Targeting GLI1 and BAX by nanonoscapine could impede prostate adenocarcinoma progression.

Prostate cancer as a critical global health issue, requires the exploration of a novel therapeutic approach. Noscapine, an opium-derived phthalide isoquinoline alkaloid, has shown promise in cancer treatment thanks to its anti-tumorigenic properties. However, limitations such as low bioavailability and potential side effects have hindered its clinical application. This study introduces nanonoscapine as a novel medication to overcome these challenges, leveraging the advantages of improved drug delivery and efficacy achieved in nanotechnology. We monitored the effects of nanonoscapine on the androgen-sensitive human prostate adenocarcinoma cell line, LNCaP, investigating its impact on GLI1 and BAX genes' expressions, crucial regulators of cell cycle and apoptosis. Our findings, from MTT assays, flow cytometry, and gene expression analyses, have demonstrated that nanonoscapine effectively inhibits prostate cancer cell proliferation by inducing G2/M phase arrest and apoptosis. Furthermore, through bioinformatics and computational analyses, we have revealed the underlying molecular mechanisms, underscoring the therapeutic potential of nanonoscapine in enhancing patient outcomes. This study highlights the significance of nanonoscapine as an alternative or adjunct treatment to conventional chemotherapy, warranting further investigation in clinical settings.

Identification of plant based potential antifungal compounds against BMK-1 protein of Bipolaris oryzae using molecular docking approach.

Rice brown spot is an important disease of rice worldwide that inflicts substantial yield losses. The antimicrobial potential of methanol, acetone and dimethyl sulfoxide (DMSO) extracts of different medicinal plants, viz., Syzygium aromaticum, Saussurea costus, Acorus calamus, Bergenia ciliate, Geranium pratense, Mentha longifolia, Inula racemosa, Podophyllum hexandrum, Heracleum candicans and Picrorhiza kurroa, against the brown spot pathogen Bipolaris oryzae in vitro was evaluated via mycelial growth inhibition and spore germination inhibition assays. Among the plant extracts tested, 100% mycelial inhibition was observed for the methanol extract of Syzygium aromaticum at all three concentrations (2000 ppm, 3000 ppm and 4000 ppm), followed by the methanol extract of Inula racemosa (90.33%) at 4000 ppm. A maximum conidial germination inhibition of 83.54% was exhibited by the Heracleum candicans leaf extract. Phytochemical profiling of Syzygium aromaticum and Inula racemosa through liquid chromatography and mass spectrometry (HR-LCMS) revealed the presence of several compounds, such as eugenol, ursolic acid, quercetin, chlorogenic acid, and noscapine. A molecular docking approach was used to identify key inhibitory molecules against B. oryzae. Among the compounds detected in S. aromaticum and Inula racemosa, ursolic acid and noscapine were found to have the greatest binding affinity for the Big Mitogen Activated Protein Kinase (BMK-1) enzyme present in B. oryzae. In conclusion, S. aromaticum and Inula racemosa are potent compounds that could serve as lead compounds for drug discovery in the future.

Using chitosan-coated magnetite nanoparticles as a drug carrier for opioid delivery against breast cancer.

Over the past decades, opium derivatives have been discovered as new anticancer agents. In our study, Fe3O4 superparamagnetic nanoparticles (SPIONs) decorated with chitosan were loaded with papaverine or noscapine to surmount drug delivery-related obstacles. Modifying the magnetic nanoparticles (MNP) surface with polymeric materials such as chitosan prevents oxidation and provides a site for drug linkage, which renders them a great drug carrier. The obtained systems were characterized by DLS (20-40 nm were achieved for MNPs and drug- loaded MNPs), TEM (spherical with average size of 11-20 nm) FTIR, XRD, and VSM (71.3 - 42.8 emu/g). Contrary to noscapine, papaverine-MNPs attenuated 4T1 murine breast cancer cell proliferation (11.50 ± 1.74 µg/mL) effectively compared to the free drug (62.35 ± 2.88 µg/mL) while sparing L-929 fibroblast cells (138.14 ± 4.38 µg/mL). Furthermore, SPION and SPION-chitosan displayed no cytotoxic activity. Colony-formation assay confirmed the long-term cytotoxicity of nanostructures. Both developed formulations promoted ROS production accompanied by late apoptotic cell death. The biocompatible nanoparticle exerted an augmenting effect to deliver papaverine to metastatic breast cancer cells.

Noscapine modulates hypoxia-induced angiogenesis and hemodynamics: Insights from a zebrafish model investigation.

We investigated the angiogenesis-modulating ability of noscapine in vitro using osteosarcoma cell line (MG-63) and in vivo using a zebrafish model. MTT assay and the scratch wound healing assay were performed on the osteosarcoma cell line (MG-63) to analyze the cytotoxic effect and antimigrative ability of noscapine, respectively. We also observed the antiangiogenic ability of noscapine on zebrafish embryos by analyzing the blood vessels namely the dorsal aorta, and intersegmental vessels development at 24, 48, and 72 h postfertilization. Real-time polymerase chain reaction was used to analyze the hypoxia signaling molecules' gene expression in MG-63 cells and zebrafish embryos. The findings from the scratch wound healing demonstrated that noscapine stopped MG-63 cancer cells from migrating under both hypoxia and normoxia. Blood vessel development and the heart rate in zebrafish embryos were significantly reduced by noscapine under both hypoxia and normoxia which showed the hemodynamics impact of noscapine. Noscapine also downregulated the cobalt chloride (CoCl2) induced hypoxic signaling molecules' gene expression in MG-63 cells and zebrafish embryos. Therefore, noscapine may prevent MG-63 cancer cells from proliferating and migrating, as well as decrease the formation of new vessels and the production of growth factors linked to angiogenesis in vivo under both normoxic and hypoxic conditions.

Noscapine and Apoptosis in Breast and Other Cancers.

Breast cancer is the second leading contributor to the age-standardized mortality rate, for both sexes and all ages worldwide. In Europe and the United States, it is the second leading cause of mortality, with an incidence rate of about 2.6 million cases per year. Noscapine, a well-known alkaloid used as a cough suppressant, demonstrated anti-tumor effects by triggering apoptosis in various cancer cell lines and has the potential to become another ally against breast, ovarian, colon, and gastric cancer, among other types of malignancy. Apoptosis plays a crucial role in the treatment of cancer. Noscapine affected BAX, CASP8, CASP9, NFKBIA, and RELA gene and protein expression in the MCF-7 and MDA-MB-231 cell lines. Gene expression was higher in tumor than in normal tissue, including the BAX expression levels in lung, ovary, endometrium, colon, stomach, and glioblastoma patients; BCL2L1 expression in endometrium, colon, and stomach patients; CASP8 gene expression levels in lung, endometrium, colon, stomach, and glioblastoma patients; RELA in colon, stomach, and glioblastoma patients; and NFKBIA in glioblastoma patients. It can be concluded that noscapine affected genes and proteins related to apoptosis in cancer cell lines and several types of cancer patients.

Evaluation of Anti-Nociceptive, Anti-Inflammatory, and Anti-Fibrotic effects of noscapine against a rat model of Achilles tendinopathy.

During tendinopathy, prolonged inflammation results in fibrosis and the adherence of tendons to the adjacent tissues, causing discomfort and movement disorders. As a natural compound, noscapine has several anti-inflammatory and anti-fibrotic properties. Therefore, we aimed to investigate the effects of noscapine against a rat model of tendinopathy. We created a surgical rat model of Achilles tendon damage to emulate tendinopathy. Briefly, an incision was made on the Achilles tendon, and it was then sutured using an absorbable surgical thread. Immediately, the injured area was topically treated with the vehicle, noscapine (0.2, 0.6, and 1.8 mg/kg), or dexamethasone (0.1 mg/kg) as a positive control. During the 19-day follow-up period, animals were assessed for weight, behavior, pain, and motor coordination testing. On day 20th, the rats were sacrificed, and the tendon tissue was isolated for macroscopic scoring, microscopic (H&E, Masson's trichrome, Ki67, p53) analyses, and cytokine secretion levels. The levels of macroscopic parameters, including thermal hyperalgesia, mechanical and cold allodynia, deterioration of motor coordination, tendon adhesion score, and microscopic indices, namely histological adhesion, vascular prominence and angiogenesis, and Ki67 and p53 levels, as well as fibrotic and inflammatory biomarkers (IL-6, TNF-α, TGF-ß, VEGF) were significantly increased in the vehicle group compared to the sham group (P < 0.05-0.001 for all cases). In contrast, the administration of noscapine (0.2, 0.6, and 1.8 mg/kg) attenuated the pain, fibrosis, and inflammatory indices in a dose-dependent manner compared to the vehicle group (P < 0.05-0.001). Histological research indicated that noscapine 0.6 and 1.8 mg/kg had the most remarkable healing effects. Interestingly, two higher doses of noscapine had impacts similar to those of the positive control group in both clinical and paraclinical assessments. Taken together, our findings suggested that noscapine could be a promising medicine for treating tendinopathies.

Preparation and characterization of solid lipid nanoparticles encapsulated noscapine and evaluation of its protective effects against imiquimod-induced psoriasis-like skin lesions.

Psoriasis is a chronic inflammatory skin disease characterized by thickening the epidermis with erythema, scaling, and proliferation. Noscapine (NOS) has several anti-inflammatory, anti-angiogenic, and anti-fibrotic effects, but its low solubility and large size results in its lower efficacy in the clinic. In this regard, solid lipid nanoparticles (SLN) encapsulated NOS (SLN-NOS) were fabricated using the well-known response surface method based on the central composite design and modified high-shear homogenization and ultrasound method. As a result, Precirol® was selected as the best lipid base for the SLN formulation based on Hildebrand-Hansen solubility parameters, in which SLN-NOS 1 % had the best zeta potential (-35.74 ± 2.59 mV), average particle size (245.66 ± 17 nm), polydispersity index (PDI, 0.226 ± 0.09), high entrapment efficiency (89.77 %), and ICH-based stability results. After 72 h, the SLN-NOS 1 % released 83.23 % and 58.49 % of the NOS at pH 5.8 and 7.4, respectively. Moreover, Franz diffusion cell's results indicated that the skin levels of NOS for SLN and cream formulations were 46.88 % and 13.5 % of the total amount, respectively. Our pharmacological assessments revealed that treatment with SLN-NOS 1 % significantly attenuated clinical parameters, namely ear thickness, length, and psoriasis area and severity index, compared to the IMQ group. Interestingly, SLN-NOS 1 % reduced the levels of interleukin (IL)-17, tumor necrosis factor-α, and transforming growth factor-ß, while elevating IL-10, compared to the IMQ group. Histology studies also showed that topical application of SLN-NOS 1 % significantly decreased parakeratosis, hyperkeratosis, acanthosis, and inflammation compared to the IMQ group. Taken together, SLN-NOS 1 % showed a high potential to attenuate skin inflammation.

Exploration of efficacy, cellular responses, and safety profile of novel 9-(3-Pyridyl) noscapine derivatives as promising anticancer candidates.

This study presented a novel derivative of the antitussive compound noscapine, named 9-3-Pyridyl noscapine (PYNos), to enhance its anticancer potential. Through in silico investigations, PYNos exhibited strong interactions with microtubules, inhibiting cancer cell proliferation both alone and in combination with docetaxel. Docking scores highlighted the affinity of PYNos -5.67 kcal/mol and docetaxel -4.94 kcal/mol to microtubules. When docked with tubulin-DOX co-complex, PYNos displayed a synergistic score of -8.99 kcal/mol. MTT assays on MCF-7 breast cancer cells showed PYNos IC50 values of 11.0 µM (48 h) and 8.4 µM (72 h), while docetaxel had three orders of magnitude lower IC50 values: 0.028 µM (48 h) and 0.015 µM (72 h). Combining PYNos (25 µM) and docetaxel (0.01 µM) reduced proliferation by 50% at both time points. Isobologram analysis confirmed strong antiproliferative synergy (sum FIC <1) at 48 and 72 h. Our comprehensive evaluation encompassing apoptosis and cell cycle arrest patterns further validated the synergistic advantages of this combination. In a xenograft mice model using MCF-7 cells, the PYNos-docetaxel co-treatment resulted in significant tumor regression, showcasing promising induction of apoptosis while mitigating docetaxel-associated toxicity. In summary, our findings underscore the substantial microtubule interactions facilitated by 9-3-Pyridyl noscapine, revealing its synergistic potential with docetaxel and establishing a solid foundation for advancing cancer therapeutic strategies.Communicated by Ramaswamy H. Sarma.

Impact of noscapine on halting the progression of pentylenetetrazole induced kindling epilepsy in mice.

Epilepsy is caused by an excessive recurrent excitatory neuronal firing, characterized by motor, psychomotor, and sensory impairments. Current therapies fail to produce 100% outcomes because of the complexity of the disease, poor diagnosis, and upsurge to drug-resistant epilepsy. The study repurposed the drug 'noscapine' mainly known for its anti-tussive properties. For the management of epilepsy and its associated secondary complications. To confirm the effect of noscapine, adult mice were injected with pentylenetetrazole (PTZ) (35 mg/kg i.p.) on an alternate day for 29 days to induce epilepsy. Animals were pretreated with noscapine in three doses (5, 10, and 20 mg/kg i.p.) for 33 days. Various behavioural assessments like the open field test, Morris water maze, and tail suspension test were performed to observe animals' locomotor activity, spatial memory, and anxiety-depressive behaviour. On the 34th day, animals were sacrificed, and brains were removed for biochemical estimations. Prolonged PTZ treatment reduced locomotor, learning activity, and increased anxiety-depressive behaviour, which was further confirmed by reduced antioxidant levels such as reduced glutathione (GSH), superoxide dismutase (SOD), and catalase because of increased oxido-nitrosative stress, that is, malondialdehyde (MDA) and nitrite in the brain. In comparison, noscapine pretreatment attenuated PTZ-induced behavioural and biochemical changes in the animals. The results indicate that noscapine ameliorates the oxido-nitrosative stress. However, studies indicate that oxido-nitrosative stress is a significant concern for the GABAergic neurons and promotes the disease progression. Further studies are required to explore the molecular mechanism of noscapine, which might be a practical approach as a newer antiepileptic agent.

A promising impact of oral administration of noscapine against imiquimod-induced psoriasis-like skin lesions.

Objective: Psoriasis is a chronic inflammatory autoimmune disease. The effectiveness of noscapine has been employed as a helpful treatment for various disorders and subjected to recent theoretical breakthroughs. Materials and Methods: Psoriasis-like lesions were induced by topical application of 5% imiquimod (IMQ) (10 mg/cm2 of skin) in male Balb/c mice and then medicated with a single oral dose of methotrexate (MET) as a positive control or daily oral treatment of noscapine (5, 15 and 45 mg/kg). In this way, skin inflammation intensity, psoriatic itchiness, psoriasis area severity index (PASI) score, ear length, thickness, and organ weight were daily measured. At the end of the study, histological and immunohistochemical and enzyme-linked immunosorbent assays (ELISA, for pro-/anti-inflammatory factors) were performed in each ear. Results: IMQ caused psoriasis-like lesions. Noscapine markedly alleviated macroscopic parameters, namely ear thickness, ear length, skin inflammation, itching, and organ weight, as well as microscopic parameters including, pathology and Ki67 and p53, and tissue immunological mediators, such as tumour necrosis factor (TNF-α), interleukin (IL)-10, transforming growth factor (TGF-ß), interferon-γ (IFN-γ), IL-6, IL-17, and IL-23p19 in the psoriatic skin in a concentration manner (p<0.05-<0.001). Conclusion: Therefore, noscapine with good pharmacological properties has considerable effects on psoriasis inflammation.

Comparative assessment of 9-bromo noscapine ionic liquid and noscapine: Synthesis, in-vitro studies plus computational & biophysical evaluation with human hemoglobin.

Noscapine is a proficient anticancer drug active against wide variety of tumors including lung cancer. Over time, several noscapine analogues have been assessed to maximize the efficiency of the drug, amongst which 9-bromo noscapine remains one of the most potent analogues till date. In the present work, we have synthesized 9-bromo noscapine ionic liquid [9-Br-Nos]IBr2, an active pharmaceutical ingredient based ionic liquid (API-IL) to address the existing issues of solubility and targeted drug delivery in the parent alkaloid as well as the synthesized analogues. We have devised a novel two-step synthesis route (first-ever ionic to ionic bromination) to obtain the desired [9-Br-Nos]IBr2 which is advantageous to its organic analogue in terms of increased solubility, lesser reaction time and better yield. Furthermore, we have compared 9-bromo noscapine ionic liquid with noscapine based on its binding interaction with human hemoglobin (Hb) studied via computational along with spectroscopic studies, and bioactivity against non-small cell lung cancer. We inferred formation of a complex between [9-Br-Nos]IBr2 and Hb in the stoichiometric ratio of 1:1, similar to noscapine. At 298 K, [9-Br-Nos]IBr2-Hb binding was found to exhibit Kb and ∆G of 36,307 M-1 and -11.5 KJmol-1, respectively, as compared to 159 M-1 and -12.5 KJmol-1 during Noscapine-Hb binding. This indicates a more stronger and viable interaction between [9-Br-Nos]IBr2 and Hb than the parent compound. From computational studies, the observed higher stability of [9-Br-Nos]I and better binding affinity with Hb with a binding energy of -91.75 kcalmol-1 supported the experimental observations. In the same light, novel [9-Br-Nos]IBr2 was found to exhibit an IC50 = 95.02 ± 6.32 µM compared to IC50 = 128.82 ± 2.87 µM for noscapine on A549 (non-small lung cancer) cell line at 48 h. Also, the desired ionic liquid proved to be more cytotoxic inducing a mortality rate of 87 % relative to 66 % evoked by noscapine at concentrations of 200 µM after 72 h.

Network pharmacology and in vitro experiments reveal that Noscapine induces ROS-mediated apoptosis and cell cycle arrest via PI3K/Akt/FoxO3a signaling pathway in human bladder cancer cells.

BACKGROUND: Noscapine (NA) has been demonstrated to have antitussive and antitumoral activities. Nonetheless, the potential mechanism of action on Bladder Cancer (BLCA) is yet to be completely grasped. METHODS: The targets of NA action and bladder cancer disease targets were found by the database. Construct the PPI network. Subsequently, conduct pathway enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) on core targets. A "drug-disease-target-pathway" network map was made. Cytotoxicity was examined via CCK-8 and colony formation assays. Both a scratch test and a transwell assay confirmed that NA was capable of suppressing the invasiveness and migratory potential of bladder cancer cells. Hoechst 33342 staining was used to visualize NA-induced apoptosis in bladder cancer cells. Flow cytometry was employed to investigate the induction of apoptosis, the distribution of the cell cycle, the production of Reactive Oxygen Species (ROS), and the Mitochondrial Membrane Potential (MMP). The Western blot was applied to show the expression of proteins that are implicated in the pathway, cell cycle, apoptotic process, and proliferation. RESULTS: 198 Noscapine-BLCA-related targets were obtained. GO functional enrichment analysis yielded 428 entries (P < 0.05 and FDR < 0.05). KEGG pathway enrichment analysis identified 138 representative signaling pathways (P < 0.01 and FDR < 0.01). NA concentration-dependently suppressed cell growth and colony formation, along with the invasiveness and migratory potential of bladder cancer cells, by promoting apoptosis, a cell cycle arrest in the G2/M phase, generation of ROS, and depolarization of MMPs. In addition, Western blotting illustrated that NA down-regulated the protein levels associated with pathway, anti-apoptotic proteins, proliferation-related proteins, and cell cycle promoters but up-regulated pro-apoptotic proteins, cell cycle modulators, and Endoplasmic Reticulum (ER) stress expression. Pretreatment with Acetylcysteine N-acetyl-L-cysteine (NAC) and YS-49 counteracted the influence of NA on ROS induction and apoptosis. CONCLUSIONS: Noscapine induces ROS-mediated apoptosis and cell cycle arrest via PI3K/Akt/FoxO3a signaling pathway in human BLCA cells.

Rational design of novel microtubule targeting anticancer drugs N-imidazopyridine noscapinoids: Chemical synthesis and experimental evaluation based on in vitro using breast cancer cells and in vivo using xenograft mice model.

We present N-imidazopyridine-noscapinoids, a new class of noscapine derivatives that bind to tubulin and exhibit antiproliferative activity against triple positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. The N-atom of the isoquinoline ring of noscapine scaffold was altered in silico by coupling the imidazo [(Ye et al., 1998; Ke et al., 2000) 1,21,2-a] pyridine pharmacophore to rationally develop a series of N-imidazopyridine-noscapinoids (7-11) with high tubulin binding affinity. The predicted ΔGbinding of the N-imidazopyridine-noscapinoids 7-11 varied from -27.45 to -36.15 kcal/mol, a much lower value than noscapine with ΔGbinding -22.49 kcal/mol. The cytotoxicity of N-imidazopyridine-noscapinoids was evaluated using hormone dependent MCF-7, triple negative MDA-MB-231 breast cancer cell lines and primary breast cancer cells. The cytotoxicity of these compounds (represented as IC50 concentration) ranges between 4.04 and 33.93 µM against breast cancer cells without affecting normal cells (IC50 value > 952 µM). All the compounds (7-11) perturbed the cell cycle progression at G2/M phase and triggered apoptosis. Among all the N-imidazopyridine-noscapinoids, N-5-Bromoimidazopyridine-noscapine (9) showed promising antiproliferative activity and was selected for detailed investigation. The onset of apoptosis treated with 9 using MDA-MB-231 revealed morphological changes like cellular shrinkage, chromatin condensation, membrane blebbing, and apoptotic bodies formation. Along with elevated reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting induction of apoptosis to cancer cells. Compound 9 was also found to significantly regress the implanted tumour in nude mice as xenografts of MCF-7 cells without any apparent side effects after drug administration. We conclude that N-imidazopyridine-noscapinoids possess excellent potential as a promising drug for treating breast cancers.

Reduced acetylated α-tubulin in SPAST hereditary spastic paraplegia patient PBMCs.

HSP-SPAST is the most common form of hereditary spastic paraplegia (HSP), a neurodegenerative disease causing lower limb spasticity. Previous studies using HSP-SPAST patient-derived induced pluripotent stem cell cortical neurons have shown that patient neurons have reduced levels of acetylated α-tubulin, a form of stabilized microtubules, leading to a chain of downstream effects eventuating in increased vulnerability to axonal degeneration. Noscapine treatment rescued these downstream effects by restoring the levels of acetylated α-tubulin in patient neurons. Here we show that HSP-SPAST patient non-neuronal cells, peripheral blood mononuclear cells (PBMCs), also have the disease-associated effect of reduced levels of acetylated α-tubulin. Evaluation of multiple PBMC subtypes showed that patient T cell lymphocytes had reduced levels of acetylated α-tubulin. T cells make up to 80% of all PBMCs and likely contributed to the effect of reduced acetylated α-tubulin levels seen in overall PBMCs. We further showed that mouse administered orally with increasing concentrations of noscapine exhibited a dose-dependent increase of noscapine levels and acetylated α-tubulin in the brain. A similar effect of noscapine treatment is anticipated in HSP-SPAST patients. To measure acetylated α-tubulin levels, we used a homogeneous time resolved fluorescence technology-based assay. This assay was sensitive to noscapine-induced changes in acetylated α-tubulin levels in multiple sample types. The assay is high throughput and uses nano-molar protein concentrations, making it an ideal assay for evaluation of noscapine-induced changes in acetylated α-tubulin levels. This study shows that HSP-SPAST patient PBMCs exhibit disease-associated effects. This finding can help expedite the drug discovery and testing process.

Biochemical interaction of human hemoglobin with ionic liquids of noscapinoids: Spectroscopic and computational approach.

In this work, we have developed noscapine based ionic liquids i.e., Noscapine (MeNOS) and 9-Bromonoscapine (MeBrNOS) as cation supported with bis(trifluoromethylsulfonyl)amide (NTf2-) as anion. We have reported the mechanism of binding interaction between noscapine based ILs and human hemoglobin (Hb) using various spectroscopic and computational techniques. The corresponding thermodynamics studies showed that the binding is exothermic in nature and major forces responsible for binding are Van der waals and hydrogen bonding interaction. The fluorescence spectra showed that the intensity of Hb decreases in the presence of [MeNOS]NTf2 and [MeBrNOS]NTf2 both shows static quenching. The secondary structural changes in Hb were observed and calculated by using CD spectroscopy. Molecular docking studies revealed that both the ILs show strong binding in ß1 fragment of the tetrameric structure of Hb, but the binding of [MeNOS]NTf2 is relatively stronger than [MeBrNOS]NTf2 and the results are supported by MD simulations.

Evaluation of noscapine-licorice combination effects on cough relieving in COVID-19 outpatients: A randomized controlled trial.

Background: As February 2023, SARS-CoV-2 is still infecting people and children worldwide. Cough and dyspnea are annoying symptoms almost present in a large proportion of COVID-19 outpatients, and the duration of these symptoms might be long enough to affect the patients' quality of life. Studies have shown positive effects for noscapine plus licorice in the previous COVID-19 trials. This study aimed to assess the effects of the combination of noscapine and licorice-for relieving cough in outpatients with COVID-19. Methods: This randomized controlled trial was conducted on 124 patients at the Dr. Masih Daneshvari Hospital. Participants over 18 years of age with confirmed COVID-19 and cough were allowed to enter the study if the onset of symptoms was less than 5 days. The primary outcome was to assess the response to treatment over 5 days using the visual analogue scale. Secondary outcomes included the assessment of cough severity after 5 days using Cough Symptom Score, as well as the cough-related quality of life and dyspnea relieving. Patients in the noscapine plus licorice group received Noscough® syrup 20 mL every 6 h for 5 days. The control group received diphenhydramine elixir 7 mL every 8 h. Results: By day five, 53 (85.48%) patients in the Noscough® group and 49 (79.03%) patients in the diphenhydramine group had response to treatment. This difference was not statistically significant (p-value = 0.34). The presence of dyspnea was significantly lower in the Noscough® group versus diphenhydramine at day five (1.61% in the Noscough® group vs. 12.9% in the diphenhydramine group; p-value = 0.03). The cough-related quality of life and severity also significantly favored Noscough® syrup (p-values <0.001). Conclusion: Noscapine plus licorice syrup was slightly superior to diphenhydramine in relieving cough symptoms and dyspnea in the COVID-19 outpatients. The severity of cough and cough-related quality of life were also significantly better in the noscapine plus licorice syrup. Noscapine plus licorice may be a valuable treatment in relieving cough in COVID-19 outpatients.

Inhibition of Myeloperoxidase Pro-Fibrotic Effect by Noscapine in Equine Endometrium.

Myeloperoxidase is an enzyme released by neutrophils when neutrophil extracellular traps (NETs) are formed. Besides myeloperoxidase activity against pathogens, it was also linked to many diseases, including inflammatory and fibrotic ones. Endometrosis is a fibrotic disease of the mare endometrium, with a large impact on their fertility, where myeloperoxidase was shown to induce fibrosis. Noscapine is an alkaloid with a low toxicity, that has been studied as an anti-cancer drug, and more recently as an anti-fibrotic molecule. This work aims to evaluate noscapine inhibition of collagen type 1 (COL1) induced by myeloperoxidase in equine endometrial explants from follicular and mid-luteal phases, at 24 and 48 h of treatment. The transcription of collagen type 1 alpha 2 chain (COL1A2), and COL1 protein relative abundance were evaluated by qPCR and Western blot, respectively. The treatment with myeloperoxidase increased COL1A2 mRNA transcription and COL1 protein, whereas noscapine was able to reduce this effect with respect to COL1A2 mRNA transcription, in a time/estrous cycle phase-dependent manner (in explants from the follicular phase, at 24 h of treatment). Our study indicates that noscapine is a promising drug to be considered as an anti-fibrotic molecule to prevent endometrosis development, making noscapine a strong candidate to be applied in future endometrosis therapies.

Antiproliferative Noscapinoids Bearing an Amidothiadiazole Scaffold as Apoptosis Inducers: Design, Synthesis and Molecular Docking.

Noscapine an FDA-approved antitussive agent. With low cytotoxicity with higher concentrations, noscapine and its derivatives have been shown to have exceptional anticancer properties against a variety of cancer cell lines. In order to increase its potency, in this study, we synthesized a series of new amido-thiadiazol coupled noscapinoids and tested their cytotoxicity in vitro. All of the newly synthesised compounds demonstrated potent cytotoxic potential, with IC50 values ranging from 2.1 to 61.2 µM than the lead molecule, noscapine (IC50 value ranges from 31 to 65.5 µM) across all cell lines, without affecting normal cells (IC50 value is>300 µM). Molecular docking of all these molecules with tubulin (PDB ID: 6Y6D, resolution 2.20 Å) also revealed better binding affinity (docking score range from -5.418 to -9.679 kcal/mol) compared to noscapine (docking score is -5.304 kcal/mol). One of the most promising synthetic derivatives 6aa (IC50 value ranges from 2.5 to 7.3 µM) was found to bind tubulin with the highest binding affinity (ΔGbinding is -28.97 kcal/mol) and induced apoptosis in cancer cells more effectively.

Substrate-directed Synthesis of Isocoumarin and 3-Ylidenephthalide Conjugated Noscapinoids and their Antiproliferative Activities.

A series of new noscapinoids designed; synthesized and assessed whether its 3-ylidenephthalide and isocoumarin conjugates improved cytotoxicity. Cu-catalysed Sonogashira coupling of N-propargyl noscapine with 2-bromobenzoic acids followed by in-situ substrate-directed 5-exo-dig or 6-endo-dig cyclization produced 3-ylidenephthalide 6 a-6 f and isocoumarin 7 a-7 h analogues in very good yields. In comparison to the lead drug, noscapine, all the newly synthesised derivatives exhibited strong cytotoxic potential in vitro with IC50 ranging from 5.4 µM to 39.5 µM across the evaluated panel of cancer cell lines, without harming normal cells (IC50 >300 µM).

Insight into the Tubulin-Targeted Anticancer Potential of Noscapine and its Structural Analogs.

Cancer is known as a notorious disease responsible for threatening millions of lives every year. Natural products which act by disrupting the microtubule assembly and dynamics have proven to be highly successful as anticancer agents but their high toxicity owing to lower selectivity has limited their usage. Recently, Noscapine (NOS), a known anti-tussive, has come out to be an effective anti-tubulin candidate with far lesser toxicity. Since its first report as an anti-mitotic agent in 1998, NOS has been extensively studied and modified by various groups of researchers to optimize its anti-tubulin activity. In this review, the recent advancements about the potential of these therapeutic candidates against various cancers have been compiled and analyzed for their inhibitory mechanism in distinct health conditions. It has been observed that the non-polar substitutions (e.g., halides, aryl groups) at specific sites (9-position and N-sites of isoquinoline ring; and modification of a methoxy group) have an enhanced effect on efficacy. The mechanistic studies of NOS and its modified analogs have shown their inhibitory action primarily through interaction with microtubules dynamics thus disrupting the cell-cycle and leading to apoptosis. This review highlights the latest research in the field by providing a rich resource for the researchers to have a hands-on analysis of NOS analogs and the inhibitory action in comparison to other microtubule disrupting anti-cancer agents. The article also documents the newer investigations in studying the potential of noscapine analogs as possible anti-microbial and antiviral agents.