Pharmacological Activities Research Articles

Ion Channel Piezo1 Induces Ferroptosis of Trabecular Meshwork Cells: A Novel Observation in the Pathogenesis in Primary Open Angle Glaucoma.

This study aims to elucidate the role of Piezo1, a mechanosensitive molecule, in trabecular meshwork cells (TMCs) in the context of Primary Open Angle Glaucoma (POAG), a leading cause of irreversible visual impairment. Dysfunction of the trabecular meshwork (TM) is a key factor in the elevated intraocular pressure (IOP) observed in POAG, yet the specific mechanisms leading to TM dysfunction are not fully understood. We performed cell stretching on human trabecular meshwork cells (HTMCs) and pharmacologically activated HTMCs with Yoda1 to study the role of Piezo1 in HTMCs. We focused on assessing cell viability, mitochondrial changes, lipid peroxidation, and the expression of ferroptosis-related targets such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). Cell stretching induces ferroptosis in HTMCs, and this phenomenon is reversed by Piezo1 knockdown. Additionally, pharmacological activation of Piezo1 also leads to ferroptosis in HTMCs. Furthermore, inhibiting the JNK/p38 signaling pathway was found to mitigate the ferroptotic response induced by Yoda1, thereby confirming that Piezo1 induces ferroptosis in TMCs through this pathway. Notably, our experiments suggest that Yoda1 may trigger ferroptosis in the TM of mouse eyes. Our findings demonstrate that the Piezo1 pathway is a crucial mediator of ferroptosis in TMCs, providing new insights into the pathogenic mechanisms of glaucoma, particularly POAG. This study highlights the potential of targeting the Piezo1 pathway as a therapeutic approach for mitigating TM dysfunction and managing POAG.

Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens.

Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

20 (S)-Protopanaxadiol Alleviates DRP1-Mediated Mitochondrial Dysfunction in a Depressive Model In Vitro and In Vivo via the SIRT1/PGC-1α Signaling Pathway.

Depression is a complex and common mental illness affecting physical and psychological health. Panax ginseng C. A. Mey is a traditional Chinese medicine with abundant pharmacological activity and applications in regulating mood disorders. 20 (S)-Protopanaxadiol is the major intestinal metabolite of ginsenoside and one of the active components in ginseng. In this study, we aimed to investigate the therapeutic effects of 20 (S)-Protopanaxadiol on neuronal damage and depression, which may involve mitochondrial dynamics. However, the mechanism underlying the antidepressant effects of 20 (S)-Protopanaxadiol is unelucidated. In the present study, we investigated the potential mechanisms underlying the antidepressant activity of 20 (S)-Protopanaxadiol by employing a corticosterone-induced HT22 cellular model and a chronic unpredicted mild stress (CUMS)-induced animal model in combination with a network pharmacology approach. In vitro, the results showed that 20 (S)-Protopanaxadiol ameliorated the corticosterone (CORT)-induced decrease in HT22 cell viability, decrease in 5-hydroxytryptamine (5-HT) levels, and increase in nitric oxide (NO) and malondialdehyde (MDA) levels. Furthermore, 20 (S)-Protopanaxadiol exerted improvement effects on the CORT-induced increase in HT22 cell mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, and apoptosis. In vivo, the results showed that 20 (S)-Protopanaxadiol ameliorated depressive symptoms and hippocampal neuronal damage in CUMS mice, and sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor-1-Alpha (PGC-1α) activity were activated in the hippocampus of mice, thereby alleviating mitochondrial dysfunction and promoting the clearance of damaged mitochondria. In both in vivo and in vitro models, after inhibiting SIRT1 expression, the protective effect of 20 (S)-Protopanaxadiol on mitochondria was significantly weakened, and dynamin-related protein 1 (DRP1)-mediated mitochondrial division was significantly reduced. These findings suggest that 20 (S)-Protopanaxadiol may exert neuroprotective and antidepressant effects by attenuating DRP1-mediated mitochondrial dysfunction and apoptosis by modulating the SIRT1/PGC-1α signaling pathway.

Floral Elegance Meets Medicinal Marvels: Traditional Uses, Phytochemistry, and Pharmacology of the Genus Lagerstroemia L.

The genus Lagerstroemia L. (Lythraceae), known for its exquisite flowers and prolonged flowering period, is commonly employed in traditional medicinal systems across Asian countries, where it has always been consumed as tea or employed to address ailments such as diabetes, urinary disorders, coughs, fevers, inflammation, pain, and anesthesia. Its diverse uses may be attributed to its rich active ingredients. Currently, at least 364 biological compounds have been identified from Lagerstroemia extracts, encompassing various types such as terpenes, flavonoids, phenolic acids, alkaloids, and phenylpropanoids. Extensive in vitro and in vivo experiments have examined the pharmacological activities of different extracts, revealing their potential in various domains, including but not limited to antidiabetic, anti-obesity, antitumor, antimicrobial, antioxidant, anti-inflammatory, analgesic, and hepatoprotective effects. Additionally, 20 core components have been proven to be associated with antidiabetic and hypoglycemic effects of Lagerstroemia. Overall, Lagerstroemia exhibit substantial medicinal potential, and the alignment between its traditional applications and contemporary pharmacological findings present promising opportunities for further investigation, particularly in food and health products, drug development, herbal teas, and cosmetics. However, evidence-based pharmacological research has largely been confined to in vitro screening and animal model, lacking clinical trials and bioactive compound isolations. Consequently, future endeavors should adopt a more holistic approach.

E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction-Associated Steatohepatitis.

Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis(MASH). However, the roles of macrophage E2F2 in the progression of MASH have not been elucidated. This study reveals that the expression of macrophage E2F2 is dramatically downregulated in MASH livers from mice and humans, and that this expression is adversely correlated with the severity of the disease. Myeloid-specific E2F2 depletion aggravates intrahepatic inflammation, hepatic stellate cell activation, and hepatocyte lipid accumulation during MASH progression. Mechanistically, E2F2 can inhibit the SLC7A5 transcription directly. E2F2 deficiency upregulates the expression of SLC7A5 to mediate amino acids flux, resulting in enhanced glycolysis, impaired mitochondrial function, and increased macrophages proinflammatory response in a Leu-mTORC1-dependent manner. Moreover, bioinformatics analysis and CUT &Tag assay identify the direct binding of Nrf2 to E2F2 promoter to promote its transcription and nuclear translocation. Genetic or pharmacological activation of Nrf2 effectively activates E2F2 to attenuate the MASH progression. Finally, patients treated with CDK4/6 inhibitors demonstrate reduced E2F2 activity but increased SLC7A5 activity in PBMCs. These findings indicated macrophage E2F2 suppresses MASH progression by reprogramming amino acid metabolism via SLC7A5- Leu-mTORC1 signaling pathway. Activating E2F2 holds promise as a therapeutic strategy for MASH.

Using the Cocrystal Approach as a Promising Drug Delivery System to Enhance the Dissolution and Bioavailability of Formononetin Using an Imidazole Coformer

Background: Natural isoflavones are recognized for their diverse pharmacological activities; however, their low aqueous solubility presents a significant challenge for further development. Here, we aimed to develop a cocrystal of formononetin (FMN) to improve its solubility. Methods: The formononetin-imidazole (FMN-IMD) cocrystal was prepared using liquid-assisted grinding method. The prepared cocrystal was identified through a thermal analysis of physical mixtures with various coformers. FTIR and solid-state NMR confirmed the presence of hydrogen bonds and π-π interactions in the FMN-IMD cocrystal. Results: The solubility of FMN-IMD was two to three times higher than that of crystalline FMN. The FMN-IMD cocrystal showed a 4.93-fold increase in the Cmax value and a 3.58-fold increase in the AUC compared to FMN after oral administration in rats. There were no changes in the PXRD of the FMN-IMD cocrystal after six months of storage at 40 °C. Conclusions: Thus, the FMN-IMD cocrystal is proposed as an effective solid form for oral delivery, offering enhanced solubility and physical stability.

GSK3179106 ameliorates lipopolysaccharide-induced inflammation and acute lung injury by targeting P38 MAPK

Acute lung injury (ALI) is a serious acute respiratory disease that can cause alveolar-capillary barrier disruption and pulmonary edema, respiratory failure and multiple organ dysfunction syndrome. However, there is no effective drugs in clinic until now. GSK3179106 has been reported can alleviate intestinal stress syndrome, but the protective effect of GSK3179106 on ALI has not been elucidated. The present study will evaluate the pharmacological activity of GSK3179106 on lipopolysaccharide (LPS)-induced inflammation and lung injury and clarify its underlying mechanism. We found that GSK3179106 significantly attenuated LPS-induced lung injury in vivo, accompanied by inhibited infiltration of inflammatory cells and reduced expression of inflammatory cytokines. Meanwhile, GSK3179106 dose-dependently reduced the LPS-induced IL-6 expression both in protein and gene levels in macrophages. Mechanistically, GSK3179106 could inhibited the phosphorylation of P38 MAPK induced by LPS. Importantly, results showed that there is a direct combination between GSK3179106 and P38 MAPK. Together, our findings not only clarified the anti-inflammatory activity of GSK3179106 but also discovered its new clinical indications. Therefore, compound GSK3179106 may be a potential candidate for the treatment of acute inflammatory diseases.

In vitro antifungal activity of extracts and alkaloid compounds from Piper arboreum against dermatophytes

Piper is widely distributed in subtropical regions and species of this genus are known for their potent pharmacological activities. Piper arboreum Aubl. is a traditional medicinal plant popularly known as "pau-de-angola", "jaborandi", and chili pepper, demonstrating antifungal, trypanocidal, antibacterial, and antioxidant activities. The leaves of P. arboreum were extracted using Soxhlet and dichloromethane to obtain the extract, which was then fractionated using solvents of different polarities. Samples were analyzed using ultra-high-performance liquid chromatography coupled with mass spectrometry equipped with an electrospray ionization source. Antifungal microdilution assays were performed, and scanning and transmission electron microscopy were used to assess the invasion of the pretreated nail. The minimum inhibitory concentration (MIC) values of the extract and a dichloromethane fraction were, respectively, 62.5 μg/ml and 16.0 μg/ml against Trichophyton rubrum, and 125 μg/ml and 62.5 μg/ml, and 500 μg/ml and 500 μg/ml against T. mentagrophytes, and Microsporum gypseum, respectively. No growth was observed on nail fragments exposed to the extract (at concentrations > 64 µg/ml and then inoculated with spore suspension. Transmission electron microscopy revealed strong inhibition of hyphal growth and an irregular growth pattern following treatment with the extract and the dichloromethane fraction. Results demonstrated the antifungal properties of the P. arboreum extract and its dichloromethane fraction against dermatophytes, with the identification of three different alkaloid compounds. The cytotoxicity was specific towards the fungal cells, and morphological and ultrastructural analyses indicated damage to the cell wall and cytoplasmic membrane as the potential mechanism of action. The leaf material used to generate the extract can be taken from the plant without any detrimental effect thus enabling strategies to be implemented for the exploitation of this species.

CAMP/PKA-mediated in vitro angiogenesis: A novel interplay between PKA, RhoA/ROCK, and VEGFR2 signalling

Abstract Background and Aims Others and we have previously demonstrated that cAMP/PKA signalling stabilise endothelial cell (EC) barrier function via modulating the activities of Rho GTPases, mainly RhoA and Rac1. In the present study we analysed whether cAMP/PKA also modulates EC angiogenesis capacity and whether Rho GTPases are involved in this function. Methods The study was carried out on cultured human umbilical vein ECs (HUVECs). RhoA and Rac1 activities were genetically manipulated by lentiviral-mediated over expression of dominant negative (DN) and constitutive active (CA) forms of RhoA and Rac1. Pharmacologically, specific activation and inhibition of PKA was achieved by using cAMP analogue N6-Benzoyl-cAMP (5 mM) and PKI (1 µM), respectively. Pharmacologically, Rac1 was inhibited using NSC 23766 (10 µM) and RhoA was activated using Rho activator I (Cytoskeleton Inc.). In vitro angiogenesis was analysed by 3-D spheroid assay and matrigel tube formation assay. Results Pharmacologically, specific activation of PKA induced EC migration (Wound healing assay), tube formation, and 3-D spheroids and potentiated the VEGF-induced in vitro angiogenesis. These pro-angiogenesis activities were abrogated by highly specific cell-permeable peptide inhibitor (PKI) of PKA. Activation of cAMP/PKA-signalling resulted in an increased VEGFR2 and Akt phosphorylation, increased Rac1 activity, and a strong inhibition of RhoA/Rock pathway. Pharmacological activation of RhoA but not inhibition of Rac1 abrogated PKA-induced VEGFR2 phosphorylation, tube formation and 3-D spheroids. Lentiviral mediated over-expression of constitutive active form of RhoA but not Rac1 abrogated PKA-induced VEGFR2 and Akt phosphorylation and angiogenesis. Moreover, pharmacological inhibition of Akt also abrogated PKA-mediated VEGFR2 phosphorylation and angiogenesis. Likewise, over expression of either dominant negative RhoA or pharmacological inhibitors of Rho kinase (ROCK) promoted basal and potentiated PKA-mediated VEGFR2 and Akt phosphorylation and angiogenesis. Conclusion We describe for the first time a novel interplay between PKA, RhoA/ROCK, Akt, and VEGFR2 signalling and angiogenesis. Inhibition of RhoA/ROCK plays an important role in mediating PKA-induced angiogenesis and activation of RhoA/ROCK signalling may offer an important target to intervene therapeutic angiogenesis.

Antimicrobial Potential of Scorpion-Venom-Derived Peptides.

The frequent and irrational use of antibiotics by humans has led to the escalating rise of antimicrobial resistance (AMR) with a high rate of morbidity-mortality worldwide, which poses a challenge to the development of effective treatments. A large number of host defense peptides from different organisms have gained interest due to their broad antibacterial spectrum, rapid action, and low target resistance, implying that these natural sources might be a new alternative to antimicrobial drugs. As important effectors of prey capture, defense against other animal attacks, and competitor deterrence, scorpion venoms have been developed as important candidate sources for modern drug development. With the rapid progress of bioanalytical and high throughput sequencing techniques, more and more scorpion-venom-derived peptides, including disulfide-bridged peptides (DBPs) and non-disulfide-bridged peptides (NDBPs), have been recently identified as having massive pharmacological activities in channelopathies, pathogen infections, and cancer treatments. In this review, we summarize the molecular diversity and corresponding structural classification of scorpion venom peptides with antibacterial, antifungal, and/or antiparasitic activity. We also aim to improve the understanding of the underlying mechanisms by which scorpion-venom-derived peptides exert these antimicrobial functions, and finally highlight their key aspects and prospects for antimicrobial therapeutic or pharmaceutical application.

Flavonoid Based Development of Synthetic Drugs: Chemistry and Biological Activities.

The toxicity associated with synthetic drugs used for treating various diseases is common. This led to a growing interest in searching and incorporating natural functional core structures such as flavonoid and their derivativesviachemical modifications to overcome the toxicity problems andenhance their biological spectrum. Natural core structures such as flavonoids are accepted due to their safety to the environment and owing to their varieties of biological activities such as anti-Alzheimer, antimicrobial, anticancer, anti-inflammatory, antidiabetics, and antiviral properties.Based on their chemical structure, flavonoids are classified into various classes such as flavone, flavanol, flavanone, isoflavone, and Anthocyanin, etc.The present review focuses onthe potential role of the flavonoid ring-containing derivatives, highlighting their ability to prevent and treat non-communicable diseases such as diabetes, Alzheimer's, and cancer. The pharmacological activities of the flavonoid's derivatives are mainly attributed to their antioxidant effects against free radicals, and reactive oxygen species as well as their ability to act as enzymes inhibitors. The reviewcovers the synthetic strategies of flavonoid derivatives, structure activity relationship (SAR), andin silicostudies to improve the efficacy of these compounds. TheSAR,molecular docking analysis will enable medicinal chemists to search further, develop potent and newer therapeutic agents.

Evaluating the biological activity of rolB-transgenic Nicotiana tabacum plants using phytochemical and pharmacological approaches

The present study explored the impact of rolB gene transformation on biological activities of Nicotiana tabacum. PCR, and RT-qPCR were used to validate the integration of rolB gene and its expression. HPLC analysis was used for phytochemical profiling, and various in-vitro and in-vivo assays were used to assess pharmacological activities of wild-type and transgenic extracts using ANOVA and Tukey’s multiple comparison method for data analysis. Our findings indicated increased total phenolic content (24.4 ± 0.2 mg GAE/g DW of extract) and total flavonoid content (58.8 ± 1.1 mg QE/g DW of extract) in transgenic plants. In case of antioxidant activities, an increase in reducing power (51.82 ± 0.4 AAE mg/g), and radical scavenging (IC50 188 ± 2.7 µg/mL) was observed. Similarly, transgenic lines exhibited DNA protection against damage caused by free radicals. Moreover, we detected significant antileishmanial potential (IC50 350.7 ± 8.3 µg/mL), butyrylcholinesterase (IC50 268.6 ± 4.7 µg/mL), and acetylcholinesterase inhibitions (IC50 421.6 ± 3.7 µg/mL) in transgenic plants. Similarly, compared with the non-transgenic plants, the rolB-transgenic plants showed increased analgesic (71.4%), anti-inflammatory activities (77.8%), and 35.6% decrease in depression compared to non-transgenic plants. The improved pharmacological activities in transgenic plants have been linked to the level of phytochemicals that increase the therapeutic and curative properties of N. tabacum plants.

Curcumin Administration Routes in Breast Cancer Treatment.

Breast cancer is a public health concern worldwide, characterized by increasing incidence and mortality rates, requiring novel and effective therapeutic strategies. Curcumin is a bioactive compound extracted from turmeric with several pharmacological activities. Curcumin is a multifaceted anticancer agent through mechanisms including the modulation of signaling pathways, inhibition of cell proliferation, induction of apoptosis, and production of reactive oxygen species. However, the poor water solubility and bioavailability of curcumin create important barriers in its clinical application. This review elaborates on the therapeutic potential of curcumin in breast cancer treatment, focusing on the efficacy of different administration routes and synergistic effects with other therapeutic agents. The intravenous administration of curcumin-loaded nanoparticles significantly improves bioavailability and therapeutic outcomes compared to oral routes. Innovative formulations, such as nano-emulsifying drug delivery systems, have shown promise in enhancing oral bioavailability. While intravenous delivery ensures higher bioavailability and direct action on tumor cells, it is more invasive and expensive than oral administration. Advancing research on curcumin in breast cancer treatment is essential for improving therapeutic outcomes and enhancing the quality of life of patients.

Exploring Cheura [Diploknema Butyracea (Roxb.) H. J. Lam]: Unveiling its Ethnomedicinal Heritage, Phytochemical Composition, Pharmacological Properties, and Innovative Applications.

Diploknema butyracea (Roxb) H.J Lam, also referred as "Kalpavriksha", is commonly known as Gophal, Cheura, or Indian butter tree. It is a deciduous tree with straight trunks of 15-20 m in height and white-yellow-coloured fragile flowers with fragrance, found at altitudes of 300-1500 m in the sub-Himalayan region of India, China, Nepal, and Bhutan. Diploknema have 11 taxa and 8 species, out of which 3 species are found in Uttarakhand hills, Sikkim, Darjeeling, Arunachal Pradesh, and Assam. The tree holds significant economic importance, serving various purposes within ethnic communities. Its high lipid content makes it valuable for food, medicine, construction, and the production of various value-added products. The ethno-pharmacological applications encompass treating rheumatism, burns, asthma, and various skin conditions. The plant's different components-bark, leaves, flowers, seeds, and fruits-contain a diverse array of phytoconstituents, including alkaloids, tannins, flavonoids, steroids, terpenoids, and palmitic acid, along with essential nutrients like sodium, calcium, potassium, iron, magnesium, zinc, and various sugars which shows diverse pharmacological and therapeutic activities. Beyond traditional uses, Diploknema is important for diverse industrial application in pharmaceuticals, confectionery, nutraceuticals, and cosmetics. Present paper is an attempt to understand comprehensive details on different aspects of this plant to explore new avenues for various value-added products.

Structural and Solution Speciation Studies on fac-Tricarbonylrhenium(I) Complexes of 2,2'-Bipyridine Analogues.

In this study, we report the synthesis and characterization of 12 novel rhenium(I) complexes with the general formula fac-[Re(CO)3(NN)X]n+ where (NN) is a 2,2'-bipyridine analogue ligand, X = Cl-, Br-, or H2O, and n = 0 or 1, focusing on their speciation in an aqueous solution. The prepared organorhenium complexes are stable in a wide pH range in an aqueous solution, and no release of the bidentate ligands or the carbonyl ligands was observed. The stability of the complexes in various biologically relevant matrices (cell culture medium and real blood serum) was also demonstrated. However, the simultaneous substitution of the halido ligand by water and slow hydrolysis of the ester bonds in the ligands were observed, affecting both the solubility and the lipophilicity of the compounds. The aqua complexes became more lipophilic in the presence of chloride ions, while the hydrophilicity increased significantly with time due to the hydrolysis of the ester bonds, which probably contributed to their weak pharmacological activity. The results also showed kinetically hindered aqueous solvation of the halido complexes and low chloride ion affinity of the aqua complexes. The deprotonation of the coordinated aqua ligand in the complexes occurs in the pH = 7-10 range, leading to significant formation (18-30%) of hydroxido species at pH = 7.4. The halido complexes showed somewhat higher cytotoxicity (IC50 = 60-99 μM) on human colon adenocarcinoma cancer cells (Colo205 and Colo320) than the corresponding aqua complexes (IC50 > 100 μM). In all cases, no antibacterial effect was observed (MIC > 100 μM), but some of the complexes showed moderate antiviral activity (IC50 ∼ 50 μM) on Herpes simplex virus 2.

Effects of six antipsychotic drug treatment regimens on short-term heart rate variability in patients with schizophrenia.

Many antipsychotic drugs have cardiac side effects due to their pharmacological actions. Heart rate variability (HRV) analysis can be used as a potential indicator of cardiotoxicity in cases where a decrease in HRV occurs after the administration of antipsychotics such as clozapine. The purpose of this study was to explore the effects of 6 antipsychotic drug regimens on short-term HRV in patients with schizophrenia. Data from 164 patients with schizophrenia between January 2018 and June 2023 were retrospectively analysed. Based on the drug used for treatment, the patients were categorised into clozapine combination (clozapine combined with aripiprazole, risperidone or ziprasidone), clozapine alone, olanzapine, aripiprazole, ziprasidone or risperidone groups. Heart rate variability indices were calculated using time domain analysis, including the standard deviation of the RR intervals (SDNN), the root mean square of successive RR interval differences (RMSSD) and the percentage of successive RR intervals over 50ms (PNN50). Compared with the pretreatment period, the SDNN, RMSSD and PNN50 were significantly lower in the clozapine combination, clozapine, olanzapine and aripiprazole groups at the end of weeks 2 and 4 of treatment (P < 0.05). However, these indicators in ziprasidone and risperidone groups did not show this significant decrease (P > 0.05). The effects of clozapine combination and clozapine on HRV were greater than for olanzapine, aripiprazole, ziprasidone or risperidone. Attention should be paid to controlling the dosage of clozapine combination and clozapine and monitoring the patient's electrocardiogram during administration.

In Silico and ADMET Studies of Spiro-Quinazoline Compounds as Acetylcholine Esterase Inhibitors Against Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors are used in primary pharmacotherapy for numerous neurodegenerative conditions, providing their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, quinazoline derivatives have emerged as a compelling model for neurodegenerative disease treatment, showcasing promising pharmacological features. Their unique structural features and pharmacokinetic profiles have sparked interest in their potential efficacy and safety across diverse neurodegenerative disorders. The exposure of quinazoline derivatives as a potential therapeutic way underscores the imperative for continued research exploration. Their multifaceted mechanisms of action and ability to target various pathways implicated in neurodegeneration offer exciting prospects for developing novel, effective, and well-tolerated treatments. Further investigations into their pharmacological activities and precise therapeutic roles are essential to advance our understanding of neurodegenerative disease pathophysiology and promote the development of modern therapeutic strategies to address this critical medical challenge. Quinazoline derivatives have gained eminent acetylcholinesterase (AChE) inhibitory activity. Their ability to effectively modulate AChE activity makes them promising candidates for treating neurological disorders, particularly Alzheimer's disease (AD). Their intricate molecular structures confer selectivity and affinity for AChE, offering potential for the development of novel therapeutic agents targeting cholinergic pathways. Hence, in this study, we designed, synthesized, and characterized a series of spiro[cycloalakane-1,2'-quinazoline derivatives (1-6) to assess their possible AChE inhibiting ability using docking into the active sites. The AChE inhibitory potential of spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) was explored via docking studies of the AChE active site. The findings revealed significant inhibitory activity and highlighted the promising nature of these derivatives. The synthesized spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) exhibited their notable potential as AChE inhibitors. The observed significant inhibitory activity suggested that these derivatives warrant further exploration as candidates for developing therapeutic agents in AChE inhibitory pathways. This study emphasizes the relevance of quinazoline derivatives in searching for novel treatments for neurological disorders, particularly associated with cholinergic dysfunction, and they could be a useful alternative therapeutic agent.

A Study on the Rationality of Baicalein in the Treatment of Osteoporosis: A Narrative Review.

Baicalein (BN) is an active ingredient naturally present in Chinese herbs, such as Scutellaria baicalein, Coptis chinensis, and Dendrobium officinale. It has a variety of pharmacological activities, including antioxidant, anti-inflammatory and antibacterial effects. Therefore, Baicalein (BN) is widely used in the field of medicine and is considered a potential natural medicine. Osteoporosis (OP) is a bone metabolic disease characterized by decreased bone mineral density and bone structure destruction, which is mainly caused by decreased bone formation and increased bone resorption. With the continuous development of molecular biology, the signaling pathways and gene targets of bone metabolism are also expanding. Recent studies have shown that baicalein may affect the function of osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells through MAPK/ERK and MAPKs/NF-κB signaling pathways, so as to have a therapeutic effect on OP. However, the specific mechanism of baicalein in the treatment of OP is still unclear. This article reviews the literature, analyzes and summarizes the mechanism of action of baicalein, and discusses its potential in the prevention and treatment of OP, so as to provide a basis for the clinical application of baicalein.

Coumarin Derivatives: Pioneering New Frontiers in Biological Applications

Abstract: Coumarins are a vital class of compounds recognized for their significant therapeutic potential, both in their natural forms and as synthetic derivatives. Characterized by a benzene ring fused to an α-pyranose ring, coumarins have garnered considerable attention from the scientific community due to their diverse pharmacological activities. This review article highlights the importance of coumarin hybrids, showcasing their enhanced biological properties and reactivity compared to traditional coumarin structures. We explore the pharmacological profiles of various coumarin derivatives, including their anti-cancer, anti-inflammatory, antiviral, antioxidant, antibacterial, and anti-tuberculosis activities, among others. The review examines how the incorporation of different functional groups on the coumarin scaffold can modulate its effectiveness against various diseases, particularly cancer. Furthermore, we discuss promising results from coumarin-based hybrids, such as coumarinpyridine, coumarin-uracil, and coumarin-quinoline derivatives, demonstrating their efficacy against a range of pathogens. This comprehensive overview serves as a valuable resource for researchers interested in the potential of coumarin derivatives in therapeutic applications.

Mitochondrial fatty acid oxidation drives senescence.

Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.