Boldine prevents the inflammatory response of cardiac fibroblasts induced by SGK1-NFκB signaling pathway activation.

Cardiac fibroblasts (CF) are mesenchymal-type cells responsible for maintaining the homeostasis of the heart's extracellular matrix (ECM). Their dysfunction leads to excessive secretion of ECM proteins, tissue stiffening, impaired nutrient and oxygen exchange, and electrical abnormalities in the heart. Additionally, CF act as sentinel cells in the cardiac tissue microenvironment, responding to various stimuli that may affect heart function. Deleterious stimuli induce an inflammatory response in CF, increasing the secretion of cytokines such as IL-1ß and TNF-α and the expression of cell adhesion molecules like ICAM1 and VCAM1, initially promoting damage resolution by recruiting immune cells. However, constant harmful stimuli lead to a chronic inflammatory process and heart dysfunction. Therefore, it is necessary to study the mechanisms that govern CF inflammation. NFκB is a key regulator of the cardiac inflammatory process, making the search for mechanisms of NFκB regulation and CF inflammatory response crucial for developing new treatment options for cardiovascular diseases. SGK1, a serine-threonine protein kinase, is one of the regulators of NFκB and is involved in the fibrotic effects of angiotensin II and aldosterone, as well as in CF differentiation. However, its role in the CF inflammatory response is unknown. On the other hand, many bioactive natural products have demonstrated anti-inflammatory effects, but their role in CF inflammation is unknown. One such molecule is boldine, an alkaloid obtained from Boldo (Peumus boldus), a Chilean endemic tree with proven cytoprotective effects. However, its involvement in the regulation of SGK1 and CF inflammation is unknown. In this study, we evaluated the role of SGK1 and boldine in the inflammatory response in CF isolated from neonatal Sprague-Dawley rats. The involvement of SGK1 was analyzed using GSK650394, a specific SGK1 inhibitor. Our results demonstrate that SGK1 is crucial for LPS- and IFN-γ-induced inflammatory responses in CF (cytokine expression, cell adhesion molecule expression, and leukocyte adhesion). Furthermore, a conditioned medium (intracellular content of CF subject to freeze/thaw cycles) was used to simulate a sterile inflammation condition. The conditioned medium induced a potent inflammatory response in CF, which was completely prevented by the SGK1 inhibitor. Finally, our results indicate that boldine inhibits both SGK1 activation and the CF inflammatory response induced by LPS, IFN-γ, and CF-conditioned medium. Taken together, our results position SGK1 as an important regulator of the CF inflammatory response and boldine as a promising anti-inflammatory drug in the context of cardiovascular diseases.

Cytotoxic effects of aporphine alkaloids from the stems and leaves of Stephania dielsiana Y.C.Wu.

Phytochemical studies of the stems and leaves of Stephania dielsiana Y.C.Wu yielded two new aporphine alkaloids (1 and 5), along with six known alkaloids (2-4 and 6-8). Their structures were characterised based on analyses of spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS). The cytotoxic activities of the isolated compounds against a small panel of tumour cell lines were assessed by MTS assay. Interestingly, compound 2 exhibited particularly strong cytotoxic activities against HepG2, MCF7 and OVCAR8 cancer cell lines, with IC50 values of 3.20 ± 0.18, 3.10 ± 0.06 and 3.40 ± 0.007 µM, respectively. Furthermore, molecular docking simulations were carried out to explore the interactions and binding mechanisms of the most active compound (compound 2) with proteins. Our results contribute to understanding the secondary metabolites produced by S. dielsiana and provide a scientific rationale for further investigations of cytotoxicity of this valuable medicinal plant.

Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome.

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.

Magnoflorine Ameliorates Chronic Kidney Disease in High-Fat and High-Fructose-Fed Mice by Promoting Parkin/PINK1-Dependent Mitophagy to Inhibit NLRP3/Caspase-1-Mediated Pyroptosis.

Excessive intake of fat and fructose in Western diets has been confirmed to induce renal lipotoxicity, thereby driving the progression of chronic kidney disease (CKD). This study was conducted to evaluate the efficacy of magnoflorine in a CKD mouse model subjected to high-fat and high-fructose diets. Our results demonstrated that magnoflorine treatment ameliorated abnormal renal function indices (serum creatinine, urea nitrogen, uric acid, and urine protein) in high-fat- and high-fructose-fed mice. Histologically, renal tubular cell steatosis, lipid deposition, tubular dilatation, and glomerular fibrosis were significantly reduced by the magnoflorine treatment in these mice. Mechanistically, magnoflorine promotes Parkin/PINK1-mediated mitophagy, thereby inhibiting NLRP3/Caspase-1-mediated pyroptosis. Consistent findings were observed in the palmitic acid-incubated HK-2 cell model. Notably, both silencing of Parkin and the use of a mitophagy inhibitor reversed the inhibitory effect of magnoflorine on NLRP3 inflammasome activation in vitro. Therefore, the present study provides compelling evidence that magnoflorine improves renal injury in high-fat- and high-fructose-fed mice by promoting Parkin/PINK1-dependent mitophagy to inhibit NLRP3 inflammasome activation and pyroptosis. Our findings suggest that dietary supplementation with magnoflorine and magnoflorine-rich foods (such as magnolia) might be an effective strategy for the prevention of CKD.

Nuciferine alleviates collagen-induced arthritic in rats by inhibiting the proliferation and invasion of human arthritis-derived fibroblast-like synoviocytes and rectifying Th17/Treg imbalance.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation, posing challenges in the development of effective treatments. Nuciferine, an alkaloid found in lotus leaf, has shown promising anti-inflammatory and anti-tumor effects, yet its efficacy in RA treatment remains unexplored. This study investigated the antiproliferative effects of nuciferine on the MH7A cell line, a human RA-derived fibroblast-like synoviocyte, revealing its ability to inhibit cell proliferation, promote apoptosis, induce apoptosis, and cause G1/S phase arrest. Additionally, nuciferine significantly reduced the migration and invasion capabilities of MH7A cells. The therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis (CIA) rat model, where it markedly alleviated joint swelling, synovial hyperplasia, cartilage injury, and inflammatory infiltration. Nuciferine also improved collagen-induced bone erosion, decreased pro-inflammatory cytokines and serum immunoglobulins (IgG, IgG1, IgG2a), and restored the balance between T helper (Th) 17 and regulatory T cells in the spleen of CIA rats. These results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats.

Exploring the antileishmanial activity of dicentrine from Ocotea puberula (Lauraceae) using biomembrane models.

This study aimed to assess the antiprotozoal efficacy of dicentrine, an aporphine alkaloid isolated from Ocotea puberula, against amastigote forms of Leishmania (L.) infantum. Our findings reveal that dicentrine demonstrated a notable EC50 value of 10.3 µM, comparable to the positive control miltefosine (EC50 of 10.4 µM), while maintaining moderate toxicity to macrophages (CC50 of 51.9 µM). Utilizing an in silico methodology, dicentrine exhibited commendable adherence to various parameters, encompassing lipophilicity, water solubility, molecule size, polarity, and flexibility. Subsequently, we conducted additional investigations to unravel the mechanism of action, employing Langmuir monolayers as models for protozoan cell membranes. Tensiometry analyses unveiled that dicentrine disrupts the thermodynamic and mechanical properties of the monolayer by expanding it to higher areas and increasing the fluidity of the film. The molecular disorder was further corroborated through dilatational rheology and infrared spectroscopy. These results contribute insights into the role of dicentrine as a potential antiprotozoal drug in its interactions with cellular membranes. Beyond elucidating the mechanism of action at the plasma membrane's external surface, our study sheds light on drug-lipid interface interactions, offering implications for drug delivery and other pharmaceutical applications.

Advances in the pharmacological effects and mechanisms of Nelumbo nucifera gaertn. Extract nuciferine.

ETHNOPHARMACOLOGIC RELEVANCE: The leaves of Nelumbo nucifera Gaertn. Are recorded in the earliest written documentation of traditional Chinese medicinal as "Ben Cao Gang Mu", a medicinal herb for blood clotting, dysentery and dizziness. Nuciferine, one of N. nucifera Gaertn. leaf extracts, has been shown to possess several pharmacological properties, including but not limited to ameliorating hyperlipidemia, stimulating insulin secretion, inducing vasodilation, reducing blood pressure, and demonstrating anti-arrhythmic properties. AIM OF THE STUDY: In light of the latest research findings on nuciferine, this article provides a comprehensive overview of its chemical properties, pharmacological activities, and the underlying regulatory mechanisms. It aims to serve as a dependable reference for further investigations into the pharmacological effects and mechanisms of nuciferine. MATERIALS AND METHODS: Use Google Scholar, Scifinder, PubMed, Springer, Elsevier, Wiley, Web of Science and other online database search to collect the literature on extraction, separation, structural analysis and pharmacological activity of nuciferine published before November 2023. The key words are "extraction", "isolation", "purification" and "pharmacological action" and "nuciferine". RESULTS: Nuciferine has been widely used in the treatment of ameliorating hyperlipidemia and lose weight, Nuciferine is a monomeric aporphine alkaloid extracted from the leaves of the plant Nymphaea caerulea and Nelumbo nucifera Gaertn. Nuciferine has pharmacological activities such as relaxing smooth muscles, improving hyperlipidemia, stimulating insulin secretion, vasodilation, inducing hypotension, antiarrhythmic effects, and antimicrobial and anti-HIV activities. These pharmacological properties lay a foundation for the treatment of tumors, inflammation, hyperglycemia, lipid-lowering and weight-loss, oxidative stress and other diseases with nuciferine. CONCLUSION: Nuciferine has been clinically used to treat hyperlipidemia and aid in weight loss due to its effects on lipid levels, insulin secretion, vasodilation, blood pressure reduction, anti-tumor properties, and immune enhancement. However, other potential benefits of nuciferine have not yet been fully explored in clinical practice. Future research should delve deeper into its molecular structure, toxicity, side effects, and clinical pharmacology to uncover its full range of effects and pave the way for its safe and expanded clinical use.

Nuciferine reduces vascular leakage and improves cardiac function in acute myocardial infarction by regulating the PI3K/AKT pathway.

The destruction of the microvascular structure and function can seriously affect the survival and prognosis of patients with acute myocardial infarction (AMI). Nuciferine has a potentially beneficial effect in the treatment of cardiovascular disease, albeit its role in microvascular structure and function during AMI remains unclear. This study aimed to investigate the protective effect and the related mechanisms of nuciferine in microvascular injury during AMI. Cardiac functions and pathological examination were conducted in vivo to investigate the effect of nuciferine on AMI. The effect of nuciferine on permeability and adherens junctions in endothelial cells was evaluated in vitro, and the phosphorylation level of the PI3K/AKT pathway (in the presence or absence of PI3K inhibitors) was also analyzed. In vivo results indicated that nuciferine inhibited ischemia-induced cardiomyocyte damage and vascular leakage and improved cardiac function. In addition, the in vitro results revealed that nuciferine could effectively inhibit oxygen-glucose deprivation (OGD) stimulated breakdown of the structure and function of human coronary microvascular endothelial cells (HCMECs). Moreover, nuciferine could significantly increase the phosphorylation level of the PI3K/AKT pathway. Finally, the inhibitor wortmannin could reverse the protective effect of nuciferine on HCMECs. Nuciferine inhibited AMI-induced microvascular injury by regulating the PI3K/AKT pathway and protecting the endothelial barrier function in mice.

Four unreported aporphine alkaloids with antifungal activities from Artabotrys hexapetalus.

In this study, the extract from Artabotrys hexapetalus showed strong antifungal activity against phytopathogenic fungi in vitro. Four unreported aporphine alkaloids, hexapetalusine A-D (1-4), were isolated from stems and roots of Artabotrys hexapetalus (L.f.) Bhandari, along with six known aporphine alkaloids (5-10). Their chemical structures were elucidated by extensive spectroscopic analysis. The absolute configurations of 1-3 were determined using single-crystal X-ray diffractions and ECD calculations. Hexapetalusine A-C (1-3) were special amidic isomers. Additionally, all isolated compounds were evaluated for their antifungal activity against four phytopathogenic fungi in vitro. Hexapetalusine D (4) exhibited weak antifungal activity against Curvularia lunata. Liriodenine (5) displayed significant antifungal activity against Fusarium proliferatum and Fusarium oxysporum f. sp. vasinfectum, which is obviously better than positive control nystatin, suggesting that it had great potential to be developed into an effective and eco-friendly fungicide.

Aporphine alkaloids and a naphthoquinone derivative from the leaves of Phaeanthus lucidus Oliv. and their α-glucosidase inhibitory activity.

Three previously undescribed aporphine alkaloids, phaeanthuslucidines E-G, one previously undescribed naphthoquinone derivative, phaeanthusnaphthoquinone, and three known compounds were isolated from an EtOAc extract of the leaves of Phaeanthus lucidus Oliv. The structures of all previously undescribed compounds were established through extensive spectroscopic investigations and high-resolution mass spectroscopy. The 6aR configuration of phaeanthuslucidines E-G was assigned by comparing their ECD spectra and specific rotation values with the reported known compounds. Some isolated compounds were evaluated for their α-glucosidase inhibitory activity. Among these compounds, phaeanthuslucidine E showed the highest α-glucosidase inhibitory activity with an IC50 value of 17.9 ± 0.4 µM. The molecular docking of phaeanthuslucidine E was further studied.

Nuciferine prevents obesity by activating brown adipose tissue.

Increasing evidence suggests that brown adipose tissue (BAT) plays an important role in obesity and related diseases. Increasing the amount or activity of BAT could prevent obesity. Therefore, a safe and effective method of activating BAT is urgently required. Here, we evaluated the potential effects of lotus leaf extract (LLE) on BAT function. We found that LLE substantially increased UCP1 mRNA and protein levels as well as thermogenic protein expression in primary brown adipocytes. Additionally, LLE treatment reduced diet-induced obesity and improved glucose homeostasis owing to BAT activation and increased energy expenditure. We found that nuciferine, an active ingredient of LLE, could dose-dependently activate BAT in vitro and in vivo, alleviate diet-induced obesity, and improve glucose homeostasis by increasing energy expenditure. Mechanistically, we found that nuciferine induced PPARG coactivator 1 alpha (PGC1-α) expression, which is a key gene involved in mitochondrial biogenesis promoter activity, by directly binding to RXRA. Furthermore, RXRA knockdown abolished expression of the nuciferine-induced mitochondrial and thermogenesis-related gene in primary brown adipocytes. In summary, we found that LLE and nuciferine have a notable effect on BAT activation and highlight the potential applications of the main component of LLE in preventing obesity and treating metabolic disorders.

Therapeutic Potential and Pharmacological Activities of (+)-Nantenine in Medicine: An Aporphine Class Phytocomponent of Nandina domestica Thunberg.

Plant material and their derived byproducts have been used in medicine for the treatment of human disorders and complications. Plants give us a distinct class of natural compounds, commonly called secondary metabolites and better examples are the flavonoids, phenols, terpenoids, alkaloids, tannins, and carotenoids. Plant derived phytoproducts have been used for the treatment of human disorders in both traditional as well as modern medicine. Naturally occurring aporphines and their synthetic derivatives are well known in medicine for their pharmacological activities, including an affinity for dopaminergic, adrenergic and serotonergic receptors. (+)-nantenine is an aporphine alkaloid isolated from Nandina domestica and other plants. The aim of the present study is to analyze the biological potential and therapeutic effectiveness of nantenine in medicine. In the present work scientific information of nantenine for their medicinal uses and pharmacological activities have been collected from scientific databases such as Google, Google Scholar, PubMed, Scopus, and Science Direct . Scientific information of nantenine was further analyzed to know their health beneficial aspects in medicine. However, the detail pharmacological activity of nantenine has been discussed in the present work with its analytical aspects. Scientific data analysis described the medicinal importance and pharmacological activities of nantenine. Nantenine revealed adrenergic response, behavioral response, cardiovascular effect, vasorelaxant effect, acetylcholinesterase inhibitory potential, cytotoxicity, and biphasic tracheal relaxation. Present work also signified the biological potential of nantenine for their anti-inflammatory activity, anticonvulsant effect, antiserotonergic activities, anti-MDMA effect, antileishmanial activity, effect on histamine and serotonin, human 5-hydroxytryptamine (5-HT(2A)) and h5-HT(2B) receptors and isolated tissues. Further, the analytical techniques used for the separation, isolation and identification of nantenine have also been described in this work. The present scientific data describes the therapeutic potential and pharmacological activities of (+)-nantenine in medicine.

Aporphine and amide alkaloids from Illigera parviflora.

Three undescribed alkaloids (+)-9-hydroxy-N-acetylnordicentrine (1), illigeparvinine (2), and deca-(2E,4Z)-2,4-dienoic acid 4-hydroxy-2-phenethyl amide (3), along with 19 known analogues (4-22), were isolated from the ethnic medicinal plant Illigera parviflora. Their structures were established using NMR, MS, and other spectroscopic analyses as well as X-ray diffraction. Moderate inhibition of human gastric carcinoma (MGC-803) and breast adenocarcinoma (T-47D) cell lines proliferation was observed for actinodaphnine (4) with IC50 values of 28.74 and 11.65 µM, respectively. These findings contribute new anticancer potential compounds and expand the chemical diversity known from the valuable traditional medicinal plant I. parviflora.

Diuretic, Natriuretic, And Ca2+-Sparing Effect Of The Alkaloid Boldine In Rats.

BACKGROUND: Previous studies indicate the renal vasodilating effects of boldine, an alkaloid found in Peumus boldus. However, its potential to induce diuresis still needs to be studied. METHODS: Wistar rats were used and the urine volume was noted for 8 h and further studied. RESULTS: The acute treatment at 0.1 and 0.3 mg/kg of boldine showed a diuretic, natriuretic, and Ca2+-sparing effect in rats without changing the urinary elimination of K+and Cl-. When boldine was given in combination with hydrochlorothiazide, there was an increase in urinary volume compared to the vehicle group. However, this was not different from the treatments in its isolated form. Urine Ca2+values ​​remained low but were not enhanced by this association. The excretion of Na+and Cl- was significantly increased compared to the group that received only vehicle or boldine. On the other hand, although the association of amiloride plus boldine did not result in a diuretic effect, the increase in Na+and the reduction in K+excretion were significantly potentiated. Furthermore, in the presence of the non-selective muscarinic receptor antagonist atropine, boldine showed reduced capacity to increase urinary volume, maintaining the natriuretic and Ca2+-sparing effect, besides a very evident K+-sparing action. Similar results were obtained in the presence of the non-selective cyclooxygenase inhibitor indomethacin. Furthermore, boldine showed an ex vivo antiurolithiasis activity, reducing calcium oxalate's precipitation and crystallization. CONCLUSIONS: This study reveals the diuretic, natriuretic, Ca2+-sparing, and antiurolithiatic effects of boldine, an action possibly related to muscarinic receptor activation and prostanoid generation.

Boldine Alters Serum Lipidomic Signatures after Acute Spinal Cord Transection in Male Mice.

Traumatic spinal cord injury (SCI) results in wide-ranging cellular and systemic dysfunction in the acute and chronic time frames after the injury. Chronic SCI has well-described secondary medical consequences while acute SCI has unique metabolic challenges as a result of physical trauma, in-patient recovery and other post-operative outcomes. Here, we used high resolution mass spectrometry approaches to describe the circulating lipidomic and metabolomic signatures using blood serum from mice 7 d after a complete SCI. Additionally, we probed whether the aporphine alkaloid, boldine, was able to prevent SCI-induced changes observed using these 'omics platforms'. We found that SCI resulted in large-scale changes to the circulating lipidome but minimal changes in the metabolome, with boldine able to reverse or attenuate SCI-induced changes in the abundance of 50 lipids. Multiomic integration using xMWAS demonstrated unique network structures and community memberships across the groups.

An Overview of Chemistry, Kinetics, Toxicity and Therapeutic Potential of Boldine in Neurological Disorders.

Boldine is an alkaloid obtained from the medicinal herb Peumus boldus (Mol.) (Chilean boldo tree; boldo) and belongs to the family Monimiaceae. It exhibits a wide range of pharmacological effects such as antioxidant, anticancer, hepatoprotective, neuroprotective, and anti-diabetic properties. There is a dearth of information regarding its pharmacokinetics and toxicity in addition to its potential pharmacological activity. Boldine belongs to the aporphine alkaloid class and possesses lipophilic properties which enable its efficient absorption and distribution throughout the body, including the central nervous system. It exhibits potent free radical scavenging activity, thereby reducing oxidative stress and preventing neuronal damage. Through a variety of neuroprotective mechanisms, including suppression of AChE and BuChE activity, blocking of connexin-43 hemichannels, pannexin 1 channel, reduction of NF-κß mediated interleukin release, and glutamate excitotoxicity which successfully reduces neuronal damage. These results point to its probable application in reducing neuroinflammation and oxidative stress in epilepsy, Alzheimer's disease (AD), and Parkinson's disease (PD). Moreover, its effects on serotonergic, dopaminergic, opioid, and cholinergic receptors were further investigated in order to determine its applicability for neurobehavioral dysfunctions. The article investigates the pharmacokinetics of boldine and reveals that it has a low oral bioavailability and a short half-life, requiring regular dosage to maintain therapeutic levels. The review studies boldine's potential therapeutic uses and mode of action while summarizing its neuroprotective benefits.  Given the favorable results for boldine as a potential neurotherapeutic drug in laboratory animals, more research is required. However, in order to optimise its therapeutic potential, it must be more bioavailable with fewer detrimental side effects.

Structure-activity relationship, bioactivities, molecular mechanisms, and clinical application of nuciferine on inflammation-related diseases.

Nuciferine aporphine alkaloid mainly exists in Nelumbo nucifera Gaertn and is a beneficial to human health, such as anti-obesity, lowering blood lipid, prevention of diabetes and cancer, closely associated with inflammation. Importantly, nuciferine may contribute to its bioactivities by exerting intense anti-inflammatory activities in multiple models. However, no review has summarized the anti-inflammatory effect of nuciferine. This review critically summarized the information regarding the structure-activity relationships of dietary nuciferine. Moreover, biological activities and clinical application on inflammation-related diseases, such as obesity, diabetes, liver, cardiovascular diseases, and cancer, as well as their potential mechanisms, involving oxidative stress, metabolic signaling, and gut microbiota has been reviewed. The current work provides a better understanding of the anti-inflammation properties of nuciferine against multiple diseases, thereby improving the utilization and application of nuciferine-containing plants across functional food and medicine.

Assessing the impact of boldine on the gastrocnemius using multiomics profiling at 7 and 28 days post-complete spinal cord injury in young male mice.

Spinal cord injury (SCI) results in rapid muscle loss. Exogenous molecular interventions to slow muscle atrophy after SCI have been relatively ineffective and require the search for novel therapeutic targets. Connexin hemichannels (CxHCs) allow nonselective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising preclinical results in slowing atrophy during sepsis and restoring muscle function in dysferlinopathy. We administered 50 mg/kg/day of boldine to spinal cord transected mice beginning 3 days post-injury. Tissue was collected 7 and 28 days post-SCI and the gastrocnemius was used for multiomics profiling. Boldine did not prevent body or muscle mass loss but attenuated SCI-induced changes in the abundance of the amino acids proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 days post-SCI. SCI resulted in the differential expression of ∼7,700 and ∼2,000 genes at 7 and 28 days, respectively, compared with Sham controls. Pathway enrichment of these genes highlighted ribosome biogenesis at 7 days and translation and oxidative phosphorylation at both timepoints. Boldine altered the expression of ∼150 genes at 7 days and ∼110 genes at 28 days post-SCI. Pathway enrichment of these genes indicated a potential role for boldine in suppressing protein ubiquitination and degradation at the 7-day timepoint. Methylation analyses showed minimal differences between groups. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it attenuated some SCI-induced changes across the metabolome and transcriptome.NEW & NOTEWORTHY This is the first study to describe the multiome of skeletal muscle paralyzed by a spinal cord injury (SCI) in mice across the acute and subacute timeframe after injury. We show large-scale changes in the metabolome and transcriptome at 7 days post-injury compared with 28 days. Furthermore, we show that the alkaloid boldine was able to prevent SCI-induced changes in muscle glucose and free amino acid levels at 7 days, but not 28 days, after SCI.

Nuciferine improves random skin flap survival via TFEB-mediated activation of autophagy-lysosomal pathway.

Due to their simplicity and reliability, random-pattern skin flaps are commonly utilized in surgical reconstruction to repair cutaneous wounds. However, the post-operative necrosis frequently happens because of the ischemia and high-level of oxidative stress of random skin flaps, which can severely affect the healing outcomes. Earlier evidence has shown promising effect of Nuciferine (NF) on preventing hydrogen peroxide (H2O2)-induced fibroblast senescence and ischemic injury, however, whether it can function on promoting ischemic flap survival remains unknown. In this work, using network pharmacology analysis, it was possible to anticipate the prospective targets of NF in the context of ischemia. The results revealed that NF treatment minimized H2O2-induced cellular dysfunction of human umbilical vein endothelial cells (HUVECs), and also improved flap survival through strengthening angiogenesis and alleviating oxidative stress, inflammation and apoptosis in vivo. These outcomes should be attributed to TFEB-mediated enhancement of autophagy-lysosomal degradation via the AMPK-mTOR signaling pathway, whilst the restriction of autophagy stimulation with 3MA effectively diminished the above advantages of NF treatment. The increased nuclear translocation of TFEB not only restored lysosome function, but also promoted autophagosome-lysosome fusion, eventually restoring the inhibited autophagic flux and filling the high energy levels. The outcomes of our research can provide potent proof for the application of NF in the therapy of vascular insufficiency associated disorders, including random flaps.

Aporphines: A privileged scaffold in CNS drug discovery.

Aporphine alkaloids embedded in 4H-dibenzo[de,g]quinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D1/2/5, serotonin 5-HT1A/2A/2C and 5-HT7, adrenergic α/ß receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.