Pharmacological Efficacy Research Articles

Effect of Different Extraction Techniques on Phenolic Profile and Phytochemical Potential of Gymnema inodorum Leaf Extract.

The therapeutic potential of plant extracts has attracted significant interest, especially regarding indigenous species with health-promoting properties. Gymnema inodorum, native to Northern Thailand, is recognized for its rich phytochemical profile; however, the impact of various extraction techniques on its phenolic composition and bioactivity remains underexplored. Optimizing extraction methods is essential to enhance the pharmacological efficacy of this plant's bioactive compounds. This study investigated the influence of four extraction methods-ethanol maceration, ethanol reflux, aqueous decoction, and microwave-assisted extraction-on the bioactive profile of G. inodorum leaves, with a focus on the phenolic content and biological activities. Antioxidant activities were evaluated using DPPH, ABTS, and FRAP assays, while the total phenolic and flavonoid contents were quantified by colorimetric methods. High-Performance Liquid Chromatography (HPLC) quantified gymnemic acid and key phenolic compounds. Among the methods, ethanol reflux yielded the highest antioxidant activities (DPPH and ABTS scavenging), with a total phenolic content of 82.54 mg GAE/g and flavonoid content of 31.90 mg QE/g. HPLC analysis identified sinapic acid, myricetin, and p-hydroxybenzoic acid as major phenolics. Furthermore, the ethanol reflux extract displayed potent anti-diabetic activity, with IC50 values of 13.36 mg/mL for α-amylase and 7.39 mg/mL for α-glucosidase, as well as strong anti-inflammatory activity (IC50 of 1.6 mg/mL) and acetylcholinesterase inhibition (IC50 of 1.2 mg/mL). These findings suggest that ethanol reflux extraction is a highly effective method for producing bioactive-rich G. inodorum extracts, with substantial pharmacological potential for developing herbal remedies and nutraceuticals, particularly in enhancing therapeutic approaches for diabetes and other health-related conditions.

Application of Chalcone in the Structural Modification of Natural Products: An Overview.

Natural products frequently display a range of biological activities, yet many exhibit only moderate efficacy during initial evaluations. Often, these natural substances necessitate structural alterations to yield promising lead compounds. Chalcones, characterized by their β-unsaturated carbonyl aromatic ketone structure, are prevalent in plant life and serve as fundamental scaffolds for the biosynthetic precursors of flavonoids and isoflavones. Due to their straightforward synthesis and extensive spectrum of biological effects, chalcones have found extensive application in medicinal chemistry. Chalcone analogs have demonstrated significant potential for drug discovery and development, as structural modifications can both amplify pharmacological efficacy and effectively mitigate toxic side effects. This paper endeavors to delve into the applications of chalcones in the structural modification of natural products, providing a theoretical foundation for future endeavors in derivatization and drug development. The full paper is organized into categories based on the biological activities of the derivatives, including anti-dyslipidemic, antibacterial, antimalarial, anti-inflammatory, anticancer, anti-Alzheimer, and α-glucosidase inhibitory activities.

Beyond Essential Oils: Diterpenes, Lignans, and Biflavonoids from Juniperus communis L. as a Source of Multi-Target Lead Compounds.

Common Juniper (Juniperus communis L.) is a gymnosperm that stands out through its fleshy, spherical female cones, often termed simply "berries". The cone berries and various vegetative parts (leaves, twigs and even roots) are used in traditional phytotherapy, based on the beneficial effects exerted by a variety of secondary metabolites. While the volatile compounds of Juniperus communis are known for their aromatic properties and have been well-researched for their antimicrobial effects, this review shifts focus to non-volatile secondary metabolites-specifically diterpenes, lignans, and biflavonoids. These compounds are of significant biomedical interest due to their notable pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. The aim of this review is to offer an up-to-date account of chemical composition of Juniperus communis and related species, with a primary emphasis on the bioactivities of diterpenes, lignans, and biflavonoids. By examining recent preclinical and clinical data, this work assesses the therapeutic potential of these metabolites and their mechanisms of action, underscoring their value in developing new therapeutic options. Additionally, this review addresses the pharmacological efficacy and possible therapeutic applications of Juniperus communis in treating various human diseases, thus supporting its potential role in evidence-based phytotherapy.

Complete chloroplast genomes of three Polygala species and indel marker development for identification of authentic polygalae radix (Polygala tenuifolia).

In Korea, only Polygala tenuifolia is registered as Polygalae Radix in the pharmacopoeia, while in China, both P. tenuifolia and P. sibirica are used equally. Accurate identification of herbal medicines is crucial for their safety and efficacy, but commercial products are typically sold in dried form, making morphological distinction difficult. Therefore, a quick and accurate method to distinguish P. tenuifolia is necessary for proper utilization of medicinal herb. We aimed to identify specific molecular markers for P. tenuifolia to avoid confusion regarding its pharmacological efficacy and to evaluate the classification of Polygala using plastid phylogenetic data. We analyzed the sequences of three species distributed in Korea, P. tenuifolia, P. japonica, and P. sibirica, and assembled their chloroplast genome sequences. Comparative analysis revealed regions of local divergence, and six molecular markers were developed from these hotspots. Additionally, a phylogenetic tree was constructed to determine the phylogenetic positions of the three Polygala species. The marker successfully identified the three Polygala species, and all commercial products and breeding lines tested were confirmed to be P. tenuifolia and recognized as authentic. Phylogenetic analysis revealed that P. tenuifolia forms a distinct cluster from P. sibirica and P. japonica. We determined the chloroplast genomes of the three Polygala species and performed phylogenetic tree analysis and marker development. Indel markers were developed to identify the critical herbal species, P. tenuifolia. This comprehensive study of the Polygala chloroplast genome provides useful information for P. tenuifolia identification.

Epigenetic modifications associated to diabetic peripheral neuropathic pain (Review).

The present review aimed to provide an update on the scientific progress of the role of epigenetic modifications on diabetic peripheral neuropathic pain (DPNP). DPNP is a devastating and troublesome complication of diabetes mellitus (DM), which affects one third of patients with DM and causes severe hyperalgesia and allodynia, leading to challenges in the treatment of these patients. The pathophysiology of DPNP is multifactorial and is not yet fully understood and treatment options for this disease are currently unsatisfactory. The underlying mechanisms and pathophysiology of DPNP have largely been explored in animal models and a mechanism‑derived approach might offer a potential therapeutic‑target for attenuating certain phenotypes of DPNP. Altered gene expression levels within the peripheral or central nervous systems (CNS) are a crucial mechanism of DPNP, however, the transcriptional mechanisms of these genes have not been fully elucidated. Epigenetic modifications, such as DNA methylation and histone modifications (methylation, acetylation, or phosphorylation), can alter gene expression levels via chromatin remodeling. Moreover, it has been reported that altering gene expression via epigenetic modifications within the peripheral or CNS, contributes to the changes in both pain sensitivity and pharmacological efficacy in DPNP. Therefore, the present review summarized the findings of relevant literature on the epigenetic alterations in DPNP and the therapeutic potential for targeting these alterations in the future treatment of this disease.

In vitro inhibitory effect of berberine against rotavirus combined with its antioxidant, anti-inflammatory, and cytotoxicity activities.

Although berberine (BBR) is well known as a traditional medicine used in treatment of gastrointestinal diseases, its potent against viral gastroenteritis has not been specifically reported. This study aims to investigate the antiviral activity of BBR against rotavirus and evaluate its cytotoxicity and pharmacological efficacies, including antioxidant and anti-inflammatory activities in vitro. Using ultraviolet-visible absorption spectroscopy, the saturation concentration of BBR was determined as 2261 µg/mL, indicating that BBR is a poor water-soluble compound. The inhibition rate of NO production of BBR solution at a concentration of 238 µg/mL was similar to that of Cardamonin 0.3 µM with a cell viability of 92,46±0.35%, revealing the anti-inflammatory activity of BBR. The cytotoxicity of BBR solution depended on its concentration, whereby the 50% cytotoxicity concentration (CC50) of BBR after 96 h exposure was 664 µg/mL. Investigation of cytopathic effects (CPE) of MA104 cells treated with BBR and BBR-incubated rotavirus indicates that BBR could effectively inhibit the replication of rotavirus. CPEs were not observed in the cells inoculated with rotavirus (100TCID50) which was pre-incubated with BBR for 96 hours at BBR concentration of 283 µg/mL. Therefore, the study provides reliable results to demonstrate the ability of BBR to inhibit the replication of rotavirus.

DDDR-18. TARGETTING GLIOBLASTOMA MULTIFORME USING A MULTIACTION ANTICANCER ANTI-INFLAMMATORY THERAPEUTIC STRATEGY

Abstract Glioblastoma multiforme (GBM) represents a significant challenge in adult brain tumor management, characterized by its aggressive nature and poor prognosis despite multimodal therapies. Current standard chemotherapy, Temozolomide (TMZ), offers limited survival benefits. In a recent breakthrough, the cyclic peptide cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) acetate (c2), initially developed for prostate cancer, demonstrates remarkable promise against GBM. By selectively inhibiting the inflammatory phospholipase enzyme sPLA2IIA, c2 significantly impedes GBM cell proliferation, surpassing TMZ efficacy in multiple resistant cell lines. Moreover, c2 exhibits potential to inhibit tumor growth and metastasis, confirmed in 3D tumoroid and wound healing assays. Mechanistic insights reveal modulation of crucial cellular pathways, including viral entry, cytoskeletal structure, and signaling cascades. Preclinical investigations demonstrate c2’s ability to penetrate the blood-brain barrier and attenuate tumor progression markers. At multiple levels, c2 is shown to target inhibition of ERBB2 and EGFR signalling and also have impacts on HIF1-NF-kB axis. This study proposes c2 as a potent anti-GBM candidate, warranting evaluations for its pharmacological profile, safety, and efficacy. With its potential to address the urgent need for effective GBM therapies, c2 holds promise as a significant advancement in GBM treatment, offering hope for improved patient outcomes.

Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia

Glycogen storage disease type-Ia patients, deficient in the G6PC1 gene encoding glucose-6-phosphatase-α, lack blood glucose control, resulting in life-threatening hypoglycemia. Here we show our humanized mouse model, huR83C, carrying the pathogenic G6PC1-R83C variant displays the phenotype of glycogen storage disease type-Ia and dies prematurely. We evaluate the efficacy of BEAM-301, a formulation of lipid nanoparticles containing a newly-engineered adenine base editor, to correct the G6PC1-R83C variant in huR83C mice and monitor phenotypic correction through one year. BEAM-301 can correct up to ~60% of the G6PC1-R83C variant in liver cells, restores blood glucose control, improves metabolic abnormalities of the disease, and confers long-term survival to the mice. Interestingly, just ~10% base correction is therapeutic. The durable pharmacological efficacy of base editing in huR83C mice supports the development of BEAM-301 as a potential therapeutic for homozygous and compound heterozygous glycogen storage disease type-Ia patients carrying the G6PC1-R83C variant.

Anti-Inflammatory Activity of Labdane and Norlabdane Diterpenoids from Leonurus sibiricus Related to Modulation of MAPKs Signaling Pathway.

Leonurus sibiricus, a widely cultivated herbaceous plant in Asian countries, exhibits diverse medicinal applications. Recent studies emphasize its pharmacological properties and efficacy in promoting bone health. In addition to the known compounds and their pharmacological activities, in this study, we isolated and elucidated two new labdane-type diterpenoids, (3R,5R,6S,10S)-3,6-dihydroxy-15-ethoxy-7-oxolabden-8(9),13(14)-dien-15,16-olide (1: ) and (4R,5R,10S)-18-hydroxy-14,15-bisnorlabda-8-en-7,13-dione (2: ), a new natural phenolic compound, and a known compound from L.sibiricus using advanced spectroscopic techniques, including circular dichroism spectroscopy, high-resolution mass spectrometry, and 1- and 2-dimensional NMR. Among these, compound 1: demonstrated potent inhibition of nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA expression levels, followed by compound 2: . Whereas compounds 3: and 4: did not exhibit effectiveness in RAW264.7 macrophages. Moreover, compound 1: suppressed pro-inflammatory markers induced by lipopolysaccharide (LPS) stimulation. Compound 1: also suppressed iNOS and cyclooxygenase-2 (COX-2) protein levels and downregulated pro-inflammatory cytokines. Additionally, compound 1: showed inhibition of the phosphorylation of p38, JNK, and ERK, key mediators of the MAPK signaling pathway. These findings indicate that a natural-derived product, compound 1,: might be a potential candidate as an anti-inflammation mediator.

Phytotherapy for Diarrhea: Bridging Herbal Medicine and Modern Treatment

Diarrhea remains a significant global health issue, responsible for approximately 1.9 million deaths annually, particularly in children under five. Conventional treatment includes oral rehydration and antibiotics; however, phytotherapy, the use of plant-based remedies, offers an alternative or complementary solution, especially for cases involving chronic diarrhea or antibiotic resistance. This paper examines the historical and scientific basis of phytotherapy, its pharmacological mechanisms, clinical efficacy, and potential integration with modern medicine. Despite the lack of robust clinical data for some herbal treatments, growing interest in complementary approaches highlights the need for further research. Phytotherapy shows promise in alleviating symptoms and modulating gut health through anti-inflammatory, anti-infectious, and gut-modulating mechanisms. The integration of herbal medicine with modern treatment protocols could enhance the therapeutic approach to managing diarrhea and improve patient outcomes, especially in settings with limited access to modern pharmaceuticals. Keywords: Phytotherapy, Herbal medicine, Diarrhea treatment, Antidiarrheal agents, Antibiotic resistance.

Bay 11-7082 mitigates oxidative stress and mitochondrial dysfunction via NLRP3 inhibition in experimental diabetic neuropathy

ObjectiveDiabetic neuropathy is associated with mitochondrial dysfunction and neuroinflammation. Chronic hyperglycemia triggers inflammatory responses and oxidative stress, causing peripheral neuropathy, whereas mitochondrial dysfunction caused by increased ROS generation and reduced bioenergetics maintains the inflammatory cycle. The purpose of this study is to evaluate the pharmacological efficacy of Bay 11–7082 (B11) against diabetic neuropathy in rats. MethodsB11 was administered at doses of 1 and 3 mg/kg to STZ-induced diabetic animals (55 mg/kg, i.p). Behavioral and functional assessments were conducted to assess neuropathy. Molecular protein expressions were evaluated for B11's efficacy against STZ-induced diabetic neuropathic rats and in SHSY5Y cells exposed to 175 mM of d-glucose. ResultsDiabetic rats exhibited deficits in nerve functions, altered nociceptive parameters, and increased expression of NLRP3, ASC, Caspase-1, and NF-κB. Additionally, diabetic animals showed reduced levels of PGC1α/Nrf2/HO-1, with an overexpression of PARP1. Compromised mitochondrial function was evident through increased mitochondrial dynamic marker DRP1 and elevated levels of inflammatory cytokines TNF-α, IL-1β, IL-18, and IL-6. However, B11 administration significantly ameliorated these changes, suggesting that B11's NLRP3 inhibition may be attributed to the activation of the mitochondrial biogenesis pathway via PGC1α/Nrf2/HO-1, along with improved mitochondrial health. In high glucose exposed SHSY5Y cells, B11 treatment attenuated neuroinflammation by inhibiting NLRP3 activation and reducing mitochondrial damage. ConclusionB11, showed a protective effect against diabetic neuropathy by inhibiting oxidative stress, NLRP3 activation, and improving mitochondrial health in experimental diabetic neuropathy. This study provides new mechanistic insights into the neuroprotective role of Bay 11–7082 against diabetic neuropathy.

Avicularin inhibits ferroptosis and improves cognitive impairments in Alzheimer's disease by modulating the NOX4/Nrf2 axis

BackgroundAlzheimer's disease (AD) is a widespread neurodegenerative disorder for which effective therapies remain elusive, primarily due to the complexity of its underlying pathophysiology. In recent years, natural products have gained attention for their therapeutic potential in AD, owing to their multi-targeted actions and low toxicity profiles. Avicularin (Avi), a flavonoid derived from the peels of Zanthoxylum bungeanum Maxim., has shown promise as an anti-AD agent. However, the specific mechanisms by which Avi mitigates oxidative stress and inhibits ferroptosis in AD models remain insufficiently understood. Further investigation is required to elucidate its therapeutic potential in these pathways. PurposeTherefore, this study aims to elucidate the neuroprotective effects of Avi in AD by investigating its impact on the NOX4/Nrf2 signaling pathway, as well as its role in modulating oxidative stress and ferroptosis. MethodsIn this study, an in vitro H2O2-induced oxidative stress model in SH-SY5Y cells was utilized to evaluate the pharmacological efficacy and underlying mechanisms of Avi. Molecular docking, cellular thermal shift assay and bio-layer interferometry assays were conducted to identify potential molecular targets of Avi. Additionally, in vivo models, including scopolamine (SCOP)-induced and APP/PS1 transgenic mice, were employed to assess the cognitive effects of Avi and further explore its associated molecular mechanisms. ResultsOur study demonstrates that Avi effectively attenuates H2O2-induced toxicity in SH-SY5Y cells by reducing apoptosis and enhancing cellular antioxidant defenses. This neuroprotective effect is mediated through the inhibition of NOX4 and the promotion of Nrf2 nuclear translocation. Furthermore, Avi improves cognitive function and mitigates ferroptosis in both SCOP-induced and APP/PS1 transgenic mouse models of AD. ConclusionAvi emerges as an effective neuroprotective agent against AD, offering a promising therapeutic approach by targeting the NOX4/Nrf2 signaling axis to alleviate oxidative stress and ferroptosis.

Novel Approach to Skin Anti-Aging: Boosting Pharmacological Effects of Exogenous Nicotinamide Adenine Dinucleotide (NAD+) by Synergistic Inhibition of CD38 Expression.

Nicotinamide adenine dinucleotide (NAD+) is indispensable for the regulation of biological metabolism. Previous studies have revealed its role in aging and degenerative diseases, while crucially showing that supplementation with NAD+ or its precursors could ameliorate or reverse the progression of aging. Despite extensive evidence for the role and action of NAD+ in aging, its pharmacological activity on the skin, or even its mechanism, has not been elucidated. In this study, we established a novel approach to effectively utilize NAD+ for skin anti-aging by enhancing the pharmacological efficacy of exogenous NAD+ using a phytochemical complex consisting of quercetin, and enoxolone through inhibition of CD38. Through the comprehensive in vitro experiments based on human fibroblasts, we observed that exogenous NAD+ could exert protective effects against both extrinsic aging induced by ultraviolet light exposure and intrinsic aging. Additionally, we found that its effects were significantly boosted by quercetin and enoxolone. In this in-depth study, we demonstrated that these beneficial effects are mediated by improved sirtuin activation, autophagy, and mitochondrial functionality. Our approach is expected to verify the applicability of the topical application of NAD+ and offer more effective solutions for the unmet needs of patients and consumers who demand more effective anti-aging effects.

Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFβRI/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation in Cancer.

The development of transforming growth factor βreceptor inhibitors (TGFβRi) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGFβ in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFβRi classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT: Only a few TGFβRi have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients.

The In vitro evaluation of in silico-designed synthetic peptides AKVUAM-1 and AKVUAM-2 on human lung fibroblast cell line MRC5 and Mycobacterium tuberculosis isolates

Tuberculosis is a major global health problem caused by Mycobacterium tuberculosis and the increase in drug resistance is driving the need for new treatments. Today, various approaches are being applied in the development of drugs for the treatment of tuberculosis. Computer-aided drug design (CADD) enables the prediction of pharmacological efficacy for potential drug molecules during the design process. Thus, new therapeutic compounds can be developed that are more potent, less toxic and have fewer side effects than existing drugs. In this study, we investigated the in vitro activities of AKVUAM-1 and AKVUAM-2 synthetic peptides designed in silico by computer-aided drug design method to inhibit the interaction between M. tuberculosis outer membrane protein Cpn T and macrophage surface receptor CR-1 and Surfactant D protein. Notably, these synthetic peptides do not show cytotoxic effect on normal lung tissue and do not kill M. tuberculosis directly. The MIC values for AKVUAM-1 were higher than 512 μg/ml for all bacterial strains except IST-16 strain (128 μg/ml). According to our results, AKVUAM-1 and AKVUAM-2 synthetic peptides have the potential to be successful candidates for investigating their potential to block macrophage entry of bacilli as targeted.

The impact of scabies in tent cities in Kahramanmaraş after the Turkish earthquakes: oral pharmacologic treatment efficacy

Background Our study was conducted to determine the impact of scabies in people living in collective living areas such as tent cities and container cities after the February 6 Kahramanmaraş earthquakes and to show the effectiveness of oral ivermectin treatment on scabies cases because topical treatments could not be used in this period when access to water was limited. Methods Among 233 patients diagnosed and treated with scabies in tent and container cities, 192 patients who met the criteria were included in the study. Descriptive statistics were given as number (n), percentage (%), mean, median, standard deviation (SD). In the comparison of categorical data, the chi-square test was applied; in the comparison of numerical data ANOVA analyses was applied. Results A total of 192 scabies patients (82.4%), 47.9% (N:92) of whom were women, were included in the study. The frequency of scabies in the total population in tent cities and container cities was found to be at least 0.54%. The most common symptoms were pruritis (99.0%) and rash (97.9%). The most common sites of lesion involvement were the umbilicus (87.0.%), forearm (75.0%), and back (70.3%). After the first dose of ivermectin, 159 (82.8%) patients showed complete recovery, while 30 (15.6%) patients showed partial recovery. 3 (1.6%) patients showed no improvement. After the second dose of ivermectin, 173 (90.1%) patients showed complete recovery. There were two (1.0%) patients who did not show improvement after two doses. Due to the deterioration of urban infrastructure after devastating earthquakes, the irregularity of mass living areas, the lack of hygiene conditions, and the difficulty of accessing clean, usable water, oral ivermectin may be the first choice for treatment in terms of ease of use and effectiveness.

Targeting the Notch-Furin axis with 2-hydroxyoleic acid: a key mechanism in glioblastoma therapy.

Glioblastomas (GBMs) are highly treatment-resistant and aggressive brain tumors. 2OHOA, which is currently running a phase IIB/III clinical trial for newly diagnosed GBM patients, was developed in the context of melitherapy. This therapy focuses on the regulation of the membrane's structure and organization with the consequent modulation of certain cell signals to revert the pathological state in several disorders. Notch signaling has been associated with tumorigenesis and cell survival, potentially driving the pathogenesis of GBM. The current study aims to determine whether 2OHOA modulates the Notch pathway as part of its antitumoral mechanism. 2OHOA's effect was evaluated on different components of the pathway by Western blot, Q-PCR, and confocal microscopy. Notch receptor processing was analyzed by subcellular fractionation and colocalization studies. Furin activity was evaluated under cleavage of its substrate by fluorescence assays and its binding affinity to 2OHOA was determined by surface plasmon resonance. We found that 2OHOA inhibits Notch2 and Notch3 signaling by dual mechanism. Notch2 inhibition is unleashed by impairment of its processing through the inactivation of furin activity by physical association. Instead, Notch3 is transcriptionally downregulated leading to a lower activation of the pathway. Moreover, we also found that HES1 overexpression highlighted the relevance of this pathway in the 2OHOA pharmacological efficacy. These findings report that the inhibition of Notch signaling by 2OHOA plays a role in its anti-tumoral activity, an effect that may be driven through direct inhibition of furin, characterizing a novel target of this bioactive lipid to treat GBM.

Erdosteine in the treatment of acute and chronic diseases of the respiratory system: resolution of the scientific forum of experts “In the Spotlight”

Airway mucus hypersecretion is a pathophysiologic manifestation of acute and chronic airway inflammatory disease. Mucolytics can reduce mucus viscosity and promote mucus discharge and therefore can be considered pathogenetically based therapy.The purpose of this publication with the resolution of the scientific forum of experts was to discuss pharmacological features, efficacy, and safety of erdosteine.Results. Experts of thescientific forum not only reviewed the results of clinical trials, but also voted on the use of mucoactive drugs according to the principle of Delphi consensus. Comparison of the efficacy and safety of mucoactive drugs (erdosteine, acetylcysteine, carbocysteine, ambroxol) in patients with respiratory diseases by the experts during voting showed that the highest level of agreement among the experts was achieved for the drug Elmucin® (erdosteine) in terms of its mucolytic activity and other pharmacological features, as well as when discussing the safety of the compared drugs in the officially recommended doses. The highest level of agreement was also noted on the erdosteine efficacy in COPD patients in reducing the frequency and duration of disease exacerbations, as well as reducing the risk of hospitalization of COPD patients when used long-term as part of combination therapy. The demonstrated safety profile was the most beneficial among the reviewed mucoactive drugs.Conclusion. Elmucin® is a mucolytic with pleiotropic effects such as complex mucoactive action, potent antioxidant, anti-inflammatory and antibacterial activity with anti-adhesive effect for pathogens that determine its clinical efficacy in the treatment of acute and chronic airway diseases.

Integrated Transcriptomics and Metabolomics Studies Reveal Steroid Biosynthesis Pathway and BCL2 Inhibitory Diazo-Progesterone of Drimia indica for Conservation and Sustainable Utilization.

This study is the first report on the sequence of the transcriptome of Drimia indica, a non-model plant with medicinal properties found in a forest tribal belt, using the Illumina NovaSeq platform. The primary objectives of this study were to elucidate the gene expression profiles in different tissues, identify key regulatory genes and pathways involved in secondary metabolite biosynthesis, and explore the plant's potential pharmacological properties. The study generated 670087 unigenes from both leaves and roots and identified putative homologs of annotated sequences against UniProt/Swiss-Prot and KEGG databases. The functional annotation of the identified unigenes revealed the secondary metabolite biosynthetic process as the most prominent pathway, with gene enrichment analysis predominantly accounting for secondary metabolite pathways, such as terpenoid, steroid, flavonoid, alkaloid, selenocompound, and cortisol synthesis. The study also identified regulatory genes NAC, Bhlh, WRKY, and C2H2 on the transcriptome dataset. The functionally annotated unigenes suggested phytocompounds in Drimia indica to have multi-potent properties, such as anti-cancer, anti-inflammatory, and anti-diabetic activities, which has been further validated by GC-MS-based metabolite profiling. Notably, we have identified two novel molecules, di-azo progesterone and 4H-pyran-4-one 2,3-dihydro-3,5-dihydroxy- 6-methyl, with potential BCL2 inhibitory anticancer properties, supported by stable binding interactions observed in molecular docking and dynamics simulations. Additionally, an abundance of mono-nucleotide SSR markers has been identified, useful for genetic diversity studies. This study provides a foundational understanding of the molecular mechanisms in Drimia indica, highlighting its potential as a source for novel therapeutic agents and contributing valuable insights for future pharmacological and agricultural applications. However, further in vivo studies are warranted to confirm these findings and validate their pharmacological efficacy and therapeutic potential. The SSR markers identified also offer valuable tools for molecular genetics, plant breeding, and sustainable drug development.

Comparison of different processed products of Allium tuberosum Rottler for the treatment of mice asthenozoospermia.

Allium tuberosum Rottler improves sexual function and is used in the treatment of impotence and spermatorrhea. However, its chemical composition and mechanism of action remain unclear. This study investigates the chemical composition and mechanism of action of Allium tuberosum Rottler co-processed with salt and wine (GZP) in modulating testicular mitochondrial autophagy for the treatment of asthenozoospermia in mice. Adenine gavage + cyclophosphamide intraperitoneal injection was used to establish the model of asthenozoospermia, and six Allium tuberosum Rottler processed products were compared in the pharmacological efficacy for the treatment of asthenozoospermia in mice. The liquid chromatograph mass spectrometer (LC-MS) assay was performed to analyse the compositional changes in the GZP. The mechanism of GZP in the treatment of asthenozoospermia in mice was further investigated. The mitophagy was detected by transmission electron microscope (TEM) and immunofluorescence, respectively. Reactive oxygen species (ROS) were detected by probe. Protein expression was determined by Western blotting. GZP exhibited optimal therapeutic effects on asthenozoospermia in mice. It showed the best therapeutic effect in improving the total number of spermatozoa, sperm survival rate, improving sperm viability and reducing sperm deformity rate, alleviating the abnormal pathological morphology of mice testis, and increasing the serum testosterone (T), follicle-stimulating hormone (FSH) and prolactin (PRL) levels in mice. The LC-MS detection found that Allicin showed the most significant increase in GZP. Besides, GZP reduced ROS level and inhibited mitophagy in mice testicular tissues. Meanwhile, it restrained the expression of PINK1, Parkin, Light chain 3II (LC3-II)/Light chain 3I (LC3-I) and Caspase-3 proteins. GZP improves asthenozoospermia via inhibiting excessive mitophagy and protects the integrity of mitochondria by blocking the PINK1/Parkin signaling pathway. During which, the Allicin may play an important role.