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Aporphine alkaloids were the characteristic compounds with hypoglycemic effects in Cassytha filiformis. Utilizing chromatographic separation techniques including silica gel and semi-preparative high-performance liquid chromatography, three new aporphine alkaloids were successfully isolated and purified. Their structures were elucidated using various spectroscopic techniques, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopy, as well as high-resolution electrospray ionization mass spectrometry (HRESIMS). The new compounds were identified as 10-demethylcassythine (1), 3-demethylcassythine (2), and N-demethyllastourvilline (3). The absolute configurations of the new compounds were determined using electronic circular dichroism (ECD) calculations. The effects of the new compounds on promoting glucose consumption in HepG2 cells at varying concentrations were tested. The results indicate that compound 1 significantly enhanced glucose consumption at 20 μM.

Cassytha filiformis is a folkloric herbal medicine used to treat type 2 diabetes mellitus (T2DM). In this study, an oxidized aporphine alkaloid, designated as Filiforidine (3,10,11-trimethoxy-1,2-methylenedioxy-7-oxoaporphine), was isolated from C. filiformis, and its structure was elucidated through comprehensive spectroscopic analysis. Owing to its novel structure and significant glucose consumption activity, the total synthesis of Filiforidine was achieved for the first time. The key steps featured an electrophilic addition reaction, involving the reduction of a nitro group to an amino group with lithium tetrahydroaluminum, and a copper bromide-catalyzed oxidative aromatization reaction as well as a photocyclization reaction. Several experimental steps were optimized. Furthermore, a complex post-treatment method was developed, which reduced the column chromatography separation steps. Specifically, 2-(4-methoxybenzo[d][1,3]dioxol -5-yl) ethan-1-amine is salted with dilute hydrochloric acid. Cytotoxicity assay and glucose oxidase assay showed that Filiforidine had significant glucose consumption-promoting effects on HL-7702 cells at 0.625 μM, 1.25 μM, and 2.5 μM but without cytotoxicity. Therefore, Filiforidine might be a promising drug candidate for the treatment of diabetes.

Fifteen compounds were extracted and purified from the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena. These compounds include liriodenine (1), lysicamine (2), (−)-anonaine (3), (−)-asimilobine (4), (−)-caaverine (5), (−)-N-methylasimilobine (6), (−)-nuciferine (7), (−)-nornuciferine (8), (−)-roemerine (9), 7-hydroxydehydronuciferine (10) cepharadione B (11), β-sitostenone (12), stigmasta-4,22-dien-3-one (13) and two chlorophylls: pheophytin-a (14) and aristophyll-C (15). The anti-oxidation activity of the compounds was examined by antiradical scavenging, metal chelating and ferric reducing power assays. The results have shown that these compounds have antioxidative activity. The study has also examined the antiproliferation activity of the isolated compounds against human melanoma, prostate and gastric cancer cells. The results shown that 7-hydroxydehydronuciferine (10) significantly inhibited the proliferation of melanoma, prostate and gastric cancer cells. Together, these findings suggest that leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena are a good resource for obtaining the biologically active substances with antioxidant properties.

Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- “off” agent for Parkinson’s disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.

Gut microbiota dysbiosis has a significant role in the pathogenesis of metabolic diseases, including obesity. Nuciferine (NUC) is a main bioactive component in the lotus leaf that has been used as food in China since ancient times. Here, we examined whether the anti-obesity effects of NUC are related to modulations in the gut microbiota. Using an obese rat model fed a HFD for 8 weeks, we show that NUC supplementation of HFD rats prevents weight gain, reduces fat accumulation, and ameliorates lipid metabolic disorders. Furthermore, 16S rRNA gene sequencing of the fecal microbiota suggested that NUC changed the diversity and composition of the gut microbiota in HFD-fed rats. In particular, NUC decreased the ratio of the phyla Firmicutes/Bacteroidetes, the relative abundance of the LPS-producing genus Desulfovibrio and bacteria involved in lipid metabolism, whereas it increased the relative abundance of SCFA-producing bacteria in HFD-fed rats. Predicted functional analysis of microbial communities showed that NUC modified genes involved in LPS biosynthesis and lipid metabolism. In addition, serum metabolomics analysis revealed that NUC effectively improved HFD-induced disorders of endogenous metabolism, especially lipid metabolism. Notably, NUC promoted SCFA production and enhanced intestinal integrity, leading to lower blood endotoxemia to reduce inflammation in HFD-fed rats. Together, the anti-obesity effects of NUC may be related to modulations in the composition and potential function of gut microbiota, improvement in intestinal barrier integrity and prevention of chronic low-grade inflammation. This research may provide support for the application of NUC in the prevention and treatment of obesity.Obesity: Getting leaner on lotus leavesA natural compound found in lotus leaf could treat and prevent obesity by stabilizing disrupted gut microbiota and reducing the associated chronic. Obesity is a considerable health burden worldwide, yet treatment options are limited. The composition of an individual’s gut microbiota influences the development of obesity; an imbalance in the ratio of two bacterial species in particular can accelerate the disease. Mingyan Liu and Minjie Wei at the China Medical University, Shenyang, and co-workers demonstrated that nuciferine, a bioactive component of lotus leaf, reduced weight gain and fat accumulation in rats fed a high-fat diet. Nuciferine changed the diversity and composition of the rats’ gut microbiota, and modified the expression of genes involved in processes such as lipid metabolism. Nuciferine also enhanced intestinal integrity, and reduced chronic low-level inflammation.

Magnofluorine, a secondary metabolite commonly found in various plants, has pharmacological potential; however, its antioxidant and enzyme inhibition effects have not been investigated. We investigated the antioxidant potential of Magnofluorine using bioanalytical assays with 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+), N,N-dimethyl-p-phenylenediamine dihydrochloride (DMPD•+), and 1,1-diphenyl-2-picrylhydrazyl (DPPH•) scavenging abilities and K3[Fe(CN)6] and Cu2+ reduction abilities. Further, we compared the effects of Magnofluorine and butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), α-Tocopherol, and Trolox as positive antioxidant controls. According to the analysis results, Magnofluorine removed 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals with an IC50 value of 10.58 μg/mL. The IC50 values of BHA, BHT, Trolox, and α-Tocopherol were 10.10 μg/mL, 25.95 μg/mL, 7.059 μg/mL, and 11.31 μg/mL, respectively. Our results indicated that the DPPH· scavenging effect of Magnofluorine was similar to that of BHA, close to that of Trolox, and better than that of BHT and α-tocopherol. The inhibition effect of Magnofluorine was examined against enzymes, such as acetylcholinesterase (AChE), α-glycosidase, butyrylcholinesterase (BChE), and human carbonic anhydrase II (hCA II), which are linked to global disorders, such as diabetes, Alzheimer’s disease (AD), and glaucoma. Magnofluorine inhibited these metabolic enzymes with Ki values of 10.251.94, 5.991.79, 25.411.10, and 30.563.36 nM, respectively. Thus, Magnofluorine, which has been proven to be an antioxidant, antidiabetic, and anticholinergic in our study, can treat glaucoma. In addition, molecular docking was performed to understand the interactions between Magnofluorine and target enzymes BChE (D: 6T9P), hCA II (A:3HS4), AChE (B:4EY7), and α-glycosidase (C:5NN8). The results suggest that Magnofluorine may be an important compound in the transition from natural sources to industrial applications, especially new drugs.

Guatteria olivacea R.E. Fries is an Amazonian species known as ‘envira-bobó’ and ‘envira-fofa’ and is common in the states of Amazonas, Acre, and Pará. Recently, the essential oil from the leaves of this species has shown promising antitumor activity both in vitro and in vivo. The presence of isoquinoline-derived alkaloids, including aporphinoids and tetrahydroprotoberberine alkaloids, has also been previously reported. In our ongoing search for bioactive compounds from Annonaceae Amazonian plants, the bark of G. olivacea was investigated via classical chromatography techniques, which revealed nine compounds, eight isoquinoline-derived alkaloids, a rare alkaloid with a α-gem-dimethyltetradehydrocularine structure known as gouregine, seven known aporphinoid alkaloids: isopiline, O-methylisopiline, melosmine, 9-hydroxyiguattescine, dihydromelosmine, lysicamine, and guattouregidine, and one known pimaradiene diterpene: acanthoic acid. All the isolated compounds were described for the first time in the bark of G. olivacea, and their structures were elucidated by extensive analyses of their 1D and 2D NMR spectra in combination with MS data. The NMR data of the alkaloids isopiline, O-methylisopiline, melosmine, dihydromelosmine, and guattouregidine were revised due to incomplete data in the literature and some ambiguities. The in vitro cytotoxic activities of the isolated compounds were evaluated against human cancer (HepG2, KG-1a, and HCT116) and noncancerous (MRC-5) cell lines via the Alamar blue assay after 72 h of incubation. Among the compounds evaluated against human cancer cell lines, the most active was the oxoaporphine alkaloid lysicamine, which has strong activity against HCT116 cells, with an IC50 value of 6.64 µg/mL (22.79 µmol/L). Melosmine had a moderate effect on HCT116 cells, with an IC50 value of 16.77 µg/mL (49.70 µmol/L), whereas acanthoic acid had moderate effects on HepG2 and HCT116 cells, with IC50 values of 14.63 µg/mL (48.37 µmol/L) and 21.25 µg/mL (70.25 µmol/L), respectively.

Pain remains a key therapeutic area with intensive efforts directed toward finding effective and safer analgesics in light of the ongoing opioid crisis. Amongst the neurotransmitter systems involved in pain perception and modulation, the mu-opioid receptor (MOR), a G protein-coupled receptor, represents one of the most important targets for achieving effective pain relief. Most clinically used opioid analgesics are agonists to the MOR, but they can also cause severe side effects. Medicinal plants represent important sources of new drug candidates, with morphine and its semisynthetic analogues as well-known examples as analgesic drugs. In this study, combining in silico (pharmacophore-based virtual screening and docking) and pharmacological (in vitro binding and functional assays, and behavioral tests) approaches, we report on the discovery of two naturally occurring plant alkaloids, corydine and corydaline, as new MOR agonists that produce antinociceptive effects in mice after subcutaneous administration via a MOR-dependent mechanism. Furthermore, corydine and corydaline were identified as G protein-biased agonists to the MOR without inducing β-arrestin2 recruitment upon receptor activation. Thus, these new scaffolds represent valuable starting points for future chemical optimization towards the development of novel opioid analgesics, which may exhibit improved therapeutic profiles.

The global syndemic of obesity and type 2 diabetes (T2D) demands safe, multi-targeted dietary interventions. FH03FS, a sterilized fermented beverage blended from five medicinal food homologous (MFH) plants, represents a promising candidate. However, the phytochemical profile and mechanistic basis for its potential efficacy remain uncharacterized. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis of FH03FS revealed a wide spectrum of compounds. Ten key bioactive ingredients, primarily aporphines and flavonoids, were identified as the primary active components based on favorable pharmacokinetic properties. In silico Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling indicated high gastrointestinal (GI) absorption and low toxicity risks for these compounds. Network pharmacology demonstrated the modulation of core pathways driving metabolic inflammation. Molecular docking preliminarily identified multiple high-affinity interactions between the bioactive compounds and core targets. The exceptional stability and strong binding of representative complexes, notably Morin-ESR1 and Asimilobine-PPARG, were further validated by molecular dynamics (MD) simulations. This study demonstrates that FH03FS, rich in aporphines and flavonoids, exerts multi-target effects against obesity and T2D. Our findings thereby provide a phytochemical and mechanistic foundation for its development as a ready-to-consume functional beverage and offer testable hypotheses for future validation.

Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1 – 3 have been synthesized and fully characterized. 1 – 3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1 – 3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80–3 and SK-OV-3/DDP cells, with IC 50 value of 0.23−4.31 μM. Interestingly, 0.5 μM 1 – 3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins. In addition, 1 – 3 induced HepG2 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by p53 activation, ROS production, Bax up-regulation and Bcl-2 down-regulation, mitochondrial dysfunction, cytochrome c release, caspase activation and PARP cleavage. Furthermore, 3 inhibited tumor growth in HepG2 xenograft model, and displayed more safety profile in vivo than cisplatin.