Comparative study of safflower yellow adjuvant to conventional treatment regimen and conventional treatment regimen on diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most important comorbidities of diabetic patients, which places large physiological and economic burdens on patients. Safflower yellow, a natural pigment extracted from the petals of safflower, has been put into adjuvant therapy. Databases including Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, MEDLINE and etc. will be searched for relevant articles. A meta-analysis was carried out to assess the efficacy and safety of safflower yellow adjuvant to conventional treatment regimen using mean differences (MD) and rate ratios (RR). A cost-effectiveness analysis was also conducted based on the result of meta-analysis. Finally, 28 articles involving 2251 patients were included in meta-analysis. The results showed that compared with conventional treatment, the fasting blood-glucose (FBG) [MD = 0.40], urinary albumin ejection rate (UAER) within 24 h [MD = 48.16], serum creatinine (Scr) [MD = 9.63], blood urea nitrogen (BUN) [MD = 1.73] were significantly lower and the clinical efficacy [RR = 1.28] was more remarkable in safflower yellow adjuvant to conventional treatment group. Our analysis suggested that safflower yellow adjuvant to conventional treatment regimen not only had better clinical efficacy but more cost-effective than conventional treatment regimen.

A Review of Experimental Studies on Natural Chalcone-Based Therapeutic Targeting of Genes and Signaling Pathways in Type 2 Diabetes Complications.

Diabetes mellitus type 2 (T2DM) is a common chronic condition that presents as unsettled hyperglycemia (HG) and results from insulin resistance (IR) and ß-cell dysfunction. T2DM is marked by an increased risk of microvascular and macrovascular complications, all of which can be the cause of increasing mortality. Diabetic nephropathy (DNE), neuropathy (DNU), and retinopathy (DR) are the most common complications of diabetic microangiopathy, while diabetic cardiomyopathy (DCM) and peripheral vascular diseases are the major diabetic macroangiopathy complications. Chalcones (CHs) are in the flavonoid family and are commonly found in certain plant species as intermediate metabolites in the biosynthesis of flavonoids and their derivatives. Natural CHs with different substituents exert diverse therapeutic activities, including antidiabetic ones. However, the therapeutic mechanisms of natural CHs through influencing genes and/or signaling pathways in T2DM complications remain unknown. Therefore, this review summarizes the existing results from experimental models which highlight the mechanisms of natural CHs as therapeutic agents for T2DM complications.

Protective Effects of Trans-Chalcone on Myocardial Ischemia and Reperfusion Challenge through Targeting Phosphoinositide 3-kinase/Akt-inflammosome Interaction.

Ischemia-reperfusion (IR) injury remains a pivotal contributor to myocardial damage following acute coronary events and revascularization procedures. Phosphoinositide 3-kinase (PI3K), a key mediator of cell survival signaling, plays a central role in regulating inflammatory responses and cell death mechanisms. Trans-chalcone (Tch), a natural compound known for its anti-inflammatory activities, has shown promise in various disease models. The aim of the current study was to investigate the potential protective effects of Tch against myocardial injury induced by ischemia and reperfusion challenges by targeting the PI3K-inflammasome interaction. Experimental models utilizing male rats subjected to an in vivo model of IR injury and myocardial infarction were employed. Administration of Tch (100 µg/kg, intraperitoneally) significantly reduced myocardial injury, as indicated by limited infarct size and decreased levels of the myocardial enzyme troponin. Mechanistically, Tch upregulated PI3K expression, thereby inhibiting the activity of the NOD-like receptor protein 3 inflammasome followed by the activation of pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. Moreover, it mitigated oxidative stress and suppressed vascular-intercellular adhesion molecules, contributing to its cardioprotective effects. The PI3K/Akt pathway inhibitor LY294002 considerably attenuated the beneficial effects of Tch. These findings highlight the therapeutic potential of Tch in ameliorating myocardial injury associated with IR insults through its modulation of the PI3K/Akt-inflammasome axis. The multifaceted mechanisms underlying its protective effects signify Tch as a promising candidate for further exploration in developing targeted therapies aimed at mitigating ischemic heart injury and improving clinical outcomes in cardiovascular diseases characterized by IR injury.

Hydroxysafflor yellow A ameliorates depression-like behavior in Parkinson's disease mice.

Depression is a common non-motor symptom of Parkinson's disease. Previous studies demonstrated that hydroxysafflor yellow A had properties of improving motor symptoms of Parkinson's disease. The effect of hydroxysafflor yellow A on depression in Parkinson's disease mice is investigated in this study. To induce Parkinson's disease model, male Swiss mice were exposed to rotenone (30 mg/kg) for 6 weeks. The chronic unpredictable mild stress was employed to induce depression from week 3 to week 6. Sucrose preference, tail suspension, and forced swimming tests were conducted. Golgi and Nissl staining of hippocampus were carried out. The levels of dopamine, 5-hydroxytryptamine and the expression of postsynaptic density protein 95, brain-derived neurotrophic factor in hippocampus were assayed. It showed that HSYA improved the depression-like behaviors of Parkinson's disease mice. Hydroxysafflor yellow A attenuated the injury of nerve and elevated contents of dopamine, 5-hydroxytryptamine in hippocampus. Treatment with hydroxysafflor yellow A also augmented the expression of postsynaptic density protein 95 and brain-derived neurotrophic factor. These findings suggest that hydroxysafflor yellow A ameliorates depression-like behavior in Parkinson's disease mice through regulating the contents of postsynaptic density protein 95 and brain-derived neurotrophic factor, therefore protecting neurons and neuronal dendrites of the hippocampus.

Hydroxysafflor Yellow A and Tenuigenin Exhibit Neuroprotection Effects Against Focal Cerebral Ischemia Via Differential Regulation of JAK2/STAT3 and SOCS3 Signaling Interaction.

Numerous natural bioactive compounds extracted from Chinese medicines have been proved to be promising and potent agents in the treatment of ischemic stroke. Hydroxysafflor yellow A (HSYA), separated from Carthamus tinctorius, has increasingly attracted attention for its broad spectrum of pharmacological effects, especially of its neuroprotective action. Our previous studies revealed that HSYA plays significant beneficial roles in a dose-dependent manner in rats with focal cerebral ischemia. However, treatment with higher doses of HSYA appeared to bring about adverse reactions in the rats. In present study, we adopted tenuigenin (TEN), extracted from the Polygala tenuifolia root, in combination with HSYA to optimize the therapeutic strategy against ischemic stroke, and further explored the underlying mechanisms of action of the combination in vivo and in vitro. We firstly confirmed the pharmacological efficacies of co-treatment of HSYA and TEN in middle cerebral ischemia occlusion (MCAO) rats and observed the synergistic improvement of infarct volume, cerebral edema, and morphology of neuron cell body. Behavioral experiments indicated that combination of HSYA and TEN could synergistically improve motor and cognitive function in MCAO rats. We also observed increased viability and suppressed cell apoptosis after HSYA and TEN co-treatments in the oxygen-glucose deprivation/reperfusion (OGD/R) SH-SY5Y cells. Furthermore, JAK2/STAT3 and SOCS3 signaling interaction was demonstrated to be a critical responsor to the co-treatment of HSYA and TEN. In the subsequent experiments with silencing SOCS3 in OGD/R-exposed cells, we found that HSYA and TEN might suppress JAK2/STAT3 pathway through different regulatory mechanisms targeting SOCS3-negative feedback signaling. HSYA seemed to impose excessive activation of JAK2/STAT3 to trigger SOCS3-negative feedback signaling, while TEN appeared to provoke SOCS3 inhibitory feedback role directly to further attenuate JAK2-mediated signaling. Collectively, HSYA and TEN might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways in different manners that eventually contributed to their synergistic therapeutic effects against cerebral ischemic stroke.

Chalcone-derivative L6H21 attenuates the OVA-induced asthma by targeting MD2.

Asthma represents a significant global challenge that affects individuals across all age groups and imposes substantial social and economic burden. Due to heterogeneity of the disease, not all patients obtain benefit with current treatments. The objective of this study was to explore the impact of MD2 on the progression of asthma using L6H21, a novel MD2 inhibitor, to identify potential targets and drug candidates for asthma treatment. To establish an asthma-related murine model and evaluate the effects of L6H21, ovalbumin (OVA) was used to sensitize and challenge mice. Pathological changes were examined with various staining techniques, such as H&E staining, glycogen staining, and Masson staining. Inflammatory cell infiltration and excessive cytokine secretion were evaluated by analyzing BALF cell count, RT-PCR, and ELISA. The TLR4/MD2 complex formation, as well as the activation of the MAPK and NF-кB pathways, was examined using western blot and co-IP. Treatment with L6H21 demonstrated alleviation of increased airway resistance, lung tissue injury, inflammatory cell infiltration and excessive cytokine secretion triggered by OVA. In addition, it also ameliorated mucus production and collagen deposition. In the L6H21 treatment group, inhibition of MAPK and NF-кB activation was observed, along with the disruption of TLR4/MD2 complex formation, in contrast to the model group. Thus, L6H21 effectively reduced the formation of the MD2 and TLR4 complex induced by OVA in a dose-dependent manner. This reduction resulted in the attenuation of MAPKs/NF-κB activation, enhanced suppression of inflammatory factor secretion, reduced excessive recruitment of inflammatory cells, and ultimately mitigated airway damage. MD2 emerges as a crucial target for asthma treatment, and L6H21, as an MD2 inhibitor, shows promise as a potential drug candidate for the treatment of asthma.

Targeting Ovarian Cancer with Chalcone Derivatives: Cytotoxicity and Apoptosis Induction in HGSOC Cells.

Ovarian cancer ranks as the eighth most prevalent form of cancer in women across the globe and stands as the third most frequent gynecological cancer, following cervical and endometrial cancers. Given its resistance to standard chemotherapy and high recurrence rates, there is an urgent imperative to discover novel compounds with potential as chemotherapeutic agents for treating ovarian cancer. Chalcones exhibit a wide array of biological properties, with a particular focus on their anti-cancer activities. In this research, we documented the synthesis and in vitro study of a small library of chalcone derivatives designed for use against high-grade serous ovarian cancer (HGSOC) cell lines, specifically OVCAR-3, OVSAHO, and KURAMOCHI. Our findings revealed that three of these compounds exhibited cytotoxic and anti-proliferative effects against all the tested HGSOC cell lines, achieving IC50 concentrations lower than 25 µM. Further investigations disclosed that these chalcones prompted an increase in the subG1 phase cell cycle and induced apoptosis in OVCAR-3 cells. In summary, our study underscores the potential of chalcones as promising agents for the treatment of ovarian cancer.

Network Analysis and Experimental Verification of the Mechanisms of Hydroxysafflor Yellow A in Ischemic Stroke Following Atherosclerosis.

Hydroxysafflor yellow A (HSYA) is derived from Carthamus tinctorius L. (Honghua in Chinese) and is used to treat cardiovascular and cerebrovascular disease. However, the mechanism by which HSYA treats ischemic stroke following atherosclerosis (ISFA) remains unclear. The targets and pathways of HSYA against ISFA were obtained using network analysis. A total of 3335 potential IFSA-related targets were predicted using the GenCards and Drugbank databases, and a total of 88 potential HSYA-related targets were predicted using the Swiss Target Prediction database. A total of 62 HSYA-related targets against IFSA were obtained. The network was composed of HSYA, 62 targets, and 20 pathways. The top 20 targets were constructed via the protein-protein interaction (PPI) network. Gene Ontology analysis revealed that the targets were involved in signal transduction, protein phosphorylation, the cytoplasm, the plasma membrane, the cytosol, zinc ion binding, ATP binding, protein kinase binding/activity, and enzyme binding. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the pathways were associated with cancer, inflammatory mediator regulation of the transient receptor potential channels, and microRNA in cancer. Additionally, molecular docking indicated that HSYA mainly interacts with five targets, namely interleukin 1 beta (IL-1ß), signal transducer and activator of transcription 3 (STAT3), E1A-binding protein p300 (EP300), protein kinase C alpha (PRKCA), and inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB). In animal experiments, HSYA administration ameliorated the infarct size, neurological deficit score, histopathological changes, carotid intima-media thickness (IMT), and blood lipid level (total cholesterol and triglycerides). Immunochemistry and quantitative PCR showed that HSYA intervention downregulated the expression of STAT3, EP300, PRKCA, and IKBKB, and the enzyme-linked immunoassay showed reduced IL-1ß levels. The findings of this study provide a reference for the development of anti-ISFA drugs.

A sulfonamide chalcone inhibited dengue virus with a potential target at the SAM-binding site of viral methyltransferase.

Dengue infection is a global health problem as climate change facilitates the spread of mosquito vectors. Infected patients could progress to severe plasma leakage and hemorrhagic shock, where current standard treatment remains supportive. Previous reports suggested that several flavonoid derivatives inhibited mosquito-borne flaviviruses. This work aimed to explore sulfonamide chalcone derivatives as dengue inhibitors and to identify molecular targets. We initially screened 27 sulfonamide chalcones using cell-based antiviral and cytotoxic screenings. Two potential compounds, SC22 and SC27, were identified with DENV1-4 EC50s in the range of 0.71-0.94 and 3.15-4.46 µM, and CC50s at 14.63 and 31.02 µM, respectively. The compounds did not show any elevation in ALT or Cr in C57BL/6 mice on the 1st, 3rd, and 7th days after being administered intraperitoneally with 50 mg/kg SC22 or SC27 in a single dose. Moreover, the SAM-binding site of NS5 methyltransferase was a potential target of SC27 identified by computational and enzyme-based assays. The main target of SC22 was in a late stage of viral replication, but the exact target molecule had yet to be identified. In summary, a sulfonamide chalcone, SC27, was a potential DENV inhibitor that targeted viral methyltransferase. Further investigation should be the study of the structure-activity relationship of SC27 derivatives for higher potency and lower toxicity.

New Benzodihydrofuran Derivatives Alter the Amyloid ß Peptide Aggregation: Strategies To Develop New Anti-Alzheimer Drugs.

Alzheimer's disease is a neurodegenerative disorder that is the leading cause of dementia in elderly patients. Amyloid-ß peptide (1-42 oligomers) has been identified as a neurotoxic factor, triggering many neuropathologic events. In this study, 15 chalcones were synthesized employing the Claisen-Schmidt condensation reaction, starting from a compound derived from fomannoxine, a natural benzodihydrofuran whose neuroprotective activity has been proven and reported, and methyl aromatic ketones with diverse patterns of halogenated substitution. As a result, chalcones were obtained, with good to excellent reaction yields from 50 to 98%. Cytotoxicity of the compounds was assessed, and their cytoprotective effect against the toxicity associated with Aß was evaluated on PC-12 cells. Out of the 15 chalcones obtained, only the 4-bromo substituted was cytotoxic at most tested concentrations. Three synthesized chalcones showed a cytoprotective effect against Aß toxicity (over 37%). The 2,4,5-trifluoro substituted chalcone was the most promising series since it showed a cytoprotective impact with more than 60 ± 5% of recovery of cellular viability; however, 3-fluoro substituted compound also exhibited important values of recovery (50 ± 6%). The fluorine substitution pattern was shown to be more effective for cytoprotective activity. Specifically, substitution with fluorine in the 3,5-positions turned out to be particularly effective for cytoprotection. Furthermore, fluorinated compounds inhibited the aggregation rate of Aß, suggesting a dual effect that can be the starting point of new molecules with therapeutic potential.

Targeting the epithelial-mesenchymal transition (EMT) pathway with combination of Wnt inhibitor and chalcone complexes in lung cancer cells.

Non-small cell lung cancer (NSCLC) is the most common type of the lung cancer. Despite development in treatment options in NSCLC, the overall survival ratios is still poor due to epithelial and mesenchymal transition (EMT) feature and associated metastasis event. Thereby there is a need to develop strategy to increase antitumor response against the NSCLC cells by targeting EMT pathway with combination drugs. Niclosamide and chalcone complexes are both affect cancer cell signaling pathways and therefore inhibit the EMT pathway. In this study, it was aimed to increase antitumor response and suppress EMT pathway in NSCLC cells by combining niclosamide and chalcone complexes. SRB cell viability assay was performed to investigate the anticancer activity of drugs. The drugs were tested on both NSCLC cells (A549 and H1299) and normal lung bronchial cells (BEAS-2B). Then the two drugs were combined and their effects on cancer cells were evaluated. Fluorescence imaging and enzyme-linked immunosorbent assay were performed on treated cells to observe the cell death manner. Wound healing assay, real-time quantitative polymerase chain reaction, and western blot analysis were performed to measure EMT pathway activity. Our results showed that niclosamide and chalcone complexes combination kill cancer cells more than normal lung bronchial cells. Compared to single drug administration, the combination of both drugs killed NSCLC cells more effectively by increasing apoptotic activity. In addition, the combination of niclosamide and chalcone complexes decreased multidrug resistance and EMT activity by lowering their gene expressions and protein levels. These results showed that niclosamide and chalcone complexes combination could be a new drug combination for the treatment of NSCLC.

A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice.

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK) stimulation by chalcones, a class of polyphenols abundantly found in plants, is proposed as a promising therapeutic approach for DM. This study aimed to identify novel chalcone derivatives with improved AMPK-stimulating activity in human podocytes and evaluate their mechanisms of action as well as in vivo efficacy in a mouse model of DN. Among 133 chalcone derivatives tested, the sulfonamide chalcone derivative IP-004 was identified as the most potent AMPK activator in human podocytes. Western blot analyses, intracellular calcium measurements and molecular docking simulation indicated that IP-004 activated AMPK by mechanisms involving direct binding at allosteric site of calcium-dependent protein kinase kinase ß (CaMKKß) without affecting intracellular calcium levels. Interestingly, eight weeks of intraperitoneal administration of IP-004 (20 mg/kg/day) significantly decreased fasting blood glucose level, activated AMPK in the livers, muscles and glomeruli, and ameliorated albuminuria in db/db type II diabetic mice. Collectively, this study identifies a novel chalcone derivative capable of activating AMPK in vitro and in vivo and exhibiting efficacy against hyperglycemia and DN in mice. Further development of AMPK activators based on chalcone derivatives may provide an effective treatment of DN.

Discovery of a chalcone derivative as an anti-fibrotic agent targeting transforming growth factor-ß1 signaling: Potential therapy of renal fibrosis.

As a final common pathway of renal injuries, renal fibrosis leads to chronic kidney disease (CKD). Currently, there is no safe and effective therapy to prevent the progression of renal fibrosis to CKD. Inhibition of transforming growth factor-ß1 (TGF-ß1) pathway is proposed as one of the most promising approaches for anti-renal fibrosis therapies. This study aimed to identify novel anti-fibrotic agents using the TGF-ß1-induced fibrosis in renal proximal tubule epithelial cells (RPTEC) and characterize their mechanism of action as well as in vivo efficacy. By screening 362 natural product-based compounds for their ability to reduce collagen accumulation assessed by picro-sirius red (PSR) staining in RPTEC cells, a chalcone derivative AD-021 was identified as an anti-fibrotic agent with IC50 of 14.93 µM. AD-021 suppressed TGF-ß1-induced collagen production, expression of pro-fibrotic proteins (fibronectin and α-smooth muscle actin (αSMA)), and Smad-dependent and Smad-independent signaling pathways via suppression of TGF-ß receptor II (TGFßRII) phosphorylation in RPTEC cells. Furthermore, TGF-ß1-induced mitochondrial fission in RPTEC cells was ameliorated by AD-021 via mechanisms involving inhibition of Drp1 phosphorylation. In a mouse model of unilateral ureteral obstruction (UUO)-induced renal fibrosis, AD-021 reduced plasma TGF-ß1, ameliorated renal fibrosis and improved renal function. Collectively, AD-021 represents a novel class of natural product-based anti-fibrotic agent that has therapeutic potential in the prevention of fibrosis-associated renal disorders including CKD.

Effects of Synthetic Ligustrazine-Based Chalcone Derivatives on Trypanosoma brucei brucei and Leishmania spp. Promastigotes.

Current medication therapy for leishmaniasis and trypanosomiasis remains a major challenge due to its limited efficacy, significant adverse effects, and inaccessibility. Consequently, locating affordable and effective medications is a pressing concern. Because of their easy-to-understand structure and high functionalization potential, chalcones are promising candidates for use as bioactive agents. Thirteen synthetic ligustrazine-containing chalcones were evaluated for their ability to inhibit the growth of leishmaniasis and trypanosomiasis in etiologic agents. The tetramethylpyrazine (TMP) analogue ligustrazine was chosen as the central moiety for the synthesis of these chalcone compounds. The most effective compound (EC50 = 2.59 µM) was the chalcone derivative 2c, which featured a pyrazin-2-yl amino on the ketone ring and a methyl substitution. Multiple actions were observed for certain derivatives, including 1c, 2a-c, 4b, and 5b, against all strains tested. Eflornithine served as a positive control, and three ligustrazine-based chalcone derivatives, including 1c, 2c, and 4b, had a higher relative potency. Compounds 1c and 2c are particularly efficacious; even more potent than the positive control, they are therefore promising candidates for the treatment of trypanosomiasis and leishmaniasis.

A natural chalcone cardamonin inhibits necroptosis and ameliorates dextran sulfate sodium (DSS)-induced colitis by targeting RIPK1/3 kinases.

Necroptosis, a new form of programmed cell death, is involved in the pathogenesis of ulcerative colitis (UC). Inhibition of necroptosis represents an attractive strategy for UC therapy. Herein, cardamonin, a natural chalcone isolated from Zingiberaceae family, was firstly identified as a potent necroptosis inhibitor. In vitro, cardamonin significantly inhibited necroptosis in TNF-α plus Smac mimetic and z-VAD-FMK (TSZ)-, cycloheximide plus TZ (TCZ)-, or lipopolysaccharide plus SZ (LSZ)-stimulated HT29, L929, or RAW264.7 cell lines. Furthermore, TSZ-induced elevated population of necrotic cells, release of LDH and HMGB1 also could be inhibited by cardamonin in HT29 cells. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay combined with molecular docking demonstrated that cardamonin interacted with RIPK1/3. Furthermore, cardamonin blocked the phosphorylation of RIPK1/3, thereby disrupting RIPK1-RIPK3 necrosome formation and MLKL phosphorylation. In vivo, orally administration of cardamonin attenuated dextran sulfate sodium (DSS)-induced colitis, which mainly manifested as mitigated intestinal barrier damage, suppressed necroinflammation, and reduced phosphorylation of MLKL. Taken together, our findings revealed that dietary cardamonin is a novel necroptosis inhibitor and has great potential for UC therapy by targeting RIPK1/3 kinases.

Structure optimization of an F-indole-chalcone (FC116) on 4-methoxyphenyl group and therapeutic potential against colorectal cancers with low cytotoxicity.

Advanced metastatic colorectal cancers (CRCs) are regarded as a challenge in clinical cancer therapy. Our previous studies have demonstrated that a representative fluoro-substituted indole-chalcone (FC116), was obtained to display highly potent activity against CRC using multiple in vitro and in vivo mouse models by targeting microtubules. However, several problems, such as low dose tolerance and highly toxic to the brain and colon, low solubility unsuitable for intravenous (i.v.) administration, are still existed and limit further development. Herein, we developed two series of FC116 derivatives on the 4-methoxyphenyl group by a structure-based design strategy. Among them, FC11619 with an amino terminus maintained the in vitro cytotoxicity against HCT-116 CRC in a low nanomolar range. This compound could induce G2/M phase arrest via regulating cyclin B1 expression, produce excess reactive oxygen species (ROS), and target tubulin in CRC cells. In vivo, FC11619 significantly suppressed tumor growth, achieving 65.3 and 73.4 % at doses of 5 and 10 mg/kg/d (i.v., 21 d), which were much better than 54.1% of Taxol at 7 mg/kg. In addition, this compound showed better in vivo tolerance compared to that of FC116 (only 3 mg/kg tolerance, intraperitoneal, i.p.), and no major organ-related toxicity, especially no apparent degenerated neurons, intestinal obstruction in clinical Taxol standard therapy. Taken together, the 4-amino-substitutedphenyl indole-chalcones represent lead compounds as chemotherapy of CRC for further drug development in this field.

Chalcones: Promising therapeutic agents targeting key players and signaling pathways regulating the hallmarks of cancer.

The need for innovative anticancer treatments with high effectiveness and low toxicity is urgent due to the development of malignancies that are resistant to chemotherapeutic agents and the poor specificity of existing anticancer treatments. Chalcones are 1,3-diaryl-2-propen-1-ones, which are the precursors for flavonoids and isoflavonoids. Chalcones are readily available from a wide range of natural resources and consist of very basic chemical scaffolds. Because the ease with which the synthesis it allows for the production of several chalcone derivatives. Various in-vitro and in-vivo studies indicate that naturally occurring and synthetic chalcone derivatives exhibit promising biological activities against cancer hallmarks such as proliferation, angiogenesis, invasion, metastasis, inflammation, stemness, and regulation of cancer epigenetics. According to their structure and functional groups, chalcones derivatives and their hybrid compounds exert a broad range of biological activities through targeting key elements and signaling molecules relevant to cancer progression. This review will provide valuable insights into the latest updates of chalcone groups as anticancer agents and extensively discuss their underlying molecular mechanisms of action.

Chalcone derivatives as xanthine oxidase inhibitors: synthesis, binding mode investigation, biological evaluation, and ADMET prediction.

Xanthine oxidase (XO) is a crucial target for the treatment of hyperuricemia and gout. A series of derivatives based on natural 3,4-dihydroxychalcone, obtained from Carthamus tinctorious and Licorice, were designed and synthesized. Nine derivatives (9a-e, 10b,c, and 15a,b) exhibited apparent XO inhibitory activity in vitro (IC50 values varied from 0.121 to 7.086 µM), 15b presented the most potent inhibitory activity (IC50 = 0.121 µM), which was 27.47-fold higher than that of allopurinol (IC50 = 3.324 µM). The SAR analysis indicated that introducing hydroxyl groups at 3'/4'/5'-position on ring A was more beneficial to the inhibition of XO than at 2'/6'-position; the removal of 3­hydroxyl group on ring B could weaken the inhibitory potency of hydroxychalcones on XO, but it was beneficial to the XO inhibitory potency of methoxychalcones. Molecule modeling studies afforded insights into the binding mode of 15b with XO and supported the findings of SAR analysis. Additionally, kinetics studies demonstrated that 15b presented a reversible and competitive XO inhibitor, which spontaneously combined with XO through hydrophobic force, and finally changed the secondary conformation of XO. Furthermore, the acute hyperuricemia model was employed to investigate the hypouricemic effect of 15b, which could effectively reduce the serum uric acid levels of rats at an oral dose of 10 mg/kg. ADMET prediction suggested that compound 15b possessed good pharmacokinetic properties. Briefly, compound 15b emerges as an interesting XO inhibitor for the treatment of hyperuricemia and gout with beneficial effects on serum uric acid levels regulating. Meanwhile, the XO inhibitors with chalcone skeleton will deserve further attention and discussion.

Antimalarial and immunomodulatory potential of chalcone derivatives in experimental model of malaria.

BACKGROUND: Malaria is a complex issue due to the availability of few therapies and chemical families against Plasmodium and mosquitoes. There is increasing resistance to various drugs and insecticides in Plasmodium and in the vector. Additionally, human behaviors are responsible for promoting resistance as well as increasing the risk of exposure to infections. Chalcones and their derivatives have been widely explored for their antimalarial effects. In this context, new derivatives of chalcones have been evaluated for their antimalarial efficacy. METHODS: BALB/c mice were infected with P. berghei NK-65. The efficacy of the three most potent chalcone derivations (1, 2, and 3) identified after an in vitro compound screening test was tested. The selected doses of 10 mg/kg, 20 mg/kg, and 10 mg/kg were studied by evaluating parasitemia, changes in temperature, body weights, organ weights, histopathological features, nitric oxide, cytokines, and ICAM-1 expression. Also, localization of parasites inside the two vital tissues involved during malaria infections was done through a transmission electron microscope. RESULTS: All three chalcone derivative treated groups showed significant (p < 0.001) reductions in parasitemia levels on the fifth and eighth days of post-infection compared to the infected control. These derivatives were found to modulate the immune response in a P. berghei infected malaria mouse model with a significant reduction in IL-12 levels. CONCLUSIONS: The present study indicates the potential inhibitory and immunomodulatory actions of chalcones against the rodent malarial parasite P. berghei.

A novel synthetic chalcone derivative, 2,4,6-trimethoxy-4'-nitrochalcone (Ch-19), exerted anti-tumor effects through stimulating ROS accumulation and inducing apoptosis in esophageal cancer cells.

Esophageal cancer has always been associated with poor prognosis and a low five-year survival rate. Chalcone, a flavonoid family member, has shown anti-tumor property in several types of cancer. However, few studies reported the potency and mechanisms of action of synthetic Chalcone derivatives against esophageal squamous cell carcinoma. In this study, we designed and synthesized a series of novel chalcone analogs and Ch-19 was selected for its superior anti-tumor potency. Results indicated that Ch-19 shows a dose- and time-dependent anti-tumor activity in both KYSE-450 and Eca-109 esophageal cancer cells. Moreover, treatment of Ch-19 resulted in the regression of KYSE-450 tumor xenografts in nude mice. Furthermore, we investigated the potential mechanism involved in the effective anti-tumor effects of Ch-19. As a result, we observed that Ch-19 treatment promoted ROS accumulation and caused G2/M phase arrest in both Eca-109 and KYSE-450 cancer cell lines, thereby resulting in cell apoptosis. Taken together, our study provided a novel synthetic chalcone derivative as a potential anti-tumor therapeutic candidate for treating esophageal cancer.