Potential Therapeutic Applications Research Articles

Activity Control of a Synthetic Transporter by Photodynamic Modulation of Membrane Mobility and Incorporation.

Artificial transmembrane transport systems are receiving a great deal of attention for their potential therapeutic application. A major challenge is to switch their activity in response to environmental stimuli, which has been achieved mostly by modulating the binding affinity. We demonstrate here that the activity of a synthetic anion transporter can be controlled through changes in the membrane mobility and incorporation. The transporters─equipped with azobenzene photoswitches─poorly incorporate into the bilayer membrane as their thermally stable (E,E,E)-isomers, but incorporation is triggered by UV irradiation to give the (Z)-containing isomers. The latter isomers, however, are found to have a lower mobility and are therefore the least active transporters. This opposite effect of E-Z isomerization on transport capability offers unique photocontrol as is demonstrated by in situ irradiation studies during the used transport assays. These results help to understand the behavior of artificial transporters in a bilayer and are highly important to future designs, with new modes of biological activity and with the possibility to direct motion, which may be crucial toward achieving active transport.

In Vitro Cytotoxicity and Mechanistic Investigation of Quinazolin-4(1H)-One Linked Coumarin as a Potent Anticancer Agent.

Quinazolinone-coumarin conjugates synthesized through Late-Stage Functionalization approach are evaluated for their invitro biological activity for 60 human cancer cell lines representing nine different cancer types. Among the synthesized compounds, eight displayed significant growth inhibitory activity across a spectrum of cancer types, with compound 23 demonstrating particularly notable cytotoxicity. Further investigation involved a five-dose assay of compound 23 against NCI-60 cancer cell lines, revealing its efficacy at different concentrations. Additionally, binding studies elucidated its interaction with Human Serum Albumin (HSA) and DNA. The results indicated a strong binding affinity of 23 with HSA, evidenced by a high binding constant (2.26 × 105 M-1). Moreover, its interaction with DNA occurred via intercalation, specifically between the base pairs of DNA strands, with a binding constant of 5.51 × 104 M-1. This suggests that compound 23 has the ability to bind to both DNA and transport proteins, making it a promising pharmacophore with potential therapeutic applications.

Anti-inflammatory, antioxidant, and anti-apoptotic properties of Thunbergia laurifolia Lindl. aqueous leaf extract on LPS-stimulated RAW 264.7 macrophages

Thunbergia laurifolia Lindl., a Thai medicinal herb, has garnered substantial attention among researchers due to its recognized efficacy as an antidote, antioxidant, and anti-inflammatory agent. Despite its extensive investigation, the specific role of T. laurifolia in apoptotic inhibition remains unexplored. Therefore, this study aimed to explore the protective properties of T. laurifolia leaf extract against lipopolysaccharide (LPS)-induced apoptosis in RAW 264.7 macrophages and determine the extractʼs total phenolic as well as flavonoid content, and its antioxidant. Moreover, the cytotoxicity including anti-inflammatory potential on LPS-stimulated RAW 264.7 macrophages were assessed by measuring the inhibition of nitric oxide (NO). The outcomes of this investigation revealed remarkable similarity between the total phenolic and flavonoid contents and antioxidant capacity of the leaf extract under scrutiny and those documented in prior studies. In addition, the extract demonstrated negligible cytotoxicity at low concentrations. Furthermore, it effectively impeded the LPS-mediated production of NO, inflammatory mediator, in the macrophages. Moreover, pre-treatment with T. laurifolia leaf extract improved LPS-induced apoptosis by reducing rate of apoptotic cell death up to 41 % at the same concentration (1.68 μL/mL) in LPS-stimulated RAW 264.7 macrophages. Collectively, these findings provide compelling initial evidence attesting to the ability of T. laurifolia leaf extract to inhibit LPS-induced apoptosis in RAW 264.7 macrophages, thereby augmenting our understanding of its potential therapeutic applications in inflammatory conditions.

Repurposed genipin targeting UCP2 exhibits antitumor activity through inducing ferroptosis in glioblastoma.

Uncoupling protein-2 (UCP2) controls the antioxidant response and redox homeostasis in cancer and is considered a potent molecular target for cancer treatment. However, the specific mechanism of UCP2 inhibition and its role in glioblastoma (GBM) have not yet been elucidated. Here, we attempt to identify a UCP2 inhibitor and study the underlying molecular mechanism in GBM. Bioinformatics analysis and immunohistochemistry are used to validate the high expression of UCP2 in GBM and its prognostic significance. Drug intervention and tumor xenograft experiments are conducted to determine the inhibitory effect of genipin, a UCP2 inhibitor, on UCP2. The mitochondrial membrane potential and key ferroptosis genes are examined to determine the occurrence of ferroptosis. High expression of UCP2 in GBM is associated with poor prognosis, and inhibiting UCP2 can alleviate the malignant behavior of GBM tumors. Genipin can downregulate the expression of GPX4 and upregulate the expression of ACSL4 by inhibiting UCP2, leading to ferroptosis and alleviating the malignant behavior of tumors. In summary, UCP2 is a potential therapeutic target for GBM. Genipin, which targets UCP2, effectively inhibits GBM development by inducing ferroptosis in vivo and in vitro. These findings indicate that genipin treatment based on UCP2 targeting has potential therapeutic applications with a clinical perspective for the treatment of GBM patients.

Safeguarding the brain from oxidative damage.

Oxidative stress imposes a substantial cellular burden on the brain and contributes to diverse neurodegenerative diseases. Various antioxidant signaling pathways have been implicated in oxidative stress and have a protective effect on brain cells by increasing the release of numerous enzymes and through anti-inflammatory responses to oxidative damage caused by abnormal levels of reactive oxygen species (ROS). Although many molecules evaluated as antioxidants have shown therapeutic potentials in preclinical studies, the results of clinical trials have been less than satisfactory. This review focuses on several signaling pathways involved in oxidative stress that are associated with antioxidants. These pathways have a protective effect against stressors by increasing the release of various enzymes and also exert anti-inflammatory responses against oxidative damage. There is no doubt that oxidative stress is a crucial therapeutic target in the treatment of neurological diseases. Therefore, it is essential to understand the discovery of multiple routes that can efficiently repair the damage caused by ROS and prevent neurodegenerative disorders. This paper aims to provide a concise and objective review of the oxidative and antioxidant pathways and their potential therapeutic applications in treating oxidative injury in the brain.

Microanatomy sectioning and phytochemicals overview in selected Oleaceae species

This study provides in-depth observations into the microanatomical structure of leaves and stem of eight selected Oleaceae species revealing comprehensive tissue organization using microtome sectioning and peeling leaf epidermis techniques. The phytochemicals profile overview of selected olive species extracted from leaf and stem of Oleaceae species contributes to identifying bioactive compounds with potential therapeutic and medicinal applications. An overview of histochemistry of bioactive metabolites revealed in Oleacee species shows the presence of phenolic compounds (oleuropein and hydroxytyrosol), localized in the leaves and stems, contributing to their antioxidant properties. The present study represent foliar anatomical traits; epidermal cells (ECs) polygonal shape and straight anticlinal walls, paracytic stomata and simple unicellular trichomes. The maximum ECs length (30 μm) was noted in Olea europaea and minimum (20 μm) in Jasminum fluminense was measured. Oleaceae species microtome stem sectioning examined revealed cortex type (parenchyma and collenchyma), vascular bundles (VBs) arrangements (radial, scattered and bundled), xylem vessels (scalariform, annular, spiral and reticulate), phloem fiber arrangements (banded and scattered), and uniseriate, biseriat and multiseriate medullary rays. Stem transverse section with maximum length (1300 μm) was observed in Olea europaea and the lowest (1100 μm) in Jasminum grandiflorum L. subsp. floribundum. This taxonomic histological method links the relationship between anatomy and chemistry, lead to identification of bioactive chemical compounds diversity among Oleaceae species. This anatomical methods used to enhance and consider the plant micromorphological structure-function relationships adapted to diverse environmental conditions.

Neuroprotection and mechanisms of ginsenosides in nervous system diseases: Progress and perspectives.

Ginsenosides are the primary component discernible from ginseng, including Rb1, Rb2, Rd, Rg1, Rg2, and compound K, and so forth. They have been shown to have multiple pharmacological activities. In recent years, more and more studies have been devoted to the neuroprotection of various ginsenosides against neurological diseases and their potential mechanisms. This paper comprehensively summarizes and reviews the neuroprotective effects of various ginsenosides on neurological diseases, especially acute and chronic neurodegenerative diseases, and their mechanisms, as well as their potential therapeutic applications to promote neuroprotection in disease prevention, treatment, and prognosis. Briefly, ginsenosides exert effective neuroprotective effects on neurological conditions, including stroke, Alzheimer's disease, Parkinson's disease, and brain/spinal cord injuries through a variety of molecular mechanisms, including anti-inflammatory, antioxidant, and anti-apoptotic. Among them, some signaling pathways play important roles in related processes, such as PI3K/Akt, TLR4/NF-κB, ROS/TXNIP/NLRP3, HO-1/Nrf2, Wnt/β-catenin, and Ca2+ pathway. In conclusion, the present study reviews the research progress on the neuroprotective effects of ginsenosides in the last decade, with the aim of furnishing essential theoretical underpinning and effective references for further research and exploration of the multiple medicinal values of Chinese herbal medicines and their small molecule compounds, including ginseng and panax ginseng. Because there is less evidence in the existing clinical studies, future research should be focused on clinical trials in order to truly reflect the clinical value of various ginsenosides for the benefit of patients.

Functional modulation of RAGE activation by multimeric S100B using single-domain antibodies.

S100B is a multifunctional protein primarily found in the brain, where it plays crucial roles in cell proliferation, differentiation, and survival. It has intra- and extracellular functions and, depending on S100B levels, can exhibit both neurotrophic and neurotoxic activities, both mediated by the receptor for advanced glycation end products (RAGE). Here, we report the discovery and characterization of nanobodies (Nbs) targeting dimeric and tetrameric S100B, which are the two most abundant oligomeric functional forms of the protein, aiming to modulate S100B-mediated RAGE activation. Two Nbs were selected for detailed structural and functional studies, and found to bind tetrameric S100B with high affinity, as determined by biolayer interferometry analysis and SEC-stable binary complex formation. Structural and docking analyses revealed preferential contact sites of Nbs with S100B regions implicated in interactions with RAGE, namely residues at the interfacial cleft on dimeric S100B and the at hydrophobic cleft formed by the association of two homodimeric units in the tetramer. In accordance, assays in SH-SY5Y cells showed that Nbs modulate the RAGE-mediated neurotrophic activity of S100B by hindering its functional interactions with the receptor. Biolayer interferometry competition assays between tetrameric S100B and the RAGE-VC1 domain, confirmed that Nbs selectively block S100B-mediated RAGE engagement, in agreement with cell activation experiments. These findings highlight Nbs as powerful tools for elucidating molecular and cellular mechanisms through the modulation of S100B and RAGE functions, inspiring potential therapeutic applications.

Identification and Characterization of a surfactin from Pseudomonas gessardii: A Symbiotic Bacterium with Potent Anticancer Activity

Prasiola japonica, traditionally used as food and folk medicine in South Korea, exerts pharmacological properties, including antioxidant, anti-inflammatory, antidiabetic, and anticancer effects. In this study, we explored symbiotic microbes associated with P. japonica and identified Pseudomonas gessardii as a nonpathogenic symbiotic bacterium through 16S rDNA sequencing. Bioactivity-guided fractionation of P. gessardii ethanol extracts, utilizing a series of non-polar to polar solvents, led to the isolation of a single bioactive compound (SF10) from the ethyl acetate fraction. Structural analysis using LC-MS and NMR spectroscopy identified SF10 as surfactin C15, a lipopeptide consisting of 7 amino acids and a β-hydroxy fatty acid chain containing 15 carbon atoms. This represents the first discovery of surfactin production in P. gessardii, expanding known surfactin-producing genera beyond Bacillus. In HT-29 colorectal cancer cells, surfactin C15 demonstrated significant anticancer activity through multiple mechanisms: inhibition of cancer stem cell marker CD133 expression, upregulation of pro-apoptotic factors (CHOP, PUMA, DR5), and modulation of cell cycle regulators (p21, cyclin E1, CDK5). Furthermore, surfactin C15 induced necrotic cell death, confirmed by increased lactate dehydrogenase release and flow cytometry analysis showing dose-dependent increases in necrotic cell populations. This study reveals a novel source of surfactin with unique cancer cell-targeting properties, particularly through its ability to induce necrosis in colorectal cancer cells, suggesting potential therapeutic applications in cancer treatment.

Investigation of Phytochemical Composition, Radical Scavenging Potential, Anti-Obesogenic Effects, and Anti-Diabetic Activities of Kaempferia parviflora Rhizomes.

Kaempferia parviflora or commonly known as "Kunyit hitam" by locals, is an edible plant, native to tropical regions, has been extensively utilized for culinary and medicinal applications. The present study aimed to investigate the phytochemical composition and biological activities of the rhizomes of K. parviflora. The ethanol crude and fractionated extracts (hexane and chloroform) of the rhizomes were evaluated for their total phenolic content, total steroidal content, as well as antioxidant, anti-obesogenic, and anti-diabetic activities. The chloroform extract demonstrated the highest concentration of plant sterols (432±0.23 mg BSE/g extract) and a substantial amount of phenolic compounds (1.19×103±0.41 mg GAE/g extract). Gas chromatography-mass spectrometry (GC/MS) analysis revealed that the chloroform extract of the rhizomes is predominantly composed of bioactive flavonoids including tectochrysin (1), 5,7-dimethoxyflavone (2), 3,5,7-trimethoxyflavone (3), 3,4',5,7-tetramethoxyflavone (4), and 4',5,7-trimethoxyflavone (5). Furthermore, the chloroform extract exhibited the highest overall radical scavenging and α-glucosidase inhibitory activities, which can be attributed to the presence of compounds 1-5 in the extract. Collectively, these findings suggest that the chloroform extract of the rhizomes of K. parviflora is a potentially valuable source of bioactive compounds with antioxidant, anti-obesogenic, and anti-diabetic properties, with potential application in therapeutics and functional foods.

Aminoacid functionalised magnetite nanoparticles Fe3O4@AA (AA = Ser, Cys, Pro, Trp) as biocompatible magnetite nanoparticles with potential therapeutic applications

Magnetic nanoparticles (MNPs) are of great interest for their wide applications in biomedical applications, such as bioimaging, antitumoral therapies, regenerative medicine, and drug delivery. The work aimed to obtain biocompatible magnetite nanoparticles coated with amino acids of the general formula Fe3O4@AA (AA = L-tryptophan, L-serine, L-proline and L-cysteine) for potential therapeutic application in anticancer drug delivery. The obtained materials were characterised using XRD, FTIR, DLS analysis, SEM, thermogravimetry (TG), differential scanning calorimetry (DSC), and UV–vis spectroscopy. The photocatalytic, cytotoxic and antimicrobial activity tests of the obtained materials were carried out. The choice of amino acid determines the properties of the material and its future use, for example, Fe3O4@Cys supports radical production, which may increase the efficiency of catalytic degradation, while tryptophan captures radicals, which may be an advantage in several biomedical applications. Fe3O4@Trp exhibited good antimicrobial activity (MBEC and MIC) against E. coli ATCC 25922, P. aeruginosa ATCC 27853 and C. albicans ATCC 10231 while Fe3O4@Pro exhibited the best results against S. aureus ATCC 25923.

The role of neuropeptides in cutaneous wound healing: a focus on mechanisms and neuropeptide-derived treatments.

An extensive network of cutaneous nerves, neuropeptides, and specific receptors richly innervates the skin and influences a variety of physiological and pathological processes. The sensory and autonomic nerve fibers secrete a variety of neuropeptides that are essential to the different phases of wound healing. In addition to initiating a neurogenic inflammatory response in the early stages of healing, neuropeptides also control wound healing by influencing immune cells, repair cells, and the growth factor network. However, the precise mechanism by which they accomplish these roles in the context of cutaneous wound healing is still unknown. Investigating the mechanisms of action of neuropeptides in wound healing and potential therapeutic applications is therefore urgently necessary. The present review discusses the process of wound healing, types of neuropeptides, potential mechanisms underlying the role of neuropeptides in cutaneous wound healing, as well as some neuropeptide-derived treatment strategies, such as hydrogels, new dressings, electro stimulation, and skin-derived precursors. Future in-depth mechanistic studies of neuropeptides in cutaneous wound healing may provide opportunities to develop therapeutic technologies that harness the roles of neuropeptides in the wound healing process.

Slow H2S-Releasing Donors and 3D Printable Arrays Cellular Models in Osteo-Differentiation of Mesenchymal Stem Cells for Personalized Therapies

The effects of the hydrogen sulfide (H2S) slow-releasing donor, named GSGa, a glutathione-conjugate water-soluble garlic extract, on human mesenchymal stem cells (hMSCs) in both bidimensional (2D) and three-dimensional (3D) cultures were investigated, demonstrating increased expression of the antioxidant enzyme HO-1 and decreased expression of the pro-inflammatory cytokine interleukin-6 (IL-6). The administration of the H2S donor can therefore increase the expression of antioxidant enzymes, which may have potential therapeutic applications in osteoarthritis (OA). Moreover, GSGa was able to promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but not of cardiac mesenchymal stem cells (cMSCs) in a 2D culture system. This result highlights the varying sensitivity of hMSCs to the H2S donor GSGa, suggesting that the induction of osteogenic differentiation in stem cells by chemical factors is dependent on the tissue of origin. Additionally, a 3D-printable mesenchymal stem cells–bone matrix array (MSCBM), designed to closely mimic the stiffness of bone tissue, was developed to serve as a versatile tool for evaluating the effects of drugs and stem cells on bone repair in chronic diseases, such as OA. We demonstrated that the osteogenic differentiation process in cMSCs can be induced just by simulating bone stiffness in a 3D system. The expression of osteocalcin, RUNX2, and antioxidant enzymes was also assessed after treating MSCs with GSGa and/or increasing the stiffness of the culture environment. The printability of the array may enable better customization of the cavities, enabling an accurate replication of real bone defects. This could optimize the BM array to mimic bone defects not only in terms of stiffness, but also in terms of shape. This culture system may enable a rapid screening of antioxidant and anti-inflammatory compounds, facilitating a more personalized approach to regenerative therapy.

Marine-Derived Fucose-Containing Carbohydrates: Review of Sources, Structure, and Beneficial Effects on Gastrointestinal Health.

Fucose, fucose-containing oligosaccharides, and fucose-containing polysaccharides have been widely applied in the fields of food and medicine, including applications in Helicobacter pylori eradication and renal function protection. Fucose-containing carbohydrates (FCCs) derived from marine organisms such as seaweed, invertebrates, microalgae, fungi, and bacteria have garnered growing attention due to their diverse bioactivities and potential therapeutic applications. Marine-derived FCCs characterized by high fucose residue content and extensive sulfate substitution, including fucoidan, fucosylated chondroitin sulfate, and fucose-rich microbial exopolysaccharides, have demonstrated significant potential in promoting gastrointestinal health. This review describes the unique structural features of FCCs and summarizes their health benefits, including regulation of gut microbiota, modulation of microbial metabolism, anti-adhesion activities against H. pylori and gut pathogens, protection against inflammatory injuries, and anti-tumor activities. Additionally, this review discusses the structural characteristics that influence the functional properties and the limitations related to the activity research and preparation processes of FCCs, providing a balanced perspective on the application potential and challenges of FCCs with specific structures for the regulation of gastrointestinal health and diseases.

Effect of Nattokinase in D-galactose- and Aluminum Chloride-induced Alzheimer's Disease Model of Rat.

Alzheimer's disease (AD) is the most common form of dementia worldwide. Nattokinase is a serine protease extracellularly produced by natto, a fermented product of Bacillus subtilis var. natto. In this study, we investigated the therapeutic effects of nattokinase in a rat model of AD induced by aluminum and D-galactose. Forty Wistar rats were randomly divided into four groups: normal, vehicle, and orally administered nattokinase (NK65 and NK130 groups). Except for the normal group, all groups were treated with AlCl3 and D-galactose for 10 weeks. The NK65 and NK130 groups additionally received 65 mg/kg/day and 130 mg/kg/day nattokinase, respectively. We analyzed β-amyloid levels in the cerebrospinal fluid (CSF), and the spatial reference test was evaluated using the Morris water maze test. After the Morris water maze test, rats of all groups were subjected to micro-computed tomography (μCT) to assess constructional changes in the brain. Aluminum concentration and β-amyloid levels were analyzed by histochemical staining in all brain tissues. Oral administration of nattokinase in the AD rat model increased free-form β-amyloid levels in the CSF and improved aluminum and amyloid plaque accumulation in the brain. Brain μCT images showed enhanced brain volume with fewer constructional changes after treatment with nattokinase. In the behavioral tests, both the escape latency time in the spatial reference test and the time taken to cross the platform area in the spatial probe test improved partially. The results suggest that nattokinase has potential therapeutic applications in the treatment of AD.

Construction of machine learning models of lipid metabolism-related long non-coding RNA in lung adenocarcinoma is associated with microenvironmental heterogeneity and immunotherapy

Using various bioinformatics tools, we constructed a prognostic model integrating the expression profiles of lipid metabolization-related lncRNAs and clinical features. Our study discovered that various lipid metabolism-related lncRNAs were linked to the prognosis of lung adenocarcinoma. The link between immune cell infiltration in the tumour microenvironment and the expression level of lncRNAs involved with lipid metabolism was also investigated. Our findings suggest that there is a complex interplay between lipid metabolism, microenvironmental heterogeneity, and immunotherapy in lung adenocarcinoma. Furthermore, the study has significant clinical implications for the development of effective therapies for patients with lung adenocarcinoma by investigating the potential of these lncRNAs as biomarkers for anticipating the response to immunotherapy. Finally, our study emphasises the significance of continued analysis of lncRNAs associated with lipid metabolism in tumours to better understand the mechanisms behind the incidence and progression of lung adenocarcinoma. Several of the strengths of our work are the extensive analysis of the relationship between lipid metabolism and lncRNAs in lung adenocarcinoma and the utilization of a sizable sample size from the TCGA-LUAD cohort. However, there are also some limitations. Firstly, the mechanisms of how these lncRNAs interact with lipid metabolism pathways and immune response require further investigation. Secondly, our study was based on bioinformatics analysis and lacked experimental verification. Finally, our study was limited to the TCGA-LUAD cohort and further validation using other independent cohorts is required. In conclusion, our study provides a comprehensive and systematic analysis of lncRNAs associated with lipid metabolism in lung adenocarcinoma. Lung cancer patients may benefit from using identified lncRNAs as therapeutic targets and prognostic biomarkers. Validating these findings and confirming the potential therapeutic applications of these lncRNAs will require more mechanistic research.

In vivo evaluation of anti-diarrheal activity of hydroalcoholic extract and solvent fractions of the leaf of Leucas deflexa Hook.f (Lamiaceae) in rodents

The emergence of antibiotic-resistant bacteria has intensified the search for novel antidiarrheal drug. Plant-derived extracts offer promising alternatives due to their ability to modulate gut motility and enhance water absorption. The leaves of Leucas deflexa Hook.f., a plant native to Ethiopia, have been traditionally utilized in the treatment of diarrheal diseases. Nonetheless, its traditional application has yet to be scientifically confirmed. Hence, the aim of the present study was to evaluate antidiarrheal activity of the crude extract and fractions of the leaf of Leucas deflexa Hook.f (Lamiaceae). Healthy Swiss albino mice were randomly divided into five groups per experimental model: castor oil-induced diarrhea, gastrointestinal motility, and anti-enteropooling assays. The control group received distilled water (10ml/kg), while the positive control was treated with loperamide (3mg/kg). The remaining groups were administered various dosages (LD100, LD200, and LD400 mg/kg) of a hydroalcoholic extract or its fractions from Leucas deflexa Hook.f. The crude extract and chloroform fraction substantially (P<0.001) delayed the onset of diarrhea, reduced fecal frequency, and decreased total fecal weight at all administered doses compared to the negative control. The butanol and aqueous fractions exhibited a substantial antidiarrheal effect at doses of 200mg/kg and 400mg/kg, respectively. All treatments, including the crude extract, chloroform, butanol, and aqueous fractions, substantially (P<0.001) reduced the volume and weight of intestinal contents at various doses. Additionally, the chloroform, aqueous fraction, and crude extract at doses of 100, 200, and 400mg/kg substantially inhibited gastrointestinal motility compared to the negative control. The results of this study corroborate the traditional use of Leucas deflexa leaves in the treatment of diarrhea. These findings give a scientific justification for further exploration of the underlying mechanisms and potential therapeutic applications of this plant extract.

Neutrophil-Mimetic Upconversion Photosynthetic Nanosystem Derived from Microalgae for Targeted Treatment of Thromboembolic Stroke.

Thromboembolic stroke constitutes the majority of brain strokes, resulting in elevated mortality and morbidity rates, as well as significant societal and economic burdens. Although intravenous thrombolysis serves as the standard clinical treatment, its narrow therapeutic window and the inflammatory response induced by tissue plasminogen activator (tPA) administration limit its efficacy. In the initial stages of stroke, the abrupt cessation of blood flow leads to an energy metabolism disorder, marked by a substantial decrease in adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, causing irreversible damage to neural cells. In this study, we introduce a neutrophil-mimetic, microalgae-derived upconversion photosynthetic nanosystem designed for targeted treatment of thromboembolic stroke. This system features upconversion nanoparticles coated with a thylakoid membrane and wrapped in an activated neutrophil membrane, further decorated with ROS-responsive thrombolytic tPA on its surface. The neutrophil-mimetic design facilitates high targeting specificity and accumulation at the thrombus site after intravenous administration. Upon exposure to elevated levels of reactive oxygen species (ROS) at the thrombus location, the nanosystem promptly demonstrated potent thrombolytic efficacy through the surface-modified tPA. Furthermore, near-infrared II (NIR-II) laser irradiation activated the generation of ATP and NADPH, which inhibited inflammatory cell infiltration, platelet activation, oxidative stress, and neuronal injury. This constructed nanoplatform not only showcases exceptional targeting efficiency at the stroke site and controllable release of the thrombolytic agent but also facilitates ATP/NADPH-mediated thrombolytic, anti-inflammatory, antioxidative stress, and neuroprotective effects. Additionally, it offers valuable insights into the potential therapeutic applications of microalgae-based derivatives in managing thromboembolic stroke.

PHYTOCHEMICAL SCREENING, ANTIMICROBIAL AND ANTI-OXIDANT ACTIVITIES OF SALVADORA PERSICA AND CALOTROPIS GIGANTEA EXTRACTS AGAINST SELECTED PATHOGENS

Multiple diseases are treated using medicinal plants nowadays. Salvadora persica and Calotropis Gigantea are beneficial herbs for traditional herbal medicine. The aim of the study was to Screen phytochemicals, antibacterial and antioxidant properties of Salvadora persica and Calotropis Gigantea against Staph. Aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella typhimurium. Methods: Phytochemicals of both Salvadora persica and Calotropis Gigantea were screened by GC-MS analyzer. Antibacterial and antioxidant activity of ethnolic and Methonolic extracts of screened phytochemicals was tested using Agar Well Diffusion and DPPH assay respectively. Salvadora persica leaf extracts (100g/ml) inhibited Staph. Aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella typhimurium. Density was used to establish the minimal inhibitory concentration of Salvadora persica and Calotropis Gigantea extracts. Results: Both plant extracts were rich in over 250 detected chemicals via GC-MS analyzer, with 52.5% of these having antibacterial and antioxidant properties Salvadora persica extracts were characterized by 1, 8-Cineole polyphenols (45%) and cyclic ethylene mercaptole (55%), demonstrating antibacterial and antioxidant effects. Meanwhile, Calotropis Gigantea extracts contained major components Campestrol (69%) and β-tocopherol (4%). Salvadora persica and Calotropis Gigantea extracts exhibited inhibition against Pseudomonas aeruginosa at 3.12 mg/ml. Antioxidant activity, assessed via the DPPH test, revealed 35% activity with 200μl of Methanolic extracts. Both Salvadora persica and Calotropis Gigantea leaf extracts exhibited antibacterial activity against Salmonella typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. Notably, Calotropis Gigantea was effective against all chosen pathogens, while Salvadora persica exclusively targeted Staphylococcus aureus. Although Calotropis Gigantea had fewer antioxidants compared to Salvadora persica, the latter's extracts held potential for mitigating oxidative stress, aging, and related disorders. Previous studies highlighted 1, 8-Cineole polyphenols (45%) and cyclic ethylene mercaptole (55%) as antibacterial and antifungal agents against Klebsiella pneumonia and Aspergillus nigar. Conclusion: These findings underscore the promising applications of Salvadora persica and Calotropis Gigantea extracts in both antimicrobial and antioxidant interventions. And can be effected against different diseases such as Typhoid, skin diseases, and disease caused by Escherichia coli and staphylococcus aureus. Further exploration of their specific mechanisms of action and potential therapeutic applications of different metabolites and chemical compounds are warranted to harness the benefits offered by these natural extracts.

Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer

Connexin 36 (Cx36) forms interneuronal gap junctions, establishing electrical synapses for rapid synaptic transmission. In disease conditions, inhibiting Cx36 gap junction channels (GJCs) is beneficial, as it prevents abnormal synchronous neuronal firing and apoptotic signal propagation, mitigating seizures and progressive cell death. Here, we present cryo-electron microscopy structures of human Cx36 GJC in complex with known channel inhibitors, such as mefloquine, arachidonic acid, and 1-hexanol. Notably, these inhibitors competitively bind to the binding pocket of the N-terminal helices (NTH), inducing a conformational shift from the pore-lining NTH (PLN) state to the flexible NTH (FN) state. This leads to the obstruction of the channel pore by flat double-layer densities of lipids. These studies elucidate the molecular mechanisms of how Cx36 GJC can be modulated by inhibitors, providing valuable insights into potential therapeutic applications.