammatory, antioxidant, antimicrobial and mineralizing effects of an N-isopropenylimidazole zinc metal complex derivative in experimental endodontic-periodontal lesions in rats

Introduction: The combination treatment of patients with dentition problems including endodontic-periodontal lesions (EPL) is known to widely involve anti-inflammatory drugs, including non-steroidal anti-inflammatory agents, and antimicrobial drugs, in particular antibiotics and antiseptics, from which the former often lead to the development of gastro- and neuropathy, lesions of kidneys and liver, as well as the cardiovascular system, and the latter, in addition to serious side effects, lead to the development of steady resistance of pathogenic microorganisms and dysbacteriosis. This necessitates search for and development of new molecules with a wide range of therapeutic effects aimed to block the infectious and inflammatory process and to restore the functional ability of teeth in EPLs as much as possible (depending on a lesion severity). The aim of the study was to examine the anti-inflammatory, antioxidant, antimicrobial and mineralizing effects of an N-isopropenylimidazole zinc metal complex derivative in experimental endodontic-periodontal lesions in rats. Materials and Methods: EPL simulation in experiments on the anesthetized rats was conducted in the following way: first, the pulp cavity of lower incisors was opened and left exposed to infection; then periodontal inflammation was induced using a ligature. Thirty days later, EPL developed in the animals. An N-isopropenylimidazole zinc metal complex derivative (laboratory code Pilim-1, prepared in form of gel), reference drug Metrogyl Denta® (M-D, dental gel), as well as the combination Pilim-1 + M-D were applied daily for 14 days on the lower incisors and appropriate gums, and also placed in the gingival pockets and pulp cavities, with pulp partially removed beforehands. After euthanasia of the animals on the 15th day of the experiments, gingival homogenates were assayed for the activity of elastase, urease, catalase, the level of malondialdehyde, and the antioxidant-prooxidant index was calculated, while pulp homogenates were assayed for the activity of elastase, urease, alkaline and acidic phosphatases, and the mineralizing index was calculated. Results and Discussion: In the gum in EPL, Pilim-1 and, especially, the combination Pilim-1+M-D more significantly than M-D have a pronounced anti-inflammatory, antioxidant and antimicrobial (reduce a microbial content level) effects. In the pulp in EPL, Pilim-1 and, to a greater extent, the combination Pilim-1 + M-D in a more pronounced way than M-D have anti-inflammatory, antimicrobial (reduce a microbial content level) and mineralizing effects. In the therapeutic action mechanisms of Pilim-1 and, especially, the combination Pilim-1 + M-D in EPL conditions, their ability to have an antihypoxic effect and an inhibitory effect on cyclooxygenase and 5-lipoxygenase is likely to play a very important role, in addition to their identified effect on the examined metabolic processes. Besides, a certain role may be played by the presence of zinc and imidazole in the structure of Pilim-1, as they have a wide range of biological activity. Conclusion: The presented results of studying Pilim-1 and its combination with M-D indicate their high therapeutic efficiency, especially when using the latter in the experimental EPL in rats, which makes it possible to consider Pilim-1 and Pilim-1 + M-D as potential therapeutic agents to treat EPL.

Anti-inflammatory diterpenoids from the brown alga Dictyota coriacea.

A new xenicane diterpene named 4α-acetoxyisodictyohemiacetal (1) was isolated from the brown alga Dictyota coriacea, along with 11 known diterpenoids. The structure of 1 was established by spectroscopic analyses, and its absolute configuration was determined by comparing the experimental and theoretical electronic circular dichroism (ECD) spectra. Two dictyodiacetal diastereomers (5 and 6) were isolated and the full NMR assignments were performed. The anti-inflammatory activities of the isolated compounds were evaluated using the lipopolysaccharide-stimulated mouse macrophage cell line, RAW264. The hemiacetal-containing xenicanes and dictyol-type diterpene inhibited not only the production of nitric oxide, but also the expression of inducible nitric oxide synthase, interleukin-6, and cyclooxygenase-2 mRNA in RAW264 cells. This study demonstrated that diterpenes from Dictyota coriacea may be useful as natural anti-inflammatory agents.

Jing Si Herbal Tea Modulates Macrophage Polarization and Inflammatory Signaling in LPS-Induced Inflammation.

Background: Sepsis is a lethal disease due to uncontrolled inflammatory responses. Macrophages play an important role in sepsis-associated inflammation. Jing Si Herbal Tea (JSHT) is a plant-based regimen with anti-inflammatory properties designed to treat respiratory diseases; however, its underlying therapeutic mechanism remains unclear. This study aimed to investigate the effects of JSHT on macrophage polarization and inflammatory signaling in lipopolysaccharide (LPS)-induced inflammation to provide therapeutic approaches for inflammatory diseases. Methods: RAW264.7 cells were stimulated with LPS (1 µg/mL for 16 h) to induce inflammatory responses and treated by JSHT (0.0125% concentration for 4 h) in the experimental groups (Control, JSHT, LPS, Pre-JSHT, and Post-JSHT groups). We investigated the protein and cytokine expression levels using western blotting and enzyme-linked immunosorbent assay (ELISA). Macrophage morphology was observed using immunofluorescence staining. The polarization surface markers were detected by flow cytometry. Results: In the LPS group, the expressions of the inflammatory signaling (pERK, pJNK, and nuclear NFκB) and the pro-inflammatory cytokine levels (TNF-α, IL-1β, and IL-6) were significantly increased, with M1 polarization (CD68+/CD80+) compared to the Control group. In the Pre-JSHT and Post-JSHT groups, the expressions of the inflammatory signaling and the pro-inflammatory cytokine levels were significantly decreased, with a higher M2 polarization ratio (CD163+/CD206+) compared to the LPS group. RAW264.7 cells exhibited filopodia protruding from the cell surface in the LPS group, which were inhibited in the Pre-JSHT and Post-JSHT groups. Conclusions: LPS induced M1 polarization with elevated inflammatory signaling and cytokine levels, while JSHT not only decreased M1 polarization but also promoted M2 polarization with decreased inflammatory responses. We propose JSHT as a potential anti-inflammatory agent against LPS-induced inflammation.

COF-SO3H-Catalyzed Synthesis of Pyrazoline-Pyridine Hybrids with Dual Antioxidant and Anti-Inflammatory Activity Targeting PDE4B.

This study explores new anti-inflammatory agents by synthesizing pyrazoline-pyridine hybrids with N-butylsulfonated covalent organic framework (COF-SO3H) as a recyclable catalyst, achieving excellent yields in just one minute. The protocol was successfully scaled up to a multi-gram scale, highlighting its robustness and efficiency, and it operates without the need for column chromatography. Among the synthesized hybrids, compound 5d, a pyrazoline-pyridine hybrid bearing an indole moiety, emerged as a potent anti-inflammatory and antioxidant agent. It effectively inhibited PDE4B activation with an IC50 value of 99.38 nM, without adversely affecting HEK cells. Compound 5d demonstrated its dual activity by significantly reducing ROS production and restoring mitochondrial health in LPS-stimulated A549 and HEK cells, while also downregulating IL-1β and NF-ĸB/p65 expression in LPS-stimulated A549 cells. In silico studies confirmed compound 5d's strong binding to PDE4B, with stable RMSD and RMSF values, indicating its potential as a stable and effective PDE4B inhibitor. The compound exhibited favorable physicochemical properties, met drug-likeness criteria, and showed low toxicity as predicted in silico. These findings suggest that compound 5d has significant potential as a therapeutic agent for inflammatory diseases due to its dual anti-inflammatory and antioxidant activities.

Iota-Carrageenan from Marine Alga Solieria filiformis Prevents Naproxen-Induced Gastrointestinal Injury via Its Antioxidant and Anti-Inflammatory Activities.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in therapy due to their anti-inflammatory and analgesic properties. However, their clinical use is often associated with gastrointestinal complications. Thus, this study aimed to investigate the protective effect of a sulfated iota-carrageenan isolated from the marine alga Solieria filiformis (IC-Sf) against naproxen-induced gastrointestinal injury. Methods: Parameters of gastrointestinal injury, secretory and motor functions, and toxicity were evaluated. Results: The results demonstrated that IC-Sf significantly reduced naproxen-induced gastrointestinal macroscopic injury, with a maximum effect observed at 30 mg/kg. IC-Sf also preserved gastrointestinal antioxidant defense and prevented lipid peroxidation, with a reduction in the non-protein sulfhydryl group (NP-SH) and malondialdehyde (MDA) concentrations induced by naproxen. Additionally, IC-Sf mitigated naproxen-induced gastrointestinal inflammation, as evidenced by reduced myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). IC-Sf did not alter gastric secretion or gastrointestinal motility. In addition, the animals treated with IC-Sf did not present toxic effects. Conclusions: In conclusion, IC-Sf protected the gastrointestinal tract against the harmful effects of naproxen by inhibiting the inflammatory response and lipid peroxidation, suggesting its potential as a new therapeutic agent or food additive.

Design, Synthesis and Biological Activities Evaluation of Novel Pterostilbene-urea Derivatives as Potential Anti- inflammatory Agents.

1. The toxicity of derivatives was removed by the reasonable modification of bioactive skeleton. 2. As potential COX-2 inhibitor with IC50 values ranging from 39.42 to 179.84 nM/L, compounds (Q4-Q10, Q20) exhibited superior anti-inflammatory activity at low micromolar concentrations. 3. Q7 (IC50 (COX-2)=61.05 nM/L), Q10 (IC50 (COX-2)=54.68 nM/L) and Q20 (IC50 (COX-2)=39.42 nM/L) showed stronger COX-2 inhibitory abilities than Celecoxib (IC50 (COX-2)=67.89 nM/L). 4. The strongest anti-inflammatory agent, Q20 (IC50 NO= 9.96 μM/L, IC50 (COX-2)=39.42 nM/L) effectively inhibited the secretion of IL-1β and TNF-α, exhibited the IC50 values of 12.30 and 9.07 μM/L respectively. 5. Q20 exerted as anti-inflammatory actives via targeting COX-2, down-regulating iNOS and TLR4 protein, and inhibiting the activation of NLRP3 inflammasome and NF-κB signal pathway.

Impact of treatment management on the hospital stay in patients with acute coronary syndrome

BackgroundThe length of hospital stay in patients with acute coronary syndrome (ACS) is crucial for determining clinical outcomes, managing healthcare resources, controlling costs, and ensuring patient well-being. This study aimed to explore the impact of treatment approaches on the length of stay (LOS) for ACS patients.MethodsA total of 7109 ACS cases were retrospectively recruited from a hospital between 2018 and 2023. Demographical baseline data, laboratory examinations, and diagnostic and treatment information of the included subjects were extracted from electronic medical records to investigate the factors contributing to extended hospitalization and further explore the impact of treatment management on the LOS.ResultsAdvanced age, female sex, and elevated levels of B-type natriuretic peptide, C-reactive protein and higher low-density lipoprotein cholesterol were identified as risk factors for extended hospitalization. At the 0.2–0.9 quantile of LOS, compared with the non-invasive group, the percutaneous transluminal coronary angioplasty group and the stent implantation group exhibited decreases in LOS of 0.37–2.37 days and 0.12–2.28 days, respectively. Stratified analysis based on diagnosis showed that percutaneous coronary intervention decreased hospitalization time in the high quantile of LOS but conversely increased it in the low quantile.ConclusionPercutaneous coronary intervention is important for reducing hospitalization duration, particularly for patients susceptible to prolonged stays. Early and assertive management intervention, incorporating elements such as lipid-lowering therapy, and anti-inflammatory agents, is essential for improving outcomes within high-risk groups.

A review of migraine treatment methods: a comparative analysis of therapeutic approaches

Migraine, a complex neurological disorder, affects a significant portion of the population and presents both medical and societal challenges. The aim of this paper is to provide a detailed review and analysis of available therapeutic methods for patients suffering from migraines, considering both pharmacological and non-pharmacological therapies. The approaches presented include acute treatment with triptans and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as preventive therapies, such as beta-blockers and antiepileptic drugs. The section on non-pharmacological therapies focuses on cognitive-behavioral therapy (CBT), biofeedback, and lifestyle recommendations, including diet and sleep hygiene. A review of the literature indicates that integrating pharmacological and non-pharmacological approaches can significantly improve treatment effectiveness and the quality of life for patients with migraines.

Design, Synthesis of Flurbiprofen Based 1,3,4-Oxadiazoles and Constrained Anticancer, Antioxidant Agents: In silico Docking Analysis.

Flurbiprofen, a primary component of a nonsteroidal anti-inflammatory drug (NSAID) used to relieve symptoms of arthritis, and is a considerable interest in medicinal chemistry due to its demonstrated potential as an effective agent in various therapeutic applications. In consideration of the 1,3,4-oxadiazole therapeutic potential and anticancer activity, a new series of flurbiprofen scaffolds have been prepared through a straightforward reaction between 5-(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,3,4-oxadiazole-2-thiol (4) and various organic active 2-chloro-N-phenyl acetamides (5). The synthesized series (6a-6k) was characterized using a combination of spectroscopic techniques, including FT-IR, mass, 1H-NMR, and 13C NMR, followed by physical data. The cytotoxicity of the newly synthesized congeners was investigated against MCF-7 (human breast cancer cell line) and A-549 (human lung carcinoma epithelial) cell lines and anti-inflammatory activity as DPPH and H2O2 radical scavenging ability. In the series, analogues 6c, 6e, 6h, and 6k showed excellent inhibitory activity against MCF-7 cells in the range of IC50 values of 9.10-13.67 μg mL-1 compared to DXN (IC50=9.24 μg mL-1). In this series, analogues 6c, 6f, 6h, and 6j show remarkable H2O2 radical scavenging inhibition IC50 of 48.25±0.21, 47.33±0.15, 51.10±0.25, and 44.40±0.07 μM by using ascorbic acid as a standard, whose IC50 is 49.90±0.27 μM. According to the docking results, the most potent cytotoxic compounds have a stronger binding affinity with the Flurbiprofen complex (PDB: 1R9O) because of their interactions with residues such as Arg416(A), Trp103(A), Phe97(A), Gly279(A), Ile188(A), Glu283(A), Thr287(A), Val462(A), Phe459(A), Leu345(A), Ile417(A), and Cys418(A). Furthermore, in silico drug-likeness prediction analysis suggested that the majority of the synthesized compounds exhibit good oral bioavailability based on their Lipinski's Rule of Five and toxicity using ADME/Tox predictions.

Quantitative Analysis of Amorphous Form in Indomethacin by Near Infrared Spectroscopy Combined with Partial Least Squares Regression Analysis.

Indomethacin (INDO) is a synthetic non-steroidal antipyretic, analgesic, and anti-inflammatory drug that commonly exists in both amorphous and crystalline states. Its amorphous state (A-INDO) is utilized by pharmaceutical companies as an active pharmaceutical ingredient (API) in the production of INDO drugs due to its higher apparent solubility and bioavailability. The crystal state also encompasses various crystal forms such as the α-crystal form (α-INDO) and γ-crystal form (γ-INDO), with the highly crystalline and insoluble γ-INDO being commercially available. A-INDO, existing in a thermodynamically high-energy state, is susceptible to several factors during the preparation, storage, and transportation of API leading to its conversion into γ-INDO, thus impacting the bioavailability and efficacy of INDO drugs. Therefore, quantitative analysis of the A-INDO/γ-INDO content in INDO API becomes essential for controlling the production quality of INDO. The primary objective of this study is to investigate the feasibility of NIR for the quantitative analysis of A-INDO in INDO API, and to further elucidate its quantitative analysis mechanism. The NIR spectral data were collected for A-INDO and γ-INDO binary mixture samples with different resolutions, and these spectra were then selected and reconstructed using the interval partial least square (iPLS) method. Different pretreatment methods were employed to enhance the reconstructed spectra by highlighting relevant eigen information while eliminating invalid information caused by environmental factors or physical characteristics of samples. The most suitable PLSR model for quantitative analysis of A-INDO within the range of 0.0000-100.0000% w/w% was established, screened, and validated. From various perspectives, including distribution of spectral effective information, impact of resolution on PLSR model performance, variance contribution/cumulative variance contribution of PLSR model principal components (PCs), PCI loadings, relationship between spectral scores, and A-INDO content, feasibility assessment was conducted for the quantitative analysis of A-INDO in INDO using NIR spectroscopy. Additionally, a detailed investigation on the quantitative analysis mechanism of the optimal PLSR model was undertaken including the correlation between the characteristic peaks of spectra and information regarding hydrogen groups or hydrogen bonds in A-INDO or γ-INDO molecules. This study aims to provide theoretical support for the quantitative analysis of A-INDO in INDO API as well as serve as a reliable reference method for API quantification and quality control in similar drugs.

Dual effects of mefenamic acid on the IKs molecular complex.

Mutations in both KCNQ1 and KCNE1, which together form the cardiac IKs current, are associated with inherited conditions such as long and short QT syndromes. Mefenamic acid, a non-steroidal anti-inflammatory drug, is an IKs potentiator and may be utilised as an archetype to design therapeutically useful IKs agonists. However, here we show that mefenamic acid can also act as an IKs inhibitor, and our data reveal its dual effects on KCNQ1/KCNE1 channels. Effects of mefenamic acid on wild type (WT) and mutant KCNQ1/KCNE1 channels expressed in tsA201 cells were studied using whole cell patch clamp. Molecular dynamics simulations were used to determine trajectory clustering. Mefenamic acid inhibits WT IKs at high concentrations while preserving some attributes of current potentiation. Inhibitory actions of mefenamic acid are unmasked at lower drug concentrations by KCNE1 and KCNQ1 mutations in the mefenamic acid binding pocket, at the extracellular end of KCNE1 and in the KCNQ1 S6 helix. Mefenamic acid does not inhibit KCNQ1 in the absence of KCNE1 but inhibits IKs current in a concentration-dependent manner in the mutant channels. Inhibition involves modulation of pore kinetics and/or voltage sensor domain-pore coupling in WT and in the KCNE1 E43C mutant. This work highlights the importance of structural motifs at the extracellular inter-subunit interface of KCNQ1 and KCNE1 channels, and their interactions, in determining the nature of drug effects on the IKs channel complex and has important implications for treating patients with specific long QT mutations.

Carborane Conjugates with Ibuprofen, Fenoprofen and Flurbiprofen: Synthesis, Characterization, COX Inhibition Potential and In Vitro Activity.

The most effective anticancer drugs currently entail substantial and formidable side effects, and resistance of tumors to chemotherapeutic agents is a further challenge. Thus, the search for new anticancer drugs as well as novel therapeutic methods is still extremely important. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit COX (cyclooxygenase), overexpressed in some tumors. Carboranes are emerging as promising pharmacophores. We have therefore combined both moieties in a single molecule to design drugs with a dual mode of action and enhanced effectiveness. The NSAIDs ibuprofen, flurbiprofen, and fenoprofen were connected with 1,2-dicarba-closo-dodecaborane(12) via methylene, ethylene or propylene spacers. Three sets of carborane-NSAID conjugates were synthesized and analyzed through multinuclear (1H, 11B, and 13C) NMR spectroscopy. Conjugates with methylene spacers exhibited the most potent COX inhibition potential, particularly conjugates with flurbiprofen and fenoprofen, displaying higher selectivity towards COX-1. Furthermore, conjugates with methylene and ethylene spacers were more efficient in suppressing the growth of human cancer cell lines than their propylene counterparts. The carborane-flurbiprofen conjugate with an ethylene spacer was the most efficient and selective toward the COX-2-negative cell line HCT116. Its mode of action was basically cytostatic with minor contribution of apoptotic cell death and dominance of cells trapped in the division process.

Semaglutide Ameliorates Diabetic Neuropathic Pain by Inhibiting Neuroinflammation in the Spinal Cord.

Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1× SEMA (1.44 mg/kg, orally) or 2× SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated. SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group. These results indicate SEMA's neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects.