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The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. Tom1, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including Brwd1, Pcp4, Phb1l2 and Mmp15 were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats. Show less

Salvia miltiorrhiza, a prominent traditional Chinese medicinal resource, has been extensively employed in the management of cardiovascular and cerebrovascular ailments. Ensuring the consistency of S. miltiorrhiza raw materials revolves around the imperative task of maintaining stable tanshinones content and composition. An effective approach in this regard involves the utilization of endophytic fungi as inducers. Within this context, our study spotlights an endophytic fungus, Penicillium steckii DF33, isolated from the roots of S. miltiorrhiza. Remarkably, this fungus has demonstrated a significant capacity to boost the biosynthesis and accumulation of tanshinones. The primary objective of this investigation is to elucidate the underlying regulatory mechanism by which DF33 enhances and regulates the biosynthesis and accumulation of tanshinones. This is achieved through its influence on the differential expression of crucial CYP450 genes within the S. miltiorrhiza hairy roots system. The results revealed that the DF33 elicitor not only promotes the growth of hairy roots but also enhances the accumulation of tanshinones. Notably, the content of cryptotanshinone was reached 1.6452 ± 0.0925 mg g Show less

In the early stages of sporadic Alzheimer's disease (SAD), there is a strong correlation between memory impairment and cortical levels of soluble amyloid-β peptide oligomers (Aβ). It has become clear that Aβ disrupt glutamatergic synaptic function, which can in turn lead to the characteristic cognitive deficits of SAD, but the actual pathways are still not well understood. This opinion article describes the pathogenic mechanisms underlying cerebral amyloidosis. These mechanisms are dependent on the amyloid precursor protein and concern the synthesis of Aβ peptides with competition between the non-amyloidogenic pathway and the amyloidogenic pathway (i.e. a competition between the ADAM10 and BACE1 enzymes), on the one hand, and the various processes of Aβ residue clearance, on the other hand. This clearance mobilizes both endopeptidases (NEP, and IDE) and removal transporters across the blood-brain barrier (LRP1, ABCB1, and RAGE). Lipidated ApoE also plays a major role in all processes. The disturbance of these pathways induces an accumulation of Aβ. The description of the mechanisms reveals two key molecules in particular: (i) free estradiol, which has genomic and non-genomic action, and (ii) free DHA as a preferential ligand of PPARα-RXRα and PPARɣ-RXRα heterodimers. DHA and free estradiol are also self-regulating, and act in synergy. When a certain level of chronic DHA and free estradiol deficiency is reached, a permanent imbalance is established in the central nervous system. The consequences of these deficits are revealed in particular by the presence of Aβ peptide deposits, as well as other markers of the etiology of SAD. Show less

The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2. Potential "off-target" effects of BT2 have not been considered, however. We therefore tested for metabolic off-target effects of BT2 in Show less

Alzheimer's disease is a neurodegenerative disorder accounting for 60-80% of dementia cases and is accompanied by a high mortality rate in patients above 70 years of age. The formation of senile plaques composed of amyloid-β protein is a hallmark of Alzheimer's disease. Beta-site APP cleaving enzyme 1 (BACE1) is a proteolytic enzyme involved in the degradation of amyloid precursor protein, which further degrades to form toxic amyloid-β fragments. Hence, inhibition of BACE1 was stated to be an effective strategy for Alzheimer's therapeutics. Keeping in mind the structures of different BACE1 inhibitors that had reached the clinical trials, we designed a library of compounds (total 164) based on a substituted 5-amino tetrazole scaffold which was an isosteric replacement of the cyclic amidine moiety, a common component of the BACE1 inhibitors which reached the clinical trials. The scaffold was linked to different structural moieties with the aid of an amide or sulfonamide bond to design some novel molecules. Molecular docking was initially performed and the top 5 molecules were selected based on docking scores and protein-ligand interactions. Furthermore, molecular dynamic simulations were performed for these molecules (3g, 7k, 8n, 9d, 9g) for 100 ns and MM-GBSA calculations were performed for each of these complexes. After critical evaluation of the obtained results, three potential molecules (9d, 8n, and 7k) were forwarded for prolonged stability studies by performing molecular dynamic simulations for 250 ns and simultaneous MM-GBSA calculations. It was observed that the compounds (9d, 8n, and 7k) were forming good interactions with the amino acid residues of the catalytic site of the enzyme with multiple non-covalent interactions. In MD simulations, the compounds have shown better stability and better binding energy throughout the runtime. Show less

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. It shares significant phenotypic overlap with several closely related disorders caused by mutations in the RAS-MAPK pathway (mosaic RASopathies). We report a diagnostically challenging case of ECCL in which next-generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. Patients with FGFR1-associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications. Show less

Accumulating evidence has illustrated that the E3 ubiquitin ligases critically participate in the development and progression of cardiovascular diseases. Dysregulation of E3 ubiquitin ligases exacerbates cardiovascular diseases. Blockade or activation of E3 ubiquitin ligases mitigates cardiovascular performance. Therefore, in this review, we mainly introduced the critical role and underlying molecular mechanisms of E3 ubiquitin ligase NEDD4 family in governing the initiation and progression of cardiovascular diseases, including ITCH, WWP1, WWP2, Smurf1, Smurf2, Nedd4-1 and Nedd4-2. Moreover, the functions and molecular insights of other E3 ubiquitin ligases, such as F-box proteins, in cardiovascular disease development and malignant progression are described. Furthermore, we illustrate several compounds that alter the expression of E3 ubiquitin ligases to alleviate cardiovascular diseases. Therefore, modulation of E3 ubiquitin ligases could be a novel and promising strategy for improvement of therapeutic efficacy of deteriorative cardiovascular diseases. Show less

Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression. Show less

The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event and increases the speed of Alzheimer's disease (AD). Additionally, the pathogenesis of AD is intricate and a single drug may not be enough to achieve a satisfactory therapeutic outcome. Herein, we reported a facile and effective gene therapy strategy for the modulation of microglia function and intervention of Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). The biomimetic nanovesicles codelivery β-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) and TREM2 plasmid (pTREM2) gene drug efficiently penetrate the blood-brain barrier and enhance the drug accumulation at AD lesions with the help of exosomes homing ability and angiopep-2 peptides. Specifically, an upregulation of TREM2 expression can reprogram microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype while also restoring its capacity to phagocytose Aβ and its nerve repair function. In addition, siRNA reduces the production of Aβ plaques at the source by knocking out the BACE1 gene, which is expected to further enhance the therapeutic effect of AD. The in vivo study suggests that TSEL through the synergistic effect of two gene drugs can ameliorate APP/PS1 mice cognitive impairment by regulating the activated microglial phenotype, reducing the accumulation of Aβ, and preventing the retriggering of neuroinflammation. This strategy employs biomimetic nanovesicles for the delivery of dual nucleic acids, achieving synergistic gene therapy for AD, thus offering more options for the treatment of AD. Show less

Fragile X syndrome (FXS) arises from the loss of fragile X messenger ribonucleoprotein (FMRP) needed for normal neuronal excitability and circuit functions. Recent work revealed that FMRP contributes to mossy fiber long-term potentiation by adjusting the Kv4 A-type current availability through interactions with a Cav3-Kv4 ion channel complex, yet the mechanism has not yet been defined. In this study using wild-type and Show less

To observe the dynamic changes in monocyte subsets during septic lung injury and to assess the anti-inflammatory role of the sulfotransferase homolog 2 (ST2) receptor. Dynamic changes of monocyte subsets from patients with septic lung injury and mice post-cecal ligation and puncture (CLP) were monitored. ST2 receptors on mice monocytes and concentrations of IL-33, IL-1β, IL-12, and IL-27 from peripheral blood or culture supernatant were detected. CD14 Changes in monocyte subsets expressing the ST2 receptor play an important role in septic lung injury by modulating inflammatory cytokine secretion. Show less

The study evaluated the association of Case-control study. Brazilian Oral Cleft Group. The study included 881 healthy controls and 800 patients with different types of NSOC: 232 with cleft lip only (NSCLO), 568 with cleft lip and palate (NSCLP), and 274 with cleft palate only (NSCPO). The genomic DNA was genotyped with allelic discrimination assays for five Although only nominal Our results demonstrate an increased risk of NSCL  ±  P in Brazilian individuals with enrichment of African ancestry in the presence of the Show less

The hypoxic microenvironment in esophageal carcinoma is an important factor promoting the rapid progression of malignant tumor. This study was to investigate the lactylation of Axin1 on glycolysis in esophageal carcinoma cells under hypoxia exposure. Hypoxia treatment increases pan lysine lactylation (pan-kla) levels of both TE1 and EC109 cells. Meanwhile, ECAR, glucose consumption and lactate production were also upregulated in both TE1 and EC109 cells. The expression of embryonic stem cell transcription factors NANOG and SOX2 were enhanced in the hypoxia-treated cells. Axin1 overexpression partly reverses the induction effects of hypoxia treatment in TE1 and EC109 cells. Moreover, lactylation of Axin1 protein at K147 induced by hypoxia treatment promotes ubiquitination modification of Axin1 protein to promote glycolysis and cell stemness of TE1 and EC109 cells. Mutant Axin1 can inhibit ECAR, glucose uptake, lactate secretion, and cell stemness in TE1 and EC109 cells under normal or hypoxia conditions. Meanwhile, mutant Axin1 further enhanced the effects of 2-DG on inhibiting glycolysis and cell stemness. Overexpression of Axin1 also inhibited tumor growth in vivo, and was related to suppressing glycolysis. In conclusion, hypoxia treatment promoted the glycolysis and cell stemness of esophageal carcinoma cells, and increased the lactylation of Axin1 protein. Overexpression of Axin1 functioned as a glycolysis inhibitor, and suppressed the effects of hypoxia exposure in vitro and inhibited tumor growth in vivo. Mechanically, hypoxia induces the lactylation of Axin1 protein and promotes the ubiquitination of Axin1 to degrade the protein, thereby exercising its anti-glycolytic function. Show less

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer related deaths globally. Despite advancements in treatment, drug resistance and adverse side effects have spurred the search for novel therapeutic strategies. This study aimed to investigate how the Show less

Bempedoic acid is a new drug that improves the control of cholesterol levels, either as monotherapy or in combination with existing lipid-lowering therapies, and shows clinical efficacy in cardiovascular disease patients. Thus, patients with comorbidities and under multiple therapies may be eligible for bempedoic acid, thus facing the potential problem of drug-drug interactions (DDIs). Bempedoic acid is a prodrug administered orally at a fixed daily dose of 180 mg. The dicarboxylic acid is enzymatically activated by conjugation with coenzyme A (CoA) to form the pharmacologically active thioester (bempedoic acid-CoA). This process is catalyzed by very-long-chain acyl-CoA synthetase 1 (ACSVL1), expressed almost exclusively at the hepatic level. Bempedoic acid-CoA is a potent and selective inhibitor of ATP citrate lyase (ACL), a key enzyme in the biosynthetic pathway of cholesterol and fatty acids. The drug reduces low-density lipoprotein-cholesterol (LDL-C) (20-25%), non-high-density lipoprotein-cholesterol (HDL-C) (19%), apolipoprotein B (apoB) (15%), and total cholesterol (16%) in patients with hypercholesterolemia or mixed dyslipidemia. The drug has a favorable pharmacokinetics profile. Bempedoic acid and its metabolites are not substrates or inhibitors/inducers of cytochrome P450 (CYP450) involved in drug metabolism. On the other hand, bempedoic acid-glucuronide is a substrate for organic anion transporter 3 (OAT3). Bempedoic acid and its glucuronide are weak inhibitors of the OAT2, OAT3, and organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Thus, bempedoic acid could inhibit (perpetrator) the hepatic uptake of OATP1B1/3 substrate drugs and the renal elimination of OAT2 and OAT3 substrates and could suffer (victim) the effect of OAT3 transporter inhibitors, reducing its renal elimination. Based on these pharmacological characteristics, here, we describe the potential DDIs of bempedoic acid with concomitant medications and the possible clinical implications. Show less

Sporadic Alzheimer's disease (SAD) represents a major health concern especially among elderly. Noteworthy, neuroinflammation and oxidative stress are highly implicated in AD pathogenesis resulting in enhanced disease progression. Moreover, most of the available anti-Alzheimer drugs have several adverse effects with variable efficacy, therefore new strategies, including agents with anti-inflammatory and antioxidant effects, are encouraged. Along these lines, canagliflozin (CAN), with its anti-inflammatory and anti-apoptotic activities, presents a promising candidate for AD treatment. Therefore, this study aimed to evaluate the therapeutic potential of CAN via regulation of AMPK/SIRT-1/BDNF/GSK-3β signaling pathway in SAD. SAD model was induced by intracerebroventricular streptozotocin injection (ICV-STZ;3 mg/kg, once), while CAN was administered (10 mg/kg/day, orally) to STZ-treated mice for 21 days. Behavioral tests, novel object recognition (NOR), Y-Maze, and Morris Water Maze (MWM) tests, histopathological examination, total adenosine monophosphate-activated protein kinase (T-AMPK) expression, p-AMPK, and silent information regulator-1 (SIRT-1) were evaluated. Furthermore, brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3β (GSK-3β), acetylcholinesterase (AChE), Tau protein, insulin-degrading enzyme (IDE), nuclear factor erythroid-2 (Nrf-2), interleukin-6 (IL-6), nuclear factor kappa-B-p65 (NFκB-p65), beta-site APP cleaving enzyme 1 (BACE-1), and amyloid beta (Aβ) plaque were assessed. CAN restored STZ-induced cognitive deficits, confirmed by improved behavioral tests and histopathological examination. Besides, CAN halted STZ-induced neurotoxicity through activation of p-AMPK/SIRT-1/BDNF pathway, subsequently reduction of GSK-3β, Tau protein, AChE, NFκB-p65, IL-6, BACE-1, and Aβ plaque associated with increased IDE and Nrf-2. Consequentially, our findings assumed that CAN, via targeting p-AMPK/SIRT-1 pathway, combated neuroinflammation and oxidative stress in STZ-induced AD. Thus, this study highlighted the promising effect of CAN for treating AD. Show less

Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a rare group of neoplasms that share features of eosinophilia and lineage promiscuity. First, we described a challenging case of acute leukemia with lineage switch and cytogenetically cryptic FGFR1. Second, we aimed to systemically review this phenomenon in published literature. A 68-year-old man with a history of chemotherapy exposure presented with acute leukemia of myeloid lineage without eosinophilia or 8p11 abnormalities on karyotyping. Over a refractory and relapsing course, the blast phenotype shifted to B lymphoid. Fluorescence in situ hybridization identified a cytogenetically cryptic FGFR1 rearrangement, likely a paracentric inversion. We identified 26 published cases of FGFR1-rearranged acute leukemia with ambiguous, mixed, or switching lineage. Although there was variability in the partner gene, anatomical location of different phenotypes, and timing of lineage switch, the prognosis was consistently poor in the absence of novel therapy. Ours is the only reported case of FGFR1-rearranged neoplasms with a disease sequence of acute myeloid leukemia transforming to B-cell acute lymphoblastic leukemia and 1 of only 3 reported cases with cytogenetically cryptic FGFR1 rearrangement. Fluorescence in situ hybridization testing for FGFR1 rearrangement should be a standard investigation in leukemia of mixed or switching lineage. Show less

Alzheimer's disease is the most common neurodegenerative disease with therapeutic limitations. Insulin resistance plays a role in the progression of Alzheimer's disease. Therapies that modulate insulin secretion and signaling, as well as oxidative stress in the brain are now being investigated for their potential role in the prevention of Alzheimer's disease (AD). Terminalia macroptera (Combretaceae) is a plant that different parts have been used traditionally for the treatment of metabolic and neurological conditions. Previous study has indicated that the crude extract exhibit anti-diabetic property. In addition, the plant is a rich source of tannins, phenolic acids, flavonoids, triterpenes. However, there is no study on its protective effect against biochemical alterations of AD in diabetic rats. The present research study investigated the neuroprotective effects of TeMac™ on Alzheimer-like pathology induced by aluminum chloride (AlCl A phytochemical analysis of TeMac™ was carried out to quantify tannins. The potential effect of the tannins-enriched fraction (TEF) of TeMac™ to prevent the formation of senile plaques was conducted by its ability to inhibit the activities of β-secretase (EC 3.4.23.46), monoamine oxidase A (EC 1.4.3.4) and the fibrillation of Aβ. A diabetic model was induced from female Wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 35 mg/kg BW). After that, the blood glucose level was measured to confirm the induction of diabetes. Three days after induction, animals received AlCl TEF of TeMac™ displays a potential ability to inhibit the activities of β-secretase, monoamine oxidase, and Aβ fibrillation. Treatment with TEF of TeMac™ significantly inhibited DPP4 and BACE1 activities and reduced brain glucose and amyloid fibril levels, and improved cerebral albumin levels and modulated oxidative stress markers. Our findings indicate that TEF of TeMac™ prevents Alzheimer's-type pathology linked to insulin resistance in rats. TEF of TeMac™ may be a potential drug candidate for the treatment of diabetes-associated cognitive impairment. Show less

Introduction Diabetes mellitus is characterized by chronic hyperglycemia due to insulin deficiency, leading to complications in vital organs. Among these, dyslipidemia is common, presenting as low high-density lipoprotein cholesterol (HDL-c), high triglycerides (TG), Apolipoprotein-B (Apo-B), and small dense low-density lipoprotein (sdLDL) predominance, collectively known as diabetic dyslipidemia. To assess the atherogenic risk in individuals with type 2 diabetes, the atherogenic index of plasma (AIP) and atherogenic coefficient (AC) provide valuable insights beyond routine lipid tests. AIP, calculated as log (serum TG/serum HDL-c), correlates positively with the occurrence and severity of diabetic microvascular complications. The AC ((total cholesterol (TC)-HDL-c)/HDL-c) serves as an atherogenicity marker. Waist circumference (WC), reflecting central adiposity and body mass index (BMI), are directly related to both AIP and AC, making them useful non-invasive tools to monitor atherogenicity and predict cardiovascular disease (CVD) risk independently of each other in subjects with type 2 diabetes mellitus. Material and methods This was an observational cross-sectional study conducted in the Department of Medicine of a tertiary care hospital. It included 100 type 2 diabetes mellitus patients more than 18 years of age, including both males and females. Observation and results In our study, there were 42 (42%) males and 58 (58%) females. The mean WC of males and females were 105.40 and 100.98 cm, respectively. The mean for BMI, glycated hemoglobin (HbA1c), and urine albumin-to-creatinine ratio (UACR) was 28.83 kg/m Show less

Thyroid carcinoma (TC), the most commonly diagnosed malignancy of the endocrine system, has witnessed a significant rise in incidence over the past few decades. The integration of scRNA-seq with other sequencing approaches offers researchers a distinct perspective to explore mechanisms underlying TC progression. Therefore, it is crucial to develop a prognostic model for TC patients by utilizing a multi-omics approach. We acquired and processed transcriptomic data from the TCGA-THCA dataset, including mRNA expression profiles, lncRNA expression profiles, miRNA expression profiles, methylation chip data, gene mutation data, and clinical data. We constructed a tumor-related risk model using machine learning methods and developed a consensus machine learning-driven signature (CMLS) for accurate and stable prediction of TC patient outcomes. 2 strains of undifferentiated TC cell lines and 1 strain of PTC cell line were utilized for in vitro validation. mRNA, protein levels of hub genes, epithelial-mesenchymal transition (EMT)-associated phenotypes were detected by a series of in vitro experiments. We identified 3 molecular subtypes of TC based on integrated multi-omics clustering algorithms, which were associated with overall survival and displayed distinct molecular features. We developed a CMLS based on 28 hub genes to predict patient outcomes, and demonstrated that CMLS outperformed other prognostic models. TC patients of relatively lower CMLS score had significantly higher levels of T cells, B cells, and macrophages, indicating an immune-activated state. Fibroblasts were predominantly enriched in the high CMLS group, along with markers associated with immune suppression and evasion. We identified several drugs that could be suitable for patients with high CMLS, including Staurosporine₁₀₃₄, Rapamycin₁₀₈₄, gemcitabine, and topotecan. SNAI1 was elevated in both undifferentiated TC cell lines, comparing to PTC cells. Knockdown of SNAI1 reduced the cell proliferation and EMT phenotypes of undifferentiated TC cells. Our findings highlight the importance of multi-omics analysis in understanding the molecular subtypes and immune characteristics of TC, and provide a novel prognostic model and potential therapeutic targets for this disease. Moreover, we identified SNAI1 in mediating TC progression through EMT in vitro. Show less

Alzheimer's disease (AD) presents a growing global health concern. In recent decades, natural and synthetic chromenone have emerged as promising drug candidates due to their multi-target potential. Natural chromenone, quercetin, scopoletin, esculetin, coumestrol, umbelliferone, bergapten, and methoxsalen (xanthotoxin), and synthetic chromenone hybrids comprising structures like acridine, 4-aminophenyl, 3-arylcoumarins, quinoline, 1,3,4-oxadiazole, 1,2,3-triazole, and tacrine, have been explored for their potential to combat AD. Key reactions used for synthesis of chromenone hybrids include Perkin and Pechmann condensation. The activity of chromenone hybrids has been reported against several drug targets, including AChE, BuChE, BACE-1, and MAO-A/B. This review comprehensively explores natural, semisynthetic, and synthetic chromenone, elucidating their synthetic routes, possible mode of action/drug targets and structure-activity relationships (SAR). The acquired knowledge provides valuable insights for the development of new chromenone hybrids against AD. Show less