Isoquinoline Alkaloids Research Articles

Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model

Background and aimsPrimary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2−/− mice) and elucidate the underlying mechanisms.MethodsMdr2−/−mice (12–14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by qRT-PCR or Western blot analysis. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distribution of BBR were measured by LC–MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histological analysis. The impact on the gut microbiome was assessed using 16S rRNA gene sequencing.ResultsBBR treatment significantly ameliorated cholestatic liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct proliferation and hepatic fibrosis, as shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substantial inhibition of fibrotic and inflammatory gene expression. BBR also mitigated ER stress by downregulating Chop, Atf4 and Xbp-1 expression. In addition, BBR modulated bile acid metabolism by altering key gene expressions in the liver and small intestine, resulting in restored bile acid homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthermore, BBR significantly improved intestinal barrier function and reduced bacterial translocation by modulating the gut microbiota.ConclusionBBR effectively attenuates cholestatic liver injury, suggesting its potential as a therapeutic agent for PSC and other cholestatic liver diseases.

Bioactivities and Mechanisms of Action of Sinomenine and Its Derivatives: A Comprehensive Review.

Sinomenine, an isoquinoline alkaloid extracted from the roots and stems of Sinomenium acutum, has been extensively studied for its derivatives as bioactive agents. This review concentrates on the research advancements in the biological activities and action mechanisms of sinomenine-related compounds until November 2023. The findings indicate a broad spectrum of pharmacological effects, including antitumor, anti-inflammation, neuroprotection, and immunosuppressive properties. These compounds are notably effective against breast, lung, liver, and prostate cancers, exhibiting IC50 values of approximately 121.4 nM against PC-3 and DU-145 cells, primarily through the PI3K/Akt/mTOR, NF-κB, MAPK, and JAK/STAT signaling pathways. Additionally, they manifest anti-inflammatory and analgesic effects predominantly via the NF-κB, MAPK, and Nrf2 signaling pathways. Utilized in treating rheumatic arthritis, these alkaloids also play a significant role in cardiovascular and cerebrovascular protection, as well as organ protection through the NF-κB, Nrf2, MAPK, and PI3K/Akt/mTOR signaling pathways. This review concludes with perspectives and insights on this topic, highlighting the potential of sinomenine-related compounds in clinical applications and the development of medications derived from natural products.

Macleaya cordata isoquinoline alkaloids attenuate Escherichia coli lipopolysaccharide-induced intestinal epithelium injury in broiler chickens by co-regulating the TLR4/MyD88/NF-κB and Nrf2 signaling pathways.

This study sought to explore the effects and potential mechanisms of dietary supplementation with isoquinoline alkaloids (IA) from Macleaya cordata to alleviate lipopolysaccharide (LPS)-induced intestinal epithelium injury in broilers. A total of 486 1-day-old broilers were assigned at random to a control (CON) group, LPS group, and LPS+IA group in a 21-d study. The CON and LPS groups received a basal diet, while the LPS+IA group received a basal diet supplemented with 0.6 mg/kg IA. At 17, 19, and 21 days of age, the LPS and LPS+BP groups were injected intraperitoneally with LPS, and the CON group was intraperitoneally injected equivalent amount of saline solution. The results manifested that LPS injection caused intestinal inflammation and lipid peroxidation, disrupted intestinal barrier and function, and increased the abundance of harmful microorganisms. However, dietary IA supplementation alleviated LPS-induced adverse changes in intestinal morphology, apoptosis, mucosal barrier integrity, cecum microorganisms, and homeostasis disorder by decreasing inflammatory cytokines and enhancing antioxidant-related genes expressions; inhibited LPS-induced increases in TLR4 and NF-κB expressions and decreases in Nrf2 and GPX1 genes expressions. Our findings indicated that Macleaya cordata IA addition attenuated LPS-induced intestinal epithelium injury and disorder of intestinal homeostasis by enhancing the anti-inflammatory and antioxidant capacity of broiler chickens possibly via co-regulating TLR4/MyD88/NF-κB and Nrf2 signaling pathways.

Transcriptome analysis reveals cadmium exposure enhanced the isoquinoline alkaloid biosynthesis and disease resistance in Coptis chinensis

Coptis chinensis Franch is a perennial herb from the Ranunculaceae family with a long history of medicinal use. As the medicinal part, the rhizome of coptis often accumulates excessive cadmium (Cd) even at low concentrations in the soil, which not only compromises its medicinal safety but also raises concerns about adverse effects on human health. Therefore, effective strategies are needed to mitigate this accumulation and ensure its safe use in traditional medicine. This study utilized transcriptome profiling and physiological analysis to explore molecular mechanisms associated with ecological significance and the active accumulation of Cd in C. chinensis. The response to Cd in C. chinensis was assessed through RNA sequencing, Cd determination and isoquinoline alkaloid measurement using its roots, stems, and leaves. The transcriptome revealed, a total of 2667, 2998, or 2815 up-regulated deferentially expressed genes in roots, stems or leaves in response to Cd exposure. Furthermore, we identified phenylpropanoid and isoquinoline alkaloid biosynthesis as the key pathways response to Cd exposure, which suggests that C. chinensis may improve its tolerance to Cd through regulating the phenylpropanoid biosynthesis pathway. Under Cd exposure, plant-pathogen interaction in leaves was identified as the key pathway, which indicates that upregulation of genes involved in plant-pathogen interaction could enhance disease resistance in C. chinensis. WGCNA analysis identified WRKY8 (Cluster-55763.31419) and WRKY47 (Cluster-55763.221590) as potential regulators of secondary metabolic synthesis and plant-pathogen interaction pathway in C. chinensis triggered by Cd. The measurement of berberine, coptisine, palmatine, and epiberberine also demonstrated that Cd simulated the four isoquinoline alkaloids in roots. Therefore, our study not only presented a transcriptome expression profiles that revealed significant upregulation of genes involved in metal transport and detoxification pathways but also suggested a possible mechanism to cope with Cd accumulation. This knowledge provides a new insight into gene manipulation for controlling Cd accumulation, enhancing resistance and promoting synthesis of secondary metabolites with potential medicinal properties in other medicinal plant species.

Urea-Promoted Neat Synthesis of Fused Dihydroisoquinolines and Disubstituted Pyridines: A Mechanistic Observation with Molecular-Sensing Studies.

An efficient and short synthesis of fused dihydroisoquinolines, diaryl substituted pyridine derivatives in good to high yields has been established by using an environmentally safe, solvent-metal-oxidant-free tandem approach. In this article, we discuss how the electrocyclic reaction is more pronounced in the solid phase in the presence of urea, whereas the typical aza-Michael addition is more prominent in presence of arylamine in the solution phase for 3-(2-formylcycloalkenyl)acrylic ester derivative substrates. The wide range of substrates and urea-promoted neat synthesis made our approach more significant in medical and also analytical science. Moreover, an isoquinoline alkaloid decumbenine B analogue has been synthesized by using our newly developed neat methodology. We have also investigated the photophysical properties of the synthesized fused dihydroisoquinoline derivatives. One of the synthesized molecules was used as a sensor for the selective detection of toxic picric acid. Therefore, the effective neat synthesis and molecular sensing applications of these compounds made our approach more exciting in the field of heterocyclic chemistry.

Alkaloidal Extracts from Avicennia africana P. Beauv. (Avicenniaceae) Leaf: An Antiplasmodial, Antioxidant, and Erythrocyte Viable.

The emergence of drug-resistant parasites impedes disease management and eradication efforts. Hence, a reinvigorated attempt to search for potent lead compounds in the mangroves is imperative. This study evaluates in vitro antiplasmodial activity, antioxidant properties, and cytotoxicity of A. africana leaf alkaloidal extracts. The A. africana leaves were macerated with 70% ethanol to obtain a total crude extract. Dichloromethane and chloroform-isopropanol (3 : 1, v/v) were used to extract the crude alkaloids and quaternary alkaloids from the total crude. The antiplasmodial activities of the alkaloidal extracts were performed against 3D7 P. falciparum chloroquine-sensitive clone via the SYBR Green I fluorescence assay with artesunate serving as the reference drug. The alkaloidal extracts were further evaluated for antioxidant properties via the total antioxidant capacity (TAC), the total glutathione concentration (GSH), the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, and the ferric-reducing antioxidant power (FRAP) methods. The cytotoxic activity of the alkaloidal extracts was tested on erythrocytes using a 3-(4,5-dimethylthiazol-2-yl)-5-diphenyltetrazolium bromide-MTT assay with little modification. The phytocompounds in the alkaloidal extracts were identified via gas chromatography-mass spectrometry (GC-MS) techniques. The total crude extract showed good antiplasmodial activity (IC50 = 11.890 µg/mL). The crude and quaternary alkaloidal extracts demonstrated promising antiplasmodial effects with IC50 values of 6.217 and 6.285 µg/mL, respectively. The total crude and alkaloidal extracts showed good antioxidant properties with negligible cytotoxicity on erythrocytes with good selectivity indices. The GC-MS spectral analysis of crude alkaloidal extracts gave indole and isoquinoline alkaloids and several other compounds. Dexrazoxane was found to be the main compound predicted, with an 86% peak area in the quaternary alkaloidal extract. The crude and quaternary alkaloidal extracts exhibited antiplasmodial activities and ability to inhibit oxidative stress with negligible toxicity on erythrocytes. This may be good characteristics to avoid oxidative stress related to Plasmodium infection in the treatment of malaria.

Synthesis and evaluation of aromatic stationary phases based on linear solvation energy relationship model for expanded application in supercritical fluid chromatography

In the last decade, the separation application based on aromatic stationary phases has been demonstrated in supercritical fluid chromatography (SFC). In this paper, four aromatic stationary phases involving aniline (S-aniline), 1-aminonaphthalene (S-1-ami-naph), 1-aminoanthracene (S-1-ami-anth) and 1-aminopyrene (S-1-ami-py) were synthesized based on full porous particles (FPP) silica, which were not end-capped for providing extra electrostatic interaction. Retention mechanism of these phases in SFC was investigated using a linear solvation energy relationship (LSER) model. The aromatic stationary phases with five positive parameters (a, b, s, e and d+) can provide hydrogen bonding, π-π, dipole-dipole and cation exchange interactions, which belong to the moderate polar phases. The LSER results obtained using routine test solutes demonstrated that the aforementioned interactions of four aromatic stationary phases were influenced by the type and bonding density of the ligand, but to a certain extent. Furthermore, the LSER data verified that the S-1-ami-anth column based on full porous particles silica had higher cation exchange capacity (d+ value), compared to the commercialized 1-AA column (based on the ethylene-bridged hybrid particles). The relationship between the d+ value and SFC additive was quantitatively proved so as to regulate electrostatic interaction reasonably. This value was greatly increased by phosphoric acid, slightly increased by trifluoroacetic acid and formic acid, but significantly reduced by ammonium formate and diethylamine. Taking the S-1-ami-naph column as an example, better peek shape of the flavonoids was obtained after the addition of 0.1 % phosphoric acid in MeOH while isoquinoline alkaloids were eluted successfully within 11 min after adding 0.1 % diethylamine in MeOH. Combined with the unique π-π interaction and controllable electrostatic interaction, the aromatic stationary phases in this study have been proven to have expandable application potential in SFC separation.

Synthesis of New Derivatives of Berberine Canagliflozin and Study of Their Antibacterial Activity and Mechanism.

The isoquinoline alkaloid berberine, derived from Coptidis rhizoma, exhibits antibacterial, hypoglycemic, and anti-inflammatory properties. Canagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. We synthesized compounds B9OC and B9OBU by conjugating canagliflozin and n-butane at the C9 position of berberine, aiming to develop antimicrobial agents for combating bacterial infections worldwide. We utilized clinically prevalent pathogenic bacteria, namely Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, to investigate the antibacterial efficacy of B9OC. This was accomplished through the determination of the MIC80 values, analysis of bacterial growth curves, evaluation of biofilm formation using crystal violet staining, assessment of impact on bacterial proteins via SDS-PAGE analysis, and observation of alterations in bacterial morphology utilizing field emission scanning electron microscopy. Meanwhile, the ADMET of compound B9OC was predicted using a computer-aided method. The findings revealed that B9OC exhibited lower minimal inhibitory concentrations against all three bacteria compared to berberine alone or in combination with canagliflozin. The minimal inhibitory concentrations (MICs) of B9OC against the three experimental strains were determined to be 0.035, 0.258, and 0.331 mM. However, B9OBu exhibited a lower level of antimicrobial activity compared to berberine. The compound B9OC exhibits a broad spectrum of antibacterial activity by disrupting the integrity of bacterial cell walls, leading to cellular rupture and the subsequent degradation of intracellular proteins.

Electrospun radially oriented berberine-PHBV nanofiber dressing patches for accelerating diabetic wound healing.

A dressing patch made of radially oriented poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanofibers was successfully manufactured with a modified electrospinning strategy. The as-electrospun PHBV radially oriented nanofiber dressing patch exhibited uniform and bead-free nanofibrous morphology and innovative radially oriented arrangement, which was demonstrated to possess obviously improved mechanical property, increased surface hydrophilicity and enhanced biological properties compared to the PHBV nanofiber dressing patch control with traditionally randomly oriented pattern. Interestingly, it was found that the radially oriented pattern could induce the cell migration from the periphery to the center along the radially oriented nanofibers in a rapid manner. To further improve the biofunction of PHBV radially oriented nanofiber dressing patch, berberine (Beri, an isoquinoline alkaloid) with two different concentrations were encapsulated into PHBV nanofibers during electrospinning, which were found to present a sustained drug release behavior for nearly one month. Importantly, the addition of Beri could impart the dressing patch with excellent anti-inflammatory property by significantly inhibiting the secretion of pro-inflammatory factors of M1 macrophages, and also showed an additive influence on promoting the proliferation of human dermal fibroblasts (HDFs), as well as inhibiting the growth of E. coli, S. aureus and C. albicans, compared with the Beri-free dressing patch. In the animal studies, the electrospun PHBV radially oriented nanofiber dressing patch loading with high Beri content was found to obviously accelerate the healing process of diabetic mouse full-thickness skin wound with shortened healing time (100% wound closure rate after 18 days' treatment) and improved healing quality (improved collagen deposition, enhanced re-epithelialization and neovascularization and increased hair follicles). In all, this study reported an innovative therapeutic strategy integrating the excellent physical cues of electrospun PHBV radially oriented nanofiber dressing patch with the multiple biological cues of Beri for the effective treatment of hard-to-heal diabetic wounds.

Isolation, biological activity, and synthesis of isoquinoline alkaloids.

Covering: 2019 to 2023Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide. To follow up on our prior review (covering 2014-2018) and present the progress of this class of compounds, this review summarizes and provides updated literature on novel isoquinoline alkaloids isolated during the period of 2019-2023, together with their biological activity and underlying mechanisms of action. Moreover, with the rapid development of synthetic modification strategies, the synthesis strategies of isoquinoline alkaloids have been continuously optimized, and the total synthesis of these classes of natural products is reviewed critically herein. Over 250 molecules with a broad range of bioactivities, including antitumor, antibacterial, cardioprotective, anti-inflammatory, neuroprotective and other activities, are isolated and discussed. The total synthesis of more than nine classes of isoquinoline alkaloids is presented, and thirteen compounds constitute the first total synthesis. This survey provides new indications or possibilities for the discovery of new drugs from the original naturally occurring isoquinoline alkaloids.

Botanical Sources, Pharmacokinetics, and Therapeutic Efficacy of Palmatine and Its Derivatives in the Management of Cancer: A Comprehensive Mechanistic Analysis

Natural compounds and their derivatives have been identified as valuable sources of therapeutic ingredients for cancer treatment. The naturally occurring phytochemical palmatine (isoquinoline alkaloid) is extracted from plant parts (rhizomes, roots, stems, stem barks, and others) and has protective effects including antioxidant, anti‐inflammatory, and anticancer. This study aims to summarize the anticancer potential of palmatine and its derivatives in the treatment of numerous types of cancer with molecular mechanisms. We also include the pharmacokinetic features, botanical origin, and toxicological characteristics of palmatine and its derivatives. For this, data have been collected from plausible different electronic databases, including PubMed, Google Scholar, PubChem, Science Direct, Web of Science, Scopus, Springer Link, and Wiley Online. The findings demonstrate that palmatine and its derivatives have a protective anticancer effect against a variety of cancers, including breast, colorectal, gastric, ovarian, prostate, pancreatic, skin, hepatocellular cancer, and mammary gland tumors. They provoke their anticancer properties against various cancer cell lines via modifying molecular mechanisms like induction of oxidative stress, cytotoxicity, apoptosis, inhibition of cell invasion and migration, arresting the cell cycle at the S phase, antiproliferative, and antiangiogenic effects. It is suggested that palmatine and its derivatives may be a good option in the development of novel drugs for cancer therapy in the future.

Natural Immunomodulatory Agents as a Complementary Therapy for Poxviruses.

Poxviruses target innate immunity mediators such as tumor necrosis factors, interleukins, interferons, complement, and chemokines. It also targets adaptive immunity such as CD4+ T cells, CD4+ T cells, and B cells. Emerging of the recent epidemic of monkeypox virus (MPXV), a zoonotic disease native to Central and Western Africa, besides the lack of permitted treatments for poxviruses infections, encouraged researchers to identify effective inhibitors to help in preventing and treating poxviruses infections. Natural bioactive components, particularly polyphenolics, are promising for creating powerful antioxidants, anti-inflammatory, immune-stimulating, and antiviral agents. As a result, they are potentially effective therapies for preventing and treating viral diseases, such as infections caused by poxviruses including the recent pandemic MPXV. Polyphenolics: rosmarinic acid, caffeic acid, resveratrol, quercitrin, myricitrin, gingerol, gallotannin, and propolis-benzofuran A, as well as isoquinoline alkaloids: galanthamine and thalimonine represent prospective antiviral agents against MPXV, they can inhibit MPXV and other poxviruses via targeting different viral elements including DNA Topoisomerase I (TOP1), Thymidine Kinase (TK), serine/threonine protein kinase (Ser/Thr kinase), and protein A48R. The bioactive extracts of different traditional plants including Guiera senegalensis, Larrea tridentata, Sarracenia purpurea, Kalanchoe pinnata (Lam.) Pers., Zingiber officinale Roscoe, Quercus infectoria, Rhus chinensis, Prunella vulgaris L., Salvia rosmarinus, and Origanum vulgare also can inhibit the growth of different poxviruses including MPXV, vaccinia virus (VACV), variola virus, buffalopox virus, fowlpox virus, and cowpox virus. There is an urgent need for additional molecular studies to identify and confirm the anti-poxviruses properties of various natural bioactive components, especially those that showed potent antiviral activity against other viruses.

Advances in the pharmacological mechanisms of berberine in the treatment of fibrosis.

The rising incidence of fibrosis poses a major threat to global public health, and the continuous exploration of natural products for the effective treatment of fibrotic diseases is crucial. Berberine (BBR), an isoquinoline alkaloid, is widely used clinically for its anti-inflammatory, anti-tumor and anti-fibrotic pharmacological effects. Until now, researchers have worked to explore the mechanisms of BBR for the treatment of fibrosis, and multiple studies have found that BBR attenuates fibrosis through different pathways such as TGF-β/Smad, AMPK, Nrf2, PPAR-γ, NF-κB, and Notch/snail axis. This review describes the anti-fibrotic mechanism of BBR and its derivatives, and the safety evaluation and toxicity studies of BBR. This provides important therapeutic clues and strategies for exploring new drugs for the treatment of fibrosis. Nevertheless, more studies, especially clinical studies, are still needed. We believe that with the continuous implementation of high-quality studies, significant progress will be made in the treatment of fibrosis.

The Application of Berberine in Fibrosis and the Related Diseases.

The formation of fibrotic tissue, characterized by the excessive accumulation of extracellular matrix (ECM) components such as collagen and fibronectin, is a normal and crucial stage of tissue repair in all organs. The over-synthesis, deposition, and remodeling of ECM components lead to organ dysfunction, posing a significant medical burden. Berberine, an isoquinoline alkaloid, is commonly used in the treatment of gastrointestinal diseases. With the deepening of scientific research, it has been gradually discovered that berberine also plays an important role in fibrotic diseases. In this review, we systematically introduce the effective role of berberine in fibrosis-related diseases. Specifically, this paper aims to provide a comprehensive review of the therapeutic role of berberine in treating fibrosis in organs such as the heart, liver, lungs, and kidneys. By summarizing its various pathways and mechanisms of action, including the inhibition of the transforming growth factor-[Formula: see text]/Smad signaling pathway, PI3K/Akt signaling pathway, MAPK signaling pathway, RhoA/ROCK signaling, and mTOR/p70S6K signaling pathway, as well as its activation of the Nrf2-ARE signaling pathway, AMPK signaling pathway, phosphorylated Smad 2/3 and Smad 7, and other signaling pathways, this review offers additional evidence to support the treatment of fibrotic diseases.

Annotation of Alkaloids of Fusaea longifolia and Evaluation of Anti-Plasmodium Activity in vitro and in silico

Isoquinoline alkaloids, especially from the Annonaceae family, have shown biological potential against parasites. Thus, this study aimed to evaluate the potential of the alkaloid fractions of the plant Fusaea longifolia against Plasmodium falciparum and annotate the compounds present in these samples. The tentative characterization of the alkaloids from the leaves and branches of F. longifolia was performed using liquid chromatography coupled to mass spectrometry (LC-MS/MS) and molecular networks. Through manual interpretation of the MS/MS spectra, 18 alkaloids were dereplicated from F. longifolia, 17 of which were reported for the first time in this species. An unpublished putative glycosylated alkaloid was annotated by interpreting the fragmentation data profile. Regarding biological activity, the fractions studied showed high activity against P. falciparum with half-maximal inhibitory concentration (IC50) of 2.42 and 1.60 µg mL-1 for branches and from the leaves, respectively, both similar to the reference standard quinine (IC50 of 1.24 µg mL-1). The structures of the 17 alkaloids were subjected to in silico analysis using molecular docking against four enzymes related to anti-Plasmodium activity (wild type (dm-PfDHFR) and mutant type (qm-PfDHFR), dihydroorotate dehydrogenase (PfDHODH) and purine nucleoside phosphorylase (PfPNP)). Molecular docking revealed strong interactions, especially between oxoxylopine 17 and hydroxycassythicine N-oxide 10, which may be potential new sources against P. falciparum.

Nature-derived Alkaloids as a Promising Bioactive Compound in Drug Discovery to Meet Global Leishmania Needs

Background: Natural products have been important resources for potential drug development. Among the many classes of natural products, alkaloids have the most therapeutic applications. Treatment of leishmaniasis by chemical drugs remains a challenge because of toxic side effects, limited efficacy, and drug resistance. This review focuses to embrace all researches on leishmanicidal alkaloids over a specific range of time, with special consideration the molecular mechanism of action, and structure-related activity. Methods: All publications (in English) from Web of Science, PubMed, Science Direct, Scopus, and Google Scholar from 2000-2021 using a variety of keywords such as natural alkaloids, herbal alkaloids, marine alkaloids along with leishmaniasis were included in the present study. In this summary, the focus is mainly on natural alkaloids of plant, mineral, marine origin, etc., which have empirically demonstrated the antileishmanial effect. Results: Fourteen categories of alkaloids with anti-leishmaniasis activity were extracted from the articles. The highest number of alkaloids belonged to isoquinoline, indole, and quinoline alkaloids (21.78%, 20.67%, and 16.48% respectively). This review indicated that the mentioned alkaloids are able to inhibit the proliferation of parasites, the respiratory chain and protein synthesis, arrest the cell cycle, disrupt the mitochondrial membrane integrity, inhibit leishmanial topoisomerase, induce mitochondrial dysfunction, and changes in the parasite morphology. Discussion: The present study highlighted antileishmanial alkaloids that are active against different species of Leishmania in vitro and some of them are also active in visceral and cutaneous leishmaniasis models. However, more clinical studies are needed to clarify the anti-leishmanial activity of alkaloids against leishmania in detail. Conclusion: Among the reported compounds, two main classes of alkaloids including isoquinoline and indole alkaloids cover a wider range of anti-parasitic compounds, and structure-activity relationships (SAR) studies of these molecular skeletons may be good lead compounds and afford the structural clues to develop novel medicines with more selective therapeutic profiles.

Nano formulation of Berberine (Brb): Transforming a natural alkaloid into advanced therapeutics

A naturally occurring isoquinoline alkaloid “Berberine” (Brb) is found in various plant species of the genus Berberis, such as Berberis vulgaris, Berberis aristata, Berberis microphylla, and so on. This component has been studied extensively by various researchers and scientists for its diverse therapeutic properties, including anticancer, antiviral, antimicrobial antidiarrheal, and anti-inflammatory effects. One of the most remarkable applications of berberine is its efficacy in managing type-II diabetes, which is attributed to its capability to initiate adenosine monophosphate, glycolysis stimulation, protein kinases activation, inhibit mitochondrial function and thus collectively enhance the lipid and glucose metabolism. Also, Berberine has shown promising outcomes in addressing other health conditions, such as hypertension, cardiac arrhythmias, and congestive heart failure. In spite of its numerous benefits, extensive usage of berberine has been hindered by some challenges such as low bioavailability, limited absorption, and poor water solubility. Nano formulation has emerged as an auspicious approach to overcome these obstacles. This review highlights the advancements of using nano technology to overcome the limitations of berberine (Brb) associated with its absorption, dissolution, and bio-distribution, which are critical for its active application of pharmacology. While previous studies have explored the use of nano-carriers for transfer of drug, this review uniquely underlines an inclusive evaluation of several nanocarrier, together with lipid-based nanoparticles (SLNs, NLCs, micelles, and liposomes), polymeric-based nanoparticles (chitosan, alginate, dextran, and PLGA) and advanced materials (graphene, dendrimers, gold (Au), and silver (Ag) nanoparticles). It emphasizes their specific applications in treating conditions like diabetes, osteoarthritis, microbial infections, and melanoma, with special attention on innovative applications such as thermal therapy with AuNP-Brb and bio-imaging with Brb-based carbon dots. In conclusion, nanotechnology has shown an outstanding result in improving the therapeutic strength and delivery of berberine, more investigation is necessary to interpret these nanoparticle carriers into clinical applications. The detailing of specific therapeutic effects and this breadth of comparison highlight the novelty of this review, which sets a foundation for future research to translate these findings into clinical applications.

Structural variety and pharmacological potential of naphthylisoquinoline alkaloids.

Naphthylisoquinoline alkaloids are a fascinating class of natural biaryl compounds. They show characteristic mono- and dimeric scaffolds, with chiral axes and stereogenic centers. Since the appearance of the last comprehensive overview on these secondary plant metabolites in this series in 1995, the number of discovered representatives has tremendously increased to more than 280 examples known today. Many novel-type compounds have meanwhile been discovered, among them naphthylisoquinoline-related follow-up products like e.g., the first seco-type (i.e., ring-opened) and ring-contracted analogues. As highlighted in this review, the knowledge on the broad structural chemodiversity of naphthylisoquinoline alkaloids has been decisively driven forward by extensive phytochemical studies on the metabolite pattern of Ancistrocladus abbreviatus from Coastal West Africa, which is a particularly "creative" plant. These investigations furnished a considerable number of more than 80-mostly new-natural products from this single species, with promising antiplasmodial activities and with pronounced cytotoxic effects against human leukemia, pancreatic, cervical, and breast cancer cells. Another unique feature of naphthylisoquinoline alkaloids is their unprecedented biosynthetic origin from polyketidic precursors and not, as usual for isoquinoline alkaloids, from aromatic amino acids-a striking example of biosynthetic convergence in nature. Furthermore, remarkable botanical results are presented on the natural producers of naphthylisoquinoline alkaloids, the paleotropical Dioncophyllaceae and Ancistrocladaceae lianas, including first investigations on the chemoecological role of these plant metabolites and their storage and accumulation in particular plant organs.

C9-Aryl-substituted berberine derivatives with tunable AIE properties for cell imaging application.

Berberine (BBR), a widely used isoquinoline alkaloid derived from natural sources, exhibits aggregation-induced emission (AIE) characteristics and has biological applications such as in selective lipid droplet imaging and photodynamic therapy. However, natural BBR suffers from low fluorescence quantum yield (ΦF) and monotonous emission wavelength. In this paper, a series of C9-position-aryl-substituted berberine derivatives with a D-A structure were designed and synthesized. The electronic effect of the substitution groups can tune the intramolecular charge transfer (ICT) effect of the berberine derivatives, resulting in bluish green to NIR (508-682 nm) luminescence with AIE characteristics and enhanced ΦF up to 36% in the solid state. Interestingly, berberine derivatives containing an amino or a pyridyl group can exhibit fluorescence response to TFA. Cell imaging of the berberine derivatives was conducted using Caco-2 cancer cells, demonstrating their multi-color and efficient wash-free imaging capabilities. This work presents a new strategy for developing novel berberine derivatives with tunable AIE properties for application in biological imaging.

Mycorrhiza-triggered changes in leaf food quality and secondary metabolite profile in tea at low temperatures

Tea is a popular cash crop around the world that often endures low temperatures in the spring, thereby negatively affecting tea yield and quality. The objective of this study was to examine the effects of an arbuscular mycorrhizal fungus, Clariodeoglomus etunicatum, on plant growth, root morphology, leaf food quality, associated gene expression, and secondary metabolite profiles in tea (Camellia sinensis cv. Fuding Dabaicha) seedlings grown at low temperatures. A seven-day low temperature (4 °C) treatment significantly reduced root colonization rate by C. etunicatum by 21.08%. Uninoculated plants' growth was considerably impeded by low temperatures, whereas C. etunicatum inoculation significantly increased leaf number and leaf, stem and root biomass at low temperatures. Low temperatures had little effect on root morphology, whereas C. etunicatum inoculation significantly increased root surface area at low temperatures. In addition, low temperatures reduced leaf quality variables, whereas C. etunicatum significantly increased the levels of glucose, fructose, sucrose, tea polyphenols, catechin, free amino acids, and caffeine at low temperatures, along with up-regulated expression of CsGDH, CsGOGAT, and CsHMGR, as well as down-regulated expression of CsGs. Non-targeted metabolomics identified 767 differential metabolites, of which 65 differential metabolites were observed at low temperatures by C. etunicatum inoculation, including 42 (e.g., catechin, (−)-epicatechingallate, protoanemonin, epicatechin, and 4-dodecylbenzenesulfonic acid) up-regulated and 23 (e.g., 4-hydroxybenzoic acid, raffinose, L-theanine, melezitose, and D-serine) down-regulated. Mycorrhiza-triggered differential metabolites enriched 268 metabolic pathways at low temperatures, including isoquinoline alkaloid biosynthesis, lysine biosynthesis, tyrosine metabolism, and others. These findings reveal that C. etunicatum can function as a fungal stimulant to improve the plant growth and leaf quality in tea while also changing the secondary metabolite profile at low temperatures.