A High-Throughput Screening of a Natural Products Library for Mitochondria Modulators.

Mitochondria, the energy hubs of the cell, are progressively becoming attractive targets in the search for potent therapeutics against neurodegenerative diseases. The pivotal role of mitochondrial dysfunction in the pathogenesis of various diseases, including Parkinson's disease (PD), underscores the urgency of discovering novel therapeutic strategies. Given the limitations associated with available treatments for mitochondrial dysfunction-associated diseases, the search for new potent alternatives has become imperative. In this report, we embarked on an extensive screening of 4224 fractions from 384 Australian marine organisms and plant samples to identify natural products with protective effects on mitochondria. Our initial screening using PD patient-sourced olfactory neurosphere-derived (hONS) cells with rotenone as a mitochondria stressor resulted in 108 promising fractions from 11 different biota. To further assess the potency and efficacy of these hits, the 11 biotas were subjected to a subsequent round of screening on human neuroblastoma (SH-SY5Y) cells, using 6-hydroxydopamine to induce mitochondrial stress, complemented by a mitochondrial membrane potential assay. This rigorous process yielded 35 active fractions from eight biotas. Advanced analysis using an orbit trap mass spectrophotometer facilitated the identification of the molecular constituents of the most active fraction from each of the eight biotas. This meticulous approach led to the discovery of 57 unique compounds, among which 12 were previously recognized for their mitoprotective effects. Our findings highlight the vast potential of natural products derived from Australian marine organisms and plants in the quest for innovative treatments targeting mitochondrial dysfunction in neurodegenerative diseases.

Leaf extracts of eight selected southern African medicinal plants modulate pro-inflammatory cytokine secretion in LPS-stimulated RAW 264.7 macrophages.

This study investigates the anti-inflammatory properties of extracts prepared from the leaves of eight southern African medicinal plants used traditionally to treat inflammation and pain. The inhibitory effect of aqueous and ethanol extracts on the release of pro-inflammatory cytokines was determined in lipopolysaccharide (LPS) stimulated and unstimulated RAW 264.7 murine macrophage cells. The levels of interleukin (IL)-1ß, IL-6, tumour necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein (MIP)-2 release were determined using cytokine multiplex-bead assays. The ethanol extracts of Melianthus comosus Vahl (commonly known as honey flower), Tetradenia riparia (Hochst.) Codd (misty plume bush) and Warburgia salutaris (G. Bertol.) Chiov. (pepper-bark tree), demonstrated the most significant inhibitory activity, with over 50-fold inhibition of IL-1ß, IL-6 and TNF-α levels in LPS-stimulated RAW 264.7 macrophages. The aqueous extract of M. comosus also significantly inhibited the secretion of all the tested cytokines and chemokines. Phytochemical investigation of M. comosus ethanol leaf extract using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) led to the detection of crassolide, deoxylimonoic acid D-ring-lactone, 2-hydroxynonanoic acid and 5-noniloxytryptamine. To the best of our knowledge, the cytokine inhibition properties of most of the medicinal plants screened in this study are reported for the first time. Our results support the use of southern African medicinal plants as anti-inflammatory remedies and provide an insight into the immunomodulatory mechanisms of action.

Isolation and In Vitro and In Vivo Activity of Secondary Metabolites from Clerodendrum polycephalum Baker against Plasmodium Malaria Parasites.

Chemical investigation of the antimalarial medicinal plant Clerodendrum polycephalum led to the isolation of five new diterpenoids, including ajugarins VII-X (1-4) and teuvincenone K (5), along with four known compounds, namely, 12,16-epoxy-6,11,14,17-tetrahydroxy-17(15 → 16)-abeo-5,8,11,13,15-abietapentaen-7-one (6), methyl pheophorbide A (7), loliolide (8), and acacetin (9). The chemical structures of the new compounds were elucidated using NMR spectroscopy, mass spectrometry, circular dichroism, as well as density functional theory calculations. All compounds were evaluated for in vitro activity against Plasmodium falciparum 3D7 malaria parasites with methyl pheophorbide A (7) showing the strongest activity (IC50 4.49 µM). Subsequent in vivo testing in a Plasmodium berghei chemosuppression model showed that compound 7 significantly attenuated peripheral blood parasitemia, leading to 79% and 87% chemosuppression following oral doses at 10 and 20 mg/kg, respectively.

Correction: Tran et al. Antimicrobial Properties of Bacillus Probiotics as Animal Growth Promoters. Antibiotics 2023, 12, 407.

In the original publication [...].

Phytochemical investigation of Asarum sieboldii var. seoulense and the phenotypic profiles of its constituents against a Parkinson's Disease olfactory cell line.

Asarum sieboldii var. seoulense is a plant species under the family Aristolochiaceae and has been used for centuries as an ingredient in a well-known Traditional Chinese medicine (TCM), "Xixin", to treat symptoms of the neurodegenerative condition Parkinson's Disease (PD). Although there have been studies on the neuroprotective effect of this TCM, the phenotypic profiles of its chemical constituents against PD-implicated cellular organelles have not been reported. This research investigated the chemistry of A. sieboldii var. seoulense extract to identify the active small molecules that exhibited perturbation to the cellular compartments related to PD, potentially supporting its traditional application in treating this condition. 1H NMR-guided chemical investigation of this plant yielded twenty secondary metabolites which belong to isobutylamides, lignans and phenolics. The compounds were evaluated against an olfactory cell line derived from a PD patient using phenotypic assay. Several isolates, 2, 3, 7, 11, 13-16 and 18-20, were found to induce moderate perturbation to the staining of mitochondria, autophagosome and α-tubulin of the cells. Considering that PD pathogenesis is closely related to these cellular compartments, the results provided a rationale for the traditional application of Xixin in the treatment of PD.

Exploring Mycosporine-like Amino Acid UV-Absorbing Natural Products for a New Generation of Environmentally Friendly Sunscreens.

Human skin needs additional protection from damaging ultraviolet radiation (UVR: 280-400 nm). Harmful UVR exposure leads to DNA damage and the development of skin cancer. Available sunscreens offer chemical protection from detrimental sun radiation to a certain extent. However, many synthetic sunscreens do not provide sufficient UVR protection due to the lack of photostability of their UV-absorbing active ingredients and/or the lack of ability to prevent the formation of free radicals, inevitably leading to skin damage. In addition, synthetic sunscreens may negatively affect human skin, causing irritation, accelerating skin aging and even resulting in allergic reactions. Beyond the potential negative effect on human health, some synthetic sunscreens have been shown to have a harmful impact on the environment. Consequently, identifying photostable, biodegradable, non-toxic, and renewable natural UV filters is imperative to address human health needs and provide a sustainable environmental solution. In nature, marine, freshwater, and terrestrial organisms are protected from harmful UVR through several important photoprotective mechanisms, including the synthesis of UV-absorbing compounds such as mycosporine-like amino acids (MAAs). Beyond MAAs, several other promising, natural UV-absorbing products could be considered for the future development of natural sunscreens. This review investigates the damaging impact of UVR on human health and the necessity of using sunscreens for UV protection, specifically UV-absorbing natural products that are more environmentally friendly than synthetic UV filters. Critical challenges and limitations related to using MAAs in sunscreen formulations are also evaluated. Furthermore, we explain how the genetic diversity of MAA biosynthetic pathways may be linked to their bioactivities and assess MAAs' potential for applications in human health.

Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathologic progression of dopaminergic neurodegeneration. This unfortunate predicament is because of the current early stages in understanding the biologic targets and pathways involved in PD pathogenesis. Ion channels have become emerging targets for new therapeutic development for PD due to their essential roles in neuronal function and neuroinflammation. Potassium channels are the most prominent ion channel family and have been shown to be critically important in PD pathology because of their roles in modulating neuronal excitability, neurotransmitter release, synaptic transmission, and neuroinflammation. In this review, members of the subfamilies of voltage-gated K+ channels, inward rectifying K+ channels, and Ca2+-activated K+ channels are described. Evidence of the role of these channels in PD etiology is discussed together with the latest views on related pathologic mechanisms and their potential as biologic targets for developing neuroprotective drugs for PD. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, featuring progressive degeneration of dopaminergic neurons in the midbrain. It is a multifactorial disease involving multiple risk factors and complex pathobiological mechanisms. Mounting evidence suggests that ion channels play vital roles in the pathogenesis and progression of PD by regulating neuronal excitability and immune cell function. Therefore, they have become "hot" biological targets for PD, as demonstrated by multiple clinical trials of drug candidates targeting ion channels for PD therapy.

Antimicrobial Properties of Bacillus Probiotics as Animal Growth Promoters.

Antibiotic growth promoters (AGPs) suppress the growth of infectious pathogens. These pathogens negatively impact agricultural production worldwide and often cause health problems if left untreated. Here, we evaluate six Bacillus strains (BPR-11, BPR-12, BPR-13, BPR-14, BPR-16 and BPR-17), which are known for their ability to survive harsh environmental conditions, as AGP replacements in animal feed. Four of these Bacillus strains (BPR-11, BPR-14, BPR-16 and BPR-17) showed antimicrobial activity against the pathogenic strains Clostridium perfringens, Escherichia coli and Staphylococcus aureus at 25 µg/mL, with BPR-16 and BPR-17 also able to inhibit Pseudomonas aeruginosa and Salmonella enterica at 100 µg/mL. Further chemical investigation of BPR-17 led to the identification of eight metabolites, namely C16, C15, C14 and C13 surfactin C (1-4), maculosin (5), maculosine 2 (6), genistein (7) and daidzein (8). Purified compounds (1-4) were able to inhibit all the tested pathogens with MIC values ranging from 6.25 to 50 µg/mL. Maculosin (5) and maculosine 2 (6) inhibited C. perfringens, E. coli and S. aureus with an MIC of 25 µg/mL while genistein (7) and daidzein (8) showed no activity. An animal trial involving feeding BPR-11, BPR-16 and BPR-17 to a laboratory poultry model led to an increase in animal growth, and a decrease in feed conversion ratio and mortality. The presence of surfactin C analogues (3-4) in the gut following feeding with probiotics was confirmed using an LC-MS analysis. The investigation of these Bacillus probiotics, their metabolites, their impacts on animal performance indicators and their presence in the gastrointestinal system illustrates that these probiotics are effective alternatives to AGPs.

Mitochondrial Modulators: The Defender.

Mitochondria are widely considered the "power hub" of the cell because of their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond the production of ATP, which is the major source of chemical energy supply in eukaryotes, mitochondria are also central to calcium homeostasis, reactive oxygen species (ROS) balance, and cell apoptosis. The mitochondria also perform crucial multifaceted roles in biosynthetic pathways, serving as an important source of building blocks for the biosynthesis of fatty acid, cholesterol, amino acid, glucose, and heme. Since mitochondria play multiple vital roles in the cell, it is not surprising that disruption of mitochondrial function has been linked to a myriad of diseases, including neurodegenerative diseases, cancer, and metabolic disorders. In this review, we discuss the key physiological and pathological functions of mitochondria and present bioactive compounds with protective effects on the mitochondria and their mechanisms of action. We highlight promising compounds and existing difficulties limiting the therapeutic use of these compounds and potential solutions. We also provide insights and perspectives into future research windows on mitochondrial modulators.

Steroidal Saponins from the Rhizomes of Smilax china and Their Inhibitory Effects on Lipopolysaccharide-Induced Proinflammatory Cytokines Expression.

Four new furostanol saponins (1:  - 4: ) and a new pregane-type saponin (5: ) along with six known steroidal saponins (6:  - 11: ) were isolated from the rhizomes of Smilax china. The structures of 1:  - 5: were elucidated by extensive analysis of NMR and HR-ESI-MS data in addition to enzymatic hydrolysis and other chemical methods. Compounds 1, 4: , and 11: showed inhibitory activity against the expression of proinflammatory mediators, inducible nitric oxide synthase, interleukin-1ß, interleukin-6, and tumor necrosis factor-α in lipopolysaccharide-induced RAW264.7 cells. Compound 1: , at a concentration of 20 µM, decreased the production of inducible nitric oxide synthase, interleukin-1ß, interleukin-6, and tumor necrosis factor-α by 36, 62, 72, and 67%, respectively, which is comparable to that of the positive control dexamethasone.

Meeting the Challenge 2: Identification of Potential Chemical Probes for Parkinson's Disease from Ligusticum chuanxiong Hort Using Cytological Profiling.

Traditional Chinese medicine (TCM) has been around for thousands of years and is increasingly gaining popularity in the Western world to treat various complex disorders including the incurable neurodegenerative condition, Parkinson's Disease (PD). One of the many directions in recent studies of PD is utilizing the phenotypic assay, or cytological profiling, to evaluate the phenotypic changes of PD-implicated cellular components in patient-derived olfactory neuroepithelial (hONS) cells, upon treating the cells with extracts or pure compounds. To obtain small molecules for studies utilizing PD phenotyping assays, Ligusticum chuanxiong Hort was selected for analysis as it is a popular Chinese herbal medicine used for treating PD-like symptoms. Fifty-three secondary metabolites, including six new compounds, were isolated from the ethanolic extract of L. chuanxiong; their structures were elucidated based on several spectroscopic techniques such as NMR, MS, Fourier transform infrared (FTIR), UV, and theoretical density functional theory (DFT) calculations. Cytological profiling of the afforded natural products against PD hONS cells revealed 34 compounds strongly perturbated the staining of several cellular organelles. In fact, greaterthan 1.5-fold change was observed compared to the control (dimethyl sulfoxide; DMSO), with early endosome, lysosome, and autophagosome (LC3b) being particularly affected. Given these biological compartments are closely related to PD pathogenesis, the results helped rationalize the traditional medicinal use of L. chuanxiong in PD treatment. Further, the hit compounds can serve as chemical probes to map the molecular pathways underlying PD, potentially leading to new therapeutic targets for PD.

Phlegmacaritones A and B, a Pair of Serratane-Related Triterpenoid Epimers with an Unprecedented Carbon Skeleton from Phlegmariurus carinatus.

A pair of novel serratane-related triterpenoid epimers, phlegmacaritones A (1) and B (2), possessing an unprecedented 15,30-lactone-14,15-seco skeleton, six new serratane-type triterpenoids, phlegmanols G-L (3-5 and 14-16), and 16 known compounds were isolated from the whole plant of Phlegmariurus carinatus. The structures of the new metabolites were established on the basis of comprehensive spectroscopic data analysis and electronic circular dichroism calculations. A possible biosynthetic pathway for phlegmacaritones A (1) and B (2) was proposed. All compounds were submitted to cytological profiling on a cell line derived from a patient with Parkinson's disease. Phlegmacaritone B (2) induced a distinct phenotypic profile with alterations in α-tubulin, mitochondria, and autophagosomal and early endosomal features.

Antimicrobial Bacillus: Metabolites and Their Mode of Action.

The agricultural industry utilizes antibiotic growth promoters to promote livestock growth and health. However, the World Health Organization has raised concerns over the ongoing spread of antibiotic resistance transmission in the populace, leading to its subsequent ban in several countries, especially in the European Union. These restrictions have translated into an increase in pathogenic outbreaks in the agricultural industry, highlighting the need for an economically viable, non-toxic, and renewable alternative to antibiotics in livestock. Probiotics inhibit pathogen growth, promote a beneficial microbiota, regulate the immune response of its host, enhance feed conversion to nutrients, and form biofilms that block further infection. Commonly used lactic acid bacteria probiotics are vulnerable to the harsh conditions of the upper gastrointestinal system, leading to novel research using spore-forming bacteria from the genus Bacillus. However, the exact mechanisms behind Bacillus probiotics remain unexplored. This review tackles this issue, by reporting antimicrobial compounds produced from Bacillus strains, their proposed mechanisms of action, and any gaps in the mechanism studies of these compounds. Lastly, this paper explores omics approaches to clarify the mechanisms behind Bacillus probiotics.

Austrobuxusin N, a new picrotoxane terpenoid glycoside, from the Australian endemic plant Austrobuxus swainii (Beuzev. & C.T. White) Airy Shaw.

A new picrotoxane terpenoid glycoside, austrobuxusin N (1), together with four known compounds, austrobuxusin A-D (2-5), were isolated from the leaves of the Australian endemic plant Austrobuxus swainii (Beuzev. & C.T. White) Airy Shaw. The chemical structure of 1 was elucidated by 1D- and 2D-NMR spectroscopy, along with MS data. The sugar moiety in 1 was determined to be ß-D-glucose by acid hydrolysis and subsequent comparison of its specific rotation with that of standard. The relative configuration of the aglycone was assigned by ROESY NMR experiment and density functional theory (DFT) calculation of NMR data coupled with DP4 analysis. Cytotoxicity test revealed that compound 1 exhibited 71% inhibition against Caco-2 cell line at the concentration of 166 µM.[Formula: see text].

Anti-mycobacterial natural products and mechanisms of action.

Covering: up to June, 2020Tuberculosis (TB) continues to be a major disease with high mortality and morbidity globally. Drug resistance and long duration of treatment make antituberculosis drug discovery more challenging. In this review, we summarize recent advances on anti-TB natural products (NPs) and their potential molecular targets in cell wall synthesis, protein production, energy generation, nucleic acid synthesis and other emerging areas. We highlight compounds with activity against drug-resistant TB, and reveal several novel targets including Mtb biotin synthase, ATP synthase, 1,4-dihydroxy-2-naphthoate prenyltransferase and biofilms. These anti-TB NPs and their targets could facilitate target-based screening and accelerate TB drug discovery.

A review of the traditional use of southern African medicinal plants for the treatment of inflammation and inflammatory pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammation is a serious global concern due to its debilitating symptoms, resulting in considerable suffering and lost productivity. Chronic and auto-immune inflammatory diseases are of particular concern. Several pharmaceutical therapies are already available. However, the use of non-steroidal anti-inflammatory drugs (NSAID's) is accompanied by harmful and toxic side effects. Hence, the search for safer alternative therapeutics with limited side effects is imperative. The use of medicinal plants is common practice amongst the southern African population and may provide targets for drug development. AIM OF THE STUDY: This study aims to review and document the medicinal uses and pharmacological properties of southern African medicinal plants used for inflammation and pain-related ailments. MATERIAL AND METHODS: An extensive literature review was undertaken to identify southern African plants used traditionally to treat inflammation. A variety of ethnobotanical books and grey literature, as well as ScienceDirect, Google Scholar and Scopus search engines were used as sources of information. RESULTS: This review identified 555 medicinal plants from 118 families which were traditionally used in southern Africa to treat inflammation and pain. Fabaceae was the most prominent family with 63 species, followed by Asteraceae (54 species) and Apocynaceae (33 species). The top category of ailments indicated include non-specific inflammation with 150 species, followed by inflammatory pain (148 species), headache (114 species) and toothache (114 species). CONCLUSION: Despite a large number of southern African medicinal plants used to treat inflammation and pain, relatively few have been screened for their anti-inflammatory properties. Furthermore, biologically active plant extracts have been tested against relatively few inflammatory markers and considerable further work is required.

Application of traditional Chinese medicine as skin depigmentation agents.

Traditional Chinese medicine (TCM) has been frequently used as skin lightning agents. However, the mechanism of action of their effect is unclear. The present study aims to evaluate anti-tyrosinase activity of 10 commonly used TCM on mushroom (ab), human (hs) and mouse melanoma B16F0 (mm) tyrosinase (TYR) respectively. The results showed that at 1.0 mg/mL, extracts from Rosa rugosa Thumb, Morus alba L. and Paeonia lactiflora Pall were active against both abTYR and hsTYR (>50% inhibition), extracts from Bletilla striata (Thunb.) Rchb. F., Centella asiatica (L.) Urb, Cynanchum atratum L., Rosa canina L., Rhus chinensis Mill. and Glycyrrhiza urolensis Fisch. Ex DC. inhibited either abTYR or hsTYR (>50%), while extract from Tribulus terrestris L. had no/minimal activity (<10% inhibition). When treated with melanoma B16F0 cells, M. alba also significantly reduced mmTYR activity (70% at 250 µg/mL) and melanin content (50% at 250 µg/mL). These findings demonstrated inhibitory effects of 9 TCM against TYR and hence support their application as skin lightning agents. Our results also showed discrepancies in TYR activity from different sources, suggesting a testing regime of combining abTYR, hsTYR and mmTYR when developing depigmentation agents for human application.

Calcium channels and iron metabolism: A redox catastrophe in Parkinson's disease and an innovative path to novel therapies?

Autonomously spiking dopaminergic neurons of the substantia nigra pars compacta (SNpc) are exquisitely specialized and suffer toxic iron-loading in Parkinson's disease (PD). However, the molecular mechanism involved remains unclear and critical to decipher for designing new PD therapeutics. The long-lasting (L-type) CaV1.3 voltage-gated calcium channel is expressed at high levels amongst nigral neurons of the SNpc, and due to its role in calcium and iron influx, could play a role in the pathogenesis of PD. Neuronal iron uptake via this route could be unregulated under the pathological setting of PD and potentiate cellular stress due to its redox activity. This Commentary will focus on the role of the CaV1.3 channels in calcium and iron uptake in the context of pharmacological targeting. Prospectively, the audacious use of artificial intelligence to design innovative CaV1.3 channel inhibitors could lead to breakthrough pharmaceuticals that attenuate calcium and iron entry to ameliorate PD pathology.

Cardioprotective 22-hydroxylanostane triterpenoids from the fruiting bodies of Phellinus igniarius.

Seven undescribed 22-hydroxylanostane triterpenoids were isolated from the fruiting bodies of Phellinus igniarius, together with three known sterols. Their structures were assigned by extensive spectroscopic and HRESIMS data analyses. The absolute configurations of C-22 were determined by X-ray crystallography, chemical methods, and spectroscopic data comparison. Phellinol G was a 25,26,27-trinorlanostane triterpenoid glycoside. 22S/22R-25,26,27- Trinorlanosta-8-en-3ß,22,24-triols with the same side chain as that of phellinol G were stereoselectively synthesized from commercial lanosterol for the first time. The key step involved Sharpless asymmetrical epoxidation. Phellinols A, B, and F showed cardioprotective activity against oxygen-glucose deprivation/reoxygenation injury in H9c2 cells at a concentration of 20 µM.

Peculiarities of meroterpenoids and their bioproduction.

Meroterpenoids are a class of terpenoid-containing hybrid natural products with impressive structural architectures and remarkable pharmacological activities. Remarkable advances in enzymology and synthetic biology have greatly contributed to the elucidation of the molecular basis for their biosynthesis. Here, we review structurally unique meroterpenoids catalyzed by novel enzymes and unusual enzymatic reactions over the period of last 5 years. We also discuss recent progress on the biomimetic synthesis of chrome meroterpenoids and synthetic biology-driven biomanufacturing of tropolone sesquiterpenoids, merochlorins, and plant-derived meroterpenoid cannabinoids. In particular, we focus on the novel enzymes involved in the biosynthesis of polyketide-terpenoids, nonribosomal peptide-terpenoids, terpenoid alkaloids, and meroterpenoid with unique structures. The biological activities of these meroterpenoids are also discussed. The information reviewed here might provide useful clues and lay the foundation for developing new meroterpenoid-derived drugs. KEY POINTS: • Meroterpenoids possess intriguing structural features and relevant biological activities. • Novel enzymes are involved in the biosynthesis of meroterpenoids with unique structures. • Biomimetic synthesis and synthetic biology enable the construction and manufacturing of complex meroterpenoids.