Eugeniifoline, a Pentacyclic Indole Alkaloid from Leuconotis eugeniifolia, and Configurational Revision of Synthetic Eugeniifoline Isolated from a Diversity-Enhanced Extract.

Eugeniifoline (1), a pentacyclic indole alkaloid with a five-membered ring E, was isolated for the first time as a natural product from the stem-bark extract of Leuconotis eugeniifolia. Eugeniifoline (1) was previously reported as a synthetic product from a diversity-enhanced extract, but with the configuration at C-21 reported as S (1a). The configuration at C-21 was revised to R as shown in 1, based on the NOE data, GIAO NMR calculations, and DP4+ probability analysis, as well as the TDDFT-ECD method.

Carrageenophyte Kappaphycus malesianus Inhibits Microglia-Mediated Neuroinflammation via Suppression of AKT/NF-κB and ERK Signaling Pathways.

Neuroinflammation is an inflammatory response in any part of the central nervous system triggered by the activation of microglia and astrocytes to produce proinflammatory cytokines in the brain. However, overproduction of proinflammatory cytokines further contributes to the development of neurodegenerative disorders. Red seaweed, Kappaphycus malesianus, is a predominant carrageenophyte commercially cultivated in Semporna, Sabah, Malaysia. It is an important source of raw material for kappa-carrageenan productions in the food, pharmaceutical and cosmetics industries. However, no studies have been conducted focusing on the antineuroinflammatory effects of K. malesianus. The aim of the present study was to investigate the effect of the antineuroinflammatory activity of K. malesianus extracts (ethyl acetate, ethanol and methanol) on lipopolysaccharide-stimulated BV2 microglia and the underlying mechanisms involved in the regulation of neuroinflammatory pathways. Extract with the most promising antineuroinflammatory activity was analyzed using liquid chromatography-mass spectrometry (LC-MS). Our results show that methanol extract has a convincing antineuroinflammatory effect by suppressing both AKT/NF-κB and ERK signaling pathways to inhibit the expression of all proinflammatory cytokines without causing a cytotoxicity effect. LC-MS analysis of methanol extract revealed two compounds: prosopinine and eplerenone. Our findings indicated that metabolites of K. malesianus are potent antineuroinflammatory agents with respect to prevention of neurological disorders.

Vobasine, vincamine, voaphylline, tacaman, and iboga alkaloids from Tabernaemontana corymbosa.

Thirteen indole alkaloids comprising six vobasine/sarpagine, one vincamine, two voaphylline, two tacaman, one iboga, and one corynantheine alkaloid, were isolated from the leaf extract of Tabernaemontana corymbosa (sample from Taiping, Perak, Malaysia). The structures of these alkaloids were determined based on analysis of the spectroscopic data (NMR and MS), and in the case of vincarudine, the absolute configuration was established by ECD and X-ray diffraction analysis. Vobasidine E represents the first vobasine-type alkaloid characterized by a contracted ring C and loss of the ethylidene/ethyl side chain. A possible biogenetic pathway from a perivine precursor, which was also present in the leaf extract, is presented. Differences in the new alkaloid content between the present and previous sample of the same plant (occurring in a different location) are discussed.

Antiproliferative and Microtubule-stabilizing Activities of Two Iboga-vobasine Bisindoles Alkaloids from Tabernaemontana corymbosa in Colorectal Adenocarcinoma HT-29 Cells.

Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the ß-tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21Cip1/Chk1, and p21Cip1/Rb/E2F, as shown by microarray profiling.

Therapeutic Potential of Complementary and Alternative Medicines in Peripheral Nerve Regeneration: A Systematic Review.

Despite the progressive advances, current standards of treatments for peripheral nerve injury do not guarantee complete recovery. Thus, alternative therapeutic interventions should be considered. Complementary and alternative medicines (CAMs) are widely explored for their therapeutic value, but their potential use in peripheral nerve regeneration is underappreciated. The present systematic review, designed according to guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, aims to present and discuss the current literature on the neuroregenerative potential of CAMs, focusing on plants or herbs, mushrooms, decoctions, and their respective natural products. The available literature on CAMs associated with peripheral nerve regeneration published up to 2020 were retrieved from PubMed, Scopus, and Web of Science. According to current literature, the neuroregenerative potential of Achyranthes bidentata, Astragalus membranaceus, Curcuma longa, Panax ginseng, and Hericium erinaceus are the most widely studied. Various CAMs enhanced proliferation and migration of Schwann cells in vitro, primarily through activation of MAPK pathway and FGF-2 signaling, respectively. Animal studies demonstrated the ability of CAMs to promote peripheral nerve regeneration and functional recovery, which are partially associated with modulations of neurotrophic factors, pro-inflammatory cytokines, and anti-apoptotic signaling. This systematic review provides evidence for the potential use of CAMs in the management of peripheral nerve injury.

Neuroprotective effects of Hericium erinaceus (Bull.: Fr.) Pers. against high-dose corticosterone-induced oxidative stress in PC-12 cells.

BACKGROUND: Hericium erinaceus is a culinary and medicinal mushroom in Traditional Chinese Medicines. It has numerous pharmacological effects including immunomodulatory, anti-tumour, anti-microbial, anti-aging and stimulation of nerve growth factor (NGF) synthesis, but little is known about its potential role in negating the detrimental effects of oxidative stress in depression. The present study investigated the neuroprotective effects of H. erinaceus standardised aqueous extract (HESAE) against high-dose corticosterone-induced oxidative stress in rat pheochromocytoma (PC-12) cells, a cellular model mimicking depression. METHODS: PC-12 cells was pre-treated with HESAE for 48 h followed by 400 µM corticosterone for 24 h to induce oxidative stress. Cells in complete medium without any treatment or pre-treated with 3.125 µg/mL desipramine served as the negative and positive controls, respectively. The cell viability, lactate dehydrogenase (LDH) release, endogenous antioxidant enzyme activities, aconitase activity, mitochondrial membrane potentials (MMPs), intracellular reactive oxygen species (ROS) levels and number of apoptotic nuclei were quantified. In addition, HESAE ethanol extract was separated into fractions by chromatographic methods prior to spectroscopic analysis. RESULTS: We observed that PC-12 cells treated with high-dose corticosterone at 400 µM had decreased cell viability, reduced endogenous antioxidant enzyme activities, disrupted mitochondrial function, and increased oxidative stress and apoptosis. However, pre-treatment with HESAE ranging from 0.25 to 1 mg/mL had increased cell viability, decreased LDH release, enhanced endogenous antioxidant enzyme activities, restored MMP, attenuated intracellular ROS and protected from ROS-mediated apoptosis. The neuroprotective effects could be attributed to significant amounts of adenosine and herierin III isolated from HESAE. CONCLUSIONS: HESAE demonstrated neuroprotective effects against high-dose corticosterone-induced oxidative stress in an in vitro model mimicking depression. HESAE could be a potential dietary supplement to treat depression.

Discovering the Potentials of Medicinal Mushrooms in Combating Depression - A Review.

Depression is the most common form of mental illness and the major cause of disability worldwide. Symptoms of depression, including feelings of intense sadness and hopelessness, may occur after a specific event or in response to a gradual decline in health and functional status, often associated with aging. Current therapies for treating these symptoms include antidepressant drugs, counseling and behavioral therapy. However, antidepressant drugs are associated with mild to severe adverse effects, which has prompted the need for better treatment options. Medicinal mushrooms are valuable sources of food and medicine and are increasingly being used as supplements or as alternative medicines in standard healthcare. Numerous studies have provided insights into the neuroprotective effects of medicinal mushrooms, which are attributed to their antioxidant, anti-neuroinflammatory, cholinesterase inhibitory and neuroprotective properties. In this review, we comprehensively examine the role of these medicinal mushrooms in the treatment of depression. However, to apply these natural products in clinical settings, the therapeutic agent needs to be properly evaluated, including the active ingredients, the presence of synergistic effects, efficient extraction methods, and stabilization of the active ingredients for delivery into the body as well as crossing the blood-brain barrier.

Biologically active vallesamine, strychnan, and rhazinilam alkaloids from Alstonia: Pneumatophorine, a nor-secovallesamine with unusual incorporation of a 3-ethylpyridine moiety.

Four alkaloids comprising two vallesamine, one strychnan, and one pyranopyridine alkaloid, in addition to 32 other known alkaloids were isolated from two Malayan Alstonia species, Alstonia pneumatophora and Alstonia rostrata. The structures of these alkaloids were determined using NMR and MS analyses, and in one instance, confirmed by X-ray diffraction analysis. The nor-6,7-secovallesamine alkaloid, pneumatophorine, is notable for an unusual incorporation of a 3-ethylpyridine moiety in a monoterpenoid indole. The rhazinilam-type alkaloids (rhazinicine, nor-rhazinicine, rhazinal, and rhazinilam) showed strong cytotoxicity toward human KB, HCT-116, MDA-MB-231, and MRC-5 cells, while pneumatophorine, the uleine alkaloid undulifoline, and the strychnan alkaloids, N4-demethylalstogustine and echitamidine, induced concentration dependent relaxation in phenylephrine-precontracted rat aortic rings.

Lumusidines A-D and villalstonidine F, macroline-macroline and macroline-pleiocarpamine bisindole alkaloids from Alstonia macrophylla.

Lumusidines A-D, bisindole alkaloids of the macroline-macroline type, and one of the macroline-pleiocarpamine type, villalstonidine F, were isolated from the stem-bark extract of Alstonia macrophylla (Apocynaceae). The structures and absolute configurations of these alkaloids were established using NMR, MS, and X-ray diffraction analyses.

A cycloartane incorporating a fused tetrahydrofuran ring and a cytotoxic lactam from Monocarpia marginalis.

A new cycloartane, monocarpinine (1), incorporating a fused tetrahydrofuranyl ring, and a cytotoxic tetracyclic lactam, monomarginine (2), were isolated from a stem bark extract of the Malayan species Monocarpia marginalis. The structures of these compounds were determined using NMR and MS analysis. Monomarginine (2) showed appreciable cytotoxicity toward human KB (both drug-sensitive and drug-resistant) and Jurkat cells.