Transcutaneous Vagus Nerve Stimulation Regulates the Cholinergic Anti-inflammatory Pathway to Counteract 1, 2-Dimethylhydrazine Induced Colon Carcinogenesis in Albino wistar Rats

The present work was undertaken to study the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on 1, 2-dimethyhydrazine (DMH) induced colon cancer and role of the cholinergic anti-inflammatory pathways (CAP) in the same. Groups of rats were randomly divided into ten groups (n = 8). DMH administration was very well apparent for autonomic dysfunction as observed through distorted hemodynamic (electrocardiogram and heart rate variability), increased aberrant crypt foci and flat neoplastic lesions (methylene blue staining, scanning electron microscopy and Hematoxylin and eosin staining). DMH administration was also recorded for per-oxidative damage. taVNS application restored the autonomic function, cellular morphology and curtailed the oxidative damage. DMH application conspicuously inhibited the mitochondrial apoptosis which was restored back after taVNS application, when scrutinized through immunoblotting and quantitative real time polymerase chain reaction studies. taVNS application up-regulated the CAP as perceived through increased expression for α7 nicotinic acetylcholine receptor(α7nAchR) and decreased expression for nuclear factor kappa-ligand-chain-enhancer of activated B cells (NFκBp65), tissue necrosis factor-α and high mobility group box-1 at protein and mRNA levels. All in all, taVNS up-surged the CAP to counteract DMH induced colon carcinogenesis. Among all the stimulation parameters used, taVNS 3 (pulse width-1 ms, frequency-6 Hz, voltage-6 v, duration-240 min) was observed to be the most effective. Since only chemotherapy and surgery are available options for management of CRC, which are troublesome and painful, there is currently no non-invasive method available for management of CRC. Results of the current study affirmed the effectiveness of taVNS against DMH induced colon cancer. The present study established taVNS as a novel and non-invasive approach toward the management of CRC

Crisaborole Loaded Nanoemulsion Based Chitosan Gel: Formulation, Physicochemical Characterization and Wound Healing Studies

The development of an effective gel capable of treating eczema remains a challenge in medicine. Because of its greater retention in the affected area, good absorption of wound exudates, and induction of cell growth, nanogel is widely investigated as a topical preparation. Chitosan gel based on nanoemulsions has received much attention for its use in wound healing. In this study, four formulae (CRB-NE1-CRB-NE4) of crisaborole-loaded nanoemulsions (CRB-NEs) were developed using lauroglycol 90 as an oil, Tween-80 as a surfactant, and transcutol-HP (THP) as a co-surfactant. The prepared NEs (CRB-NE1-CRB-NE4) were evaluated for their physicochemical properties. Based on vesicle size (64.5 ± 5.3 nm), polydispersity index (PDI) (0.202 ± 0.06), zeta potential (ZP, −36.3 ± 4.16 mV), refractive index (RI, 1.332 ± 0.03), and percent transmittance (% T, 99.8 ± 0.12) was optimized and further incorporated into chitosan (2%, w/w) polymeric gels. The CRB-NE1-loaded chitosan gel was then evaluated for its drug content, spreadability, in-vitro release, flux, wound healing, and anti-inflammatory studies. The CRB-NE1-loaded chitosan gel exhibited a flux of 0.211 mg/cm2/h, a drug release of 74.45 ± 5.4% CRB released in 24 h with a Korsmeyer-Peppas mechanism release behavior. The CRB-NE1-loaded gel exhibited promising wound healing and anti-inflammatory activities

The Detailed Pharmacodynamics of the Gut Relaxant Effect and GC-MS Analysis of the Grewia tenax Fruit Extract: In Vivo and Ex Vivo Approach

The study was performed to assess and rationalize the traditional utilization of the fruit part of Grewia tenax (G. tenax). The phytoconstituents present in the methanolic extract were analyzed using Gas-Chromatography-Mass Spectroscopy (GC-MS), while the anti-diarrheal activity was investigated in the Swiss albino mice against castor oil-provoked diarrhea in vivo. The antispasmodic effect and the possible pharmacodynamics of the observed antispasmodic effect were determined in an isolated rat ileum using the organ bath setup as an ex vivo model. GC-MS findings indicate that G. tenax is rich in alcohol (6,6-dideutero-nonen-1-ol-3) as the main constituent (20.98%), while 3-Deoxy-d-mannoic lactone (15.36%) was detected as the second major constituents whereas methyl furfural, pyranone, carboxylic acid, vitamin E, fatty acid ester, hydrocarbon, steroids, sesquiterpenes, phytosterols, and ketones were verified as added constituents in the methanolic extract. In mice, the orally administered G. tenax inhibited the diarrheal episodes significantly (p < 0.05) at 200 mg/kg (40% protection), and this protection was escalated to 80% with the next higher dose of 400 mg/kg. Loperamide (10 mg/kg), a positive control drug, imparted 100% protection, whereas no protection was shown by saline. In isolated rat ileum, G. tenax completely inhibited the carbamylcholine (CCh; 1 µM) and KCl (high K+; 80 mM)-evoked spasms in a concentrations-mediated manner (0.03 to 3 mg/mL) by expressing equal potencies (p > 0.05) against both types of evoked spasms, similar to papaverine, having dual inhibitory actions at phosphodiesterase enzyme (PDE) and Ca2+ channels (CCB). Similar to papaverine, the inhibitory effect of G. tenax on PDE was further confirmed indirectly when G. tenax (0.1 and 0.3 mg/mL) preincubated ileal tissues shifted the isoprenaline-relaxation curve towards the left. Whereas, pre-incubating the tissue with 0.3 and 1 mg/mL of G. tenax established the CCB-like effect by non-specific inhibition of CaCl2–mediated concentration-response curves towards the right with suppression of the maximum peaks, similar to verapamil, a standard CCB. Thus, the present investigation revealed the phytochemical constituents and explored the detailed pharmacodynamic basis for the curative use of G. tenax in diarrhea and hyperactive gut motility disorders

Polyunsaturated Fatty Acids Mediated Regulation of Membrane Biochemistry and Tumor Cell Membrane Integrity

Particular dramatic macromolecule proteins are responsible for various cellular events in our body system. Lipids have recently recognized a lot more attention of scientists for understanding the relationship between lipid and cellular function and human health However, a biological membrane is formed with a lipid bilayer, which is called a P–L–P design. Our body system is balanced through various communicative signaling pathways derived from biological membrane proteins and lipids. In the case of any fatal disease such as cancer, the biological membrane compositions are altered. To repair the biological membrane composition and prevent cancer, dietary fatty acids, such as omega-3 polyunsaturated fatty acids, are essential in human health but are not directly synthesized in our body system. In this review, we will discuss the alteration of the biological membrane composition in breast cancer. We will highlight the role of dietary fatty acids in altering cellular composition in the P–L–P bilayer. We will also address the importance of omega-3 polyunsaturated fatty acids to regulate the membrane fluidity of cancer cells

In Silico and Ex Vivo Studies on the Spasmolytic Activities of Fenchone Using Isolated Guinea Pig Trachea

Fenchone is a bicyclic monoterpene found in a variety of aromatic plants, including Foeniculum vulgare and Peumus boldus, and is used in the management of airways disorders. This study aimed to explore the bronchodilator effect of fenchone using guinea pig tracheal muscles as an ex vivo model and in silico studies. A concentration-mediated tracheal relaxant effect of fenchone was evaluated using isolated guinea pig trachea mounted in an organ bath provided with physiological conditions. Sustained contractions were achieved using low K+ (25 mM), high K+ (80 mM), and carbamylcholine (CCh; 1 µM), and fenchone inhibitory concentration–response curves (CRCs) were obtained against these contractions. Fenchone selectively inhibited with higher potency contractions evoked by low K+ compared to high K+ with resultant EC50 values of 0.62 mg/mL (0.58–0.72; n = 5) and 6.44 mg/mL (5.86–7.32; n = 5), respectively. Verapamil (VRP) inhibited both low and high K+ contractions at similar concentrations. Pre-incubation of the tracheal tissues with K+ channel blockers such as glibenclamide (Gb), 4-aminopyridine (4-AP), and tetraethylammonium (TEA) significantly shifted the inhibitory CRCs of fenchone to the right towards higher doses. Fenchone also inhibited CCh-mediated contractions at comparable potency to its effect against high K+ [6.28 mg/mL (5.88–6.42, n = 4); CCh] and [6.44 mg/mL (5.86–7.32; n = 5); high K+]. A similar pattern was obtained with papaverine (PPV), a phosphodiesterase (PDE), and Ca2+ inhibitor which inhibited both CCh and high K+ at similar concentrations [10.46 µM (9.82–11.22, n = 4); CCh] and [10.28 µM (9.18–11.36; n = 5); high K+]. However, verapamil, a standard Ca2+ channel blocker, showed selectively higher potency against high K+ compared to CCh-mediated contractions with respective EC50 values of 0.84 mg/mL (0.82–0.96; n = 5) 14.46 mg/mL (12.24–16.38, n = 4). The PDE-inhibitory action of fenchone was further confirmed when its pre-incubation at 3 and 5 mg/mL potentiated and shifted the isoprenaline inhibitory CRCs towards the left, similar to papaverine, whereas the Ca2+ inhibitory-like action of fenchone pretreated tracheal tissues were authenticated by the rightward shift of Ca2+ CRCs with suppression of maximum response, similar to verapamil, a standard Ca2+ channel blocker. Fenchone showed a spasmolytic effect in isolated trachea mediated predominantly by K+ channel activation followed by dual inhibition of PDE and Ca2+ channels. Further in silico molecular docking studies provided the insight for binding of fenchone with Ca2+ channel (−5.3 kcal/mol) and K+ channel (−5.7), which also endorsed the idea of dual inhibition

Calcium Channel Inhibitory Effect of Marjoram (Origanum majorana L.): Its Medicinal Use in Diarrhea and Gut Hyperactivity

Background: The leaves of Origanum majorana (O. majorana) are traditionally renowned for treating diarrhea and gut spasms. This study was therefore planned to evaluate its methanolic extract. Methods: Gas chromatography–mass spectrometry (GC-MS) was used to identify the phytochemicals, and Swiss albino mice were used for an in vivo antidiarrheal assay. Isolated rat ileum was used as an ex vivo assay model to study the possible antispasmodic effect and its mechanism(s). Results: The GC-MS analysis of O. majorana detected the presence of 21 compounds, of which alpha-terpineol was a major constituent. In the antidiarrheal experiment, O. majorana showed a substantial inhibitory effect on diarrheal episodes in mice at an oral dosage of 200 mg/kg, resulting in 40% protection. Furthermore, an oral dosage of 400 mg/kg provided even greater protection, with 80% effectiveness. Similarly, loperamide showed 100% protection at oral doses of 10 mg/kg. O. majorana caused complete inhibition of carbachol (CCh, 1 µM) and high K+ (80 mM)-evoked spasms in isolated ileal tissues by expressing significantly higher potency (p < 0.05) against high K+ compared to CCh, similar to verapamil, a Ca++ antagonist. The verapamil-like predominant Ca++ ion inhibitory action of O. majorana was further confirmed in the ileal tissues that were made Ca++-free by incubating the tissues in a physiological salt solution having ethylenediaminetetraacetic acid (EDTA) as a chelating agent. The preincubation of O. majorana at increasing concentrations (0.3 and 1 mg/mL) shifted towards the right of the CaCl2-mediated concentration-response curves (CRCs) with suppression of the maximum contraction. Similarly, verapamil also caused non-specific suppression of Ca++ CRCs towards the right, as expected. Conclusions: Thus, this study conducted an analysis to determine the chemical constituents of the leaf extract of O. majorana and provided a detailed mechanistic basis for the medicinal use of O. majorana in hyperactive gut motility disorders

Effects of Essential Oils of Elettaria cardamomum Grown in India and Guatemala on Gram-Negative Bacteria and Gastrointestinal Disorders

The present study examined the chemical composition and antimicrobial and gastrointestinal activity of the essential oils of Elettaria cardamomum (L.) Maton harvested in India (EC-I) and Guatemala (EC-G). Monoterpenes were present in higher concentration in EC-I (83.24%) than in EC-G (73.03%), whereas sesquiterpenes were present in a higher concentration in EC-G (18.35%) than in EC-I (9.27%). Minimum inhibitory concentrations (MICs) of 0.5 and 0.25 mg/mL were demonstrated against Pseudomonas aeruginosa in EC-G and EC-I, respectively, whereas MICs of 1 and 0.5 mg/mL were demonstrated against Escherichia coli in EC-G and EC-I, respectively. The treatment with control had the highest kill-time potential, whereas the treatment with oils had shorter kill-time. EC-I was observed to be more potent in the castor oil-induced diarrhea model than EC-G. At 100 and 200 mg/kg, P.O., EC-I exhibited 40% and 80% protection, respectively, and EC-G exhibited 20% and 60% protection, respectively, in mice, whereas loperamide (10 mg/kg, i.p., positive control) exhibited 100% protection. In the in vitro experiments, EC-I inhibited both carbachol (CCh, 1 µM) and high K+ (80 mM)-induced contractions at significantly lower concentrations than EC-G. Thus, EC-I significantly inhibited P. aeruginosa and E. coli and exhibited more potent antidiarrheal and antispasmodic effects than EC-G

Dual Inhibition of Phosphodiesterase and Ca⁺⁺ Channels Explains the Medicinal Use of <i>Balanites aegyptiaca</i> (L.) in Hyperactive Gut Disorders

The present study attempted to evaluate and rationalize the medicinal use of the methanolic extract of the fruits of Balanites aegyptiaca (B. aegyptiaca) in the treatment of hyperactive gut disorders. The in vivo, castor oil-induced diarrhea model in mice was followed to test its antidiarrheal effect. To test the antispasmodic effect and to explore its pharmacodynamic details, isolated small intestines (ileum) obtained from rats were selected to provide physiological conditions for the ex vivo assays. In the in vivo assays, the orally administered extract of B. aegyptiaca protected mice from diarrheal drops with resultant percent inhibitions of 40% and 80% at the respective doses of 200 mg/kg and 400 mg/kg, while the highest protection (100%) was observed with a positive control drug, loperamide, at 10 mg/kg. In the ileum, B. aegyptiaca produced an antispasmodic effect in a concentration-dependent manner by inhibiting the carbachol (CCh; 1 µM) and high K+ (80 mM)-evoked spasms with resultant EC50 values of 1.44 mg/mL (1.08–1.78) and 1.27 mg/mL (0.98–1.66), respectively. Papaverine, a known phosphodiesterase enzyme (PDE) inhibitor and blocker of Ca++ channels (CCB), also inhibited both CCh and high K+ induced contractions at comparable EC50 values of 8.72 µM (7.92–9.24) and 8.14 µM (7.62–8.84), respectively. Contrary to the extract and papaverine, verapamil showed distinctly higher potency in regard to inhibiting high K+, compared to CCh-evoked spasms that had EC50 values of 0.16 µM (0.13–0.261) and 2.54 µM (2.28–2.92), respectively. The inhibitory effects of B. aegyptiaca on PDE were further confirmed when the pre-incubated extract shifted the isoprenaline-mediated relaxation curves (CRCs) towards the left, similar to papaverine, whereas the CCB-like effect was confirmed when the pre-incubated tissues with B. aegyptiaca caused deflection in the Ca++ CRCs towards the right, constructed in Ca++ free medium with suppression of the maximum response. Thus, this study provides detailed, mechanistic support for the medicinal use of B. aegyptiaca in the treatment of hyperactive gut disorders

An Overview of Nanoemulgels for Bioavailability Enhancement in Inflammatory Conditions via Topical Delivery

The anti-inflammatory drugs that are generally available possess the disadvantage of hydrophobicity, which leads to poor permeability and erratic bioavailability. Nanoemulgels (NEGs) are novel drug delivery systems that aim to improve the solubility and permeability of drugs across the biological membrane. The nano-sized droplets in the nanoemulsion enhance the permeation of the formulation, along with surfactants and co-surfactants that act as permeation enhancers and can further improve permeability. The hydrogel component of NEG helps to increase the viscosity and spreadability of the formulation, making it ideal for topical application. Moreover, oils that have anti-inflammatory properties, such as eucalyptus oil, emu oil and clove oil, are used as oil phases in the preparation of the nanoemulsion, which shows a synergistic effect with active moiety and enhances its overall therapeutic profile. This leads to the creation of hydrophobic drugs that possess enhanced pharmacokinetic and pharmacodynamic properties, and simultaneously avoid systemic side effects in individuals with external inflammatory disorders. The nanoemulsion’s effective spreadability, ease of application, non-invasive administration, and subsequent ability to achieve patient compliance make it more suitable for topical application in the combat of many inflammatory disorders, such as dermatitis, psoriasis, rheumatoid arthritis, osteoarthritis and so on. Although the large-scale practical application of NEG is limited due to problems regarding its scalability and thermodynamic instability, which arise from the use of high-energy approaches during the production of the nanoemulsion, these can be resolved by the advancement of an alternative nanoemulsification technique. Considering the potential advantages and long-term benefits of NEGs, the authors of this paper have compiled a review that elaborates the potential significance of utilizing nanoemulgels in a topical delivery system for anti-inflammatory drugs