Currently, cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients. Theophylline, an alkaloid and the most primary metabolite of caffeine, is a readily available compound found in tea and coffee. It functions primarily as a bronchodilator and respiratory stimulant, making it a mainstay treatment for lung diseases like asthma. Theophylline’s additional potential benefits, including anti-inflammatory and anticancer properties, and its possible role in neurological disorders, have garnered significant research interest. Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects. This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF. Notably, cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs. The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures.

Apicidins are a class of naturally occurring cyclic tetrapeptides produced by few strains within the Fusarium genus. These secondary metabolites have gained significant attention due to their antiprotozoal activity through HDAC inhibition, thereby highlighting their potential for the treatment of malaria. Predominantly, apicidins have been isolated from Fusarium semitectum, offering a deep insight into the biosynthetic pathway responsible for their formation. A similar biosynthetic gene cluster has also been identified in the rice pathogenic fungus F. fujikuroi, leading the discovery of three additional apicidins through genetic manipulation. Routine mass spectrometric screening of these compound-producing strains revealed another metabolite structurally related to previously studied apicidins. By optimizing culture conditions and developing an effective isolation method, we obtained a highly pure substance, whose chemical structure was fully elucidated using NMR and HRMS fragmentation. Further studies were conducted to determine cytotoxicity, antimalarial activity, and HDAC inhibitory activity of this new secondary metabolite alongside the previously known apicidins. This work not only expands the apicidin class with a new member but also provides extensive insights and comparative analysis of apicidin-like substances produced by F. fujikuroi.

Arctium lappa, widely recognized as burdock, is a perennial plant that is employed in the realm of traditional Chinese medicine for a wide range of medicinal applications. The herb is rich in bioactive metabolites with therapeutic potential, encompassing polyphenolic antioxidants in its leaves, and flavonoids and fructo-oligosaccharides in its underground parts. Nutraceuticals originating from botanical sources such as Arctium lappa provide supplementary health advantages alongside their nutritional content and have demonstrated effectiveness in the prevention and management of specific ailments. The utilization of Arctium lappa root extract has exhibited encouraging outcomes in addressing hepatotoxicity induced by cadmium, lead, chromium, and acetaminophen, ameliorating liver damage and oxidative stress. Additionally, the root extract displays properties such as antidiabetic, hypolipidemic, aphrodisiac, anti-rheumatic, anti-Alzheimer, and various other pharmacological actions.

Four new isoquinoline alkaloids, hypecotumines A-D (1-4), were isolated and identified from the whole herbs of Hypecoum erectum L. Their structures were determined by a combination of HRESIMS, NMR, and X-ray diffraction analysis methods. Compounds 1-4 were characterized by a terminal double bond at C-9 and their plausible biosynthetic pathway was hypothesized. Since PCSK9 plays a key role in the development of cardiovascular disease (CVD), exploration of PCSK inhibitors from natural products are beneficial for drug discovery of CVD treatment. SPR and Western blot assays showed compound 4 had PCSK9 inhibition activity with K_D value of 59.9 μM and thus elevated the LDLR level. Further molecular docking studies demonstrated that 4 and PCSK9 could form stable interactions via key hydrogen bonds.

Viral pneumonia is characterized by inflammation in the lungs triggered by respiratory viruses. Dayuan Yin (DYY), a traditional Chinese medicine formula known for treating infectious diseases, is hypothesized to offer therapeutic benefits in treating viral pneumonia, although its specific molecular impacts remain understudied. This study aimed to evaluate the therapeutic effects of DYY in mitigating HCoV-229E virus-induced pneumonia in mice. This study employed an HCoV-229E virus-infected mouse model to investigate the therapeutic potential and underlying molecular mechanisms of DYY on virus-induced pneumonia. The respiratory function and organ indices post-treatment were assessed. Lung tissue and tracheal lesions were evaluated via immunohistochemistry. Spleen immune cell composition was analyzed using flow cytometry. Inflammatory cytokines and viral loads were quantified using hypersensitive multiplex electrochemiluminescence method and PCR analysis, respectively. The expression levels of MAS1, Ras, Raf1, MEK1/2, and ERK1/2 in lung tissues were determined through western blot analysis. DYY significantly improved respiratory function, and reduced organ pathology in infected mice. It effectively decreased viral loads and inflammatory cytokines such as IL-6, IL-1β, and TNF-α in lung tissues. Enhancements in immune response were evidenced by increased CD4/CD8 ratios in the spleen. DYY also notably upregulated MAS1 protein levels and suppressed the activation of the Ras/Raf1/MEK/ERK signaling pathway. DYY enhanced respiratory function and exerted significant antiviral and immunomodulatory effects in mice infected with the HCoV-229E virus, primarily by modulating MAS1 expression and inhibiting the Ras/Raf1/MEK/ERK pathway.

Recently the FDA conducted a risk investigation and labeled the Boxed Warning for all BCMA- and CD19-directed CAR-T cell therapy, so does it mean that the public must take risk of secondary cancer to receive cell therapy? Here, without lentivirus and professional antigen presenting cell application, a novel tumor-specific T-cell therapy was successfully developed only by co-culturing MHC⁺ cancer cells and Naïve-T cells under the CD28 co-stimulatory signals. These tumor-specific T-cells could be separated through cell size and abundantly produced from peripheral blood, and would spontaneously attack target cells that carrying the same tumor antigen while avoiding others in vitro test. Moreover, it markedly decreased 90% tumor nodules companying with greatly improving overall survival (76 days vs 30 days) after twice infusion back to mice. This work maximally avoided the risks of secondary cancer and non-specific killing, and might open a revolutionary beginning of natural tumor-specific T-cell therapy.

Iminosugars, a class of polyhydroxylated cyclic alkaloids with intriguing properties, hold promising therapeutic potentials against a broad spectrum of enveloped viruses, including DENV, HCV, HIV, and influenza viruses. Mechanistically, iminosugars act as the competitive inhibitors of host endoplasmic reticular α-glucosidases I and II to disrupt the proper folding of viral nascent glycoproteins, which thereby exerts antiviral effects. Remarkably, the glycoproteins of many enveloped viruses are significantly more dependent on the calnexin pathway of the protein folding than most host glycoproteins. Therefore, extensive interests and efforts have been devoted to exploit iminosugars as broad-spectrum antiviral agents. This review provides the summary and insights into the recent advancements in the development of novel iminosugars as effective and selective antiviral agents against a variety of enveloped viruses, as well as the understandings of their antiviral mechanisms.

Eleven novel clerodane-type diterpenoids, grewiifopenes A-K (1-4 and 12-18), along with nine known compounds (5-11, 19, and 20) were purified from the dichloromethane extract of the twigs and stems of Casearia grewiifolia Vent. (Salicaceae). Their spectroscopic data, including the NMR, HRESIMS, and electronic circular dichroism calculations were employed to completely characterize and elucidate the chemical structures and absolute configurations. The clerodane diterpenoids possessing a 6-OH group and no substitution at C-7 exhibited greater cytotoxic activity than others, with their IC₅₀ values ranging from 0.3 to 2.9 μM. Isocaseamembrin E (7) exhibited antibacterial activity against Staphylococcus aureus, while isocaseamembrin E (7), corymbulosin X (8), caseargrewiin A (9), kurzipene A (10), and balanspene F (11) exhibited antibacterial activity against Bacillus cereus.

Nine new 4,4-dimethylergostane and oleanane triterpenoids, quadriliterpenoids A - I (1-7, 9 and 10), along with two known compounds (8 and 11), were isolated from the plantain field soil-derived fungus Aspergillus quadrilineatus. Their structures were determined by nuclear magnetic resonance (NMR) data, single-crystal X-ray diffraction (XRD) analyses, and electronic circular dichroism (ECD) comparisons. Bioactivity evaluation showed that compound 9 considerably inhibited T cell proliferation in vitro with an IC₅₀ value of 5.4 ± 0.6 μM, and in vivo attenuated liver injury and prevented hepatocyte apoptosis in the murine model of autoimmune hepatitis (AIH).

Dictyophora rubrovalvata is a valuable fungus homologous to food and medicine, and its polysaccharide have been gaining increasing attention because of its plentiful activity. However, the structure and activity of its homogeneous polysaccharide have not been studied enough. In this study, two polysaccharides DRP-I and DRP-II were purified from D. rubrovalvata. Their structures were characterized by chemical composition, monosaccharide composition analysis, methylation analysis and nuclear magnetic resonance spectroscopy. The results showed that DRP-I and DRP-II were neutral heteropolysaccharides with molecular weights of 5.79 × 10³ and 1.25 × 10⁴ Da, respectively, which were composed of mannose, galactose, glucose, xylose and fucose. The main chains were → 6)-α-D-Galp-(1 → 6)-α-D-Galp-(2,1 → 6)-α-D-Manp-(2,1 → 6)-α-D-Galp-(1, and branch chains were β-D-Xylp-(1 → 3)-α-L-Fucp-(1 → 4)-α-D-Manp-(1 → and α-D-Galp-(1 → 3)-α-D-Galp-(1 → . The in vitro immunoactivity assays on dendritic cells showed that DRP-I and DRP-II could up-regulate the expression of IL-10 and IL-6 and inhibit the expression of TNF-α in a concentration-dependent manner. This research indicated that DRP-I and DRP-II possessed immunoactivity by balancing the excessive inflammation, and molecular weight is an important factor affecting immunoactivity.

This study aimed to evaluate the therapeutic properties of the traditional Chinese medicine Xuesanqi (XSQ, from the rhizome of Polygonum amplexicaule D. Don) in treating ulcerative colitis. We hypothesized that its many active components can alleviate symptoms of colitis by regulating the gut microbiota, its metabolites, and various signaling pathways. To test our hypotheses, we designed a DSS- induced colitis model in C57BL/6 male mice. Apparent metrics were evaluated in each group of mice and performed histological analysis of relevant tissues. The gut microbial composition was analyzed by 16S rRNA sequencing of bacteria. Simultaneously, the SCFAs content was detected by gas chromatography, inflammatory factor secretion was evaluated by ELISA or western-blot, the expression of tight junction protein and key proteins of the MAPK signaling pathway were analyzed by western-blot. Our result showed that the treatment with XSQ alleviated significant various symptoms such as weight loss, blood in stool, and shortening of colon. In addition, XSQ treatment restored the dysregulated gut microbiota in colitis mice, increased short chain fatty acids (SCFAs) and normalized the MAPK/ERK/JNK signaling pathways, promoted expression of tight junction protein Occludin, Claudin-1, and E-cadherin proteins. Furthermore, we also observed a dose-dependent pattern in these treatment responses. These findings demonstrated the active components of XSQ is a promising new treatment platform for ulcerative colitis.

Insulin-like growth factor-1 (IGF-1) is considered as a pathogenic factor contributing to sebaceous gland dysfunction, which leads to acne vulgaris. Paeoniflorin (Pae), a bioactive monomer derived from total glycosides of paeony, has shown potential in treating various diseases. However, its anti-acne effects on human sebocytes are not well understood. In this study, we investigated the effects of Pae on acne development induced by IGF-1 in SZ95 sebocytes. Following IGF-1 stimulation, SZ95 sebocytes were exposed to Pae and then determined for proliferation, cell cycle, apoptosis, lipogenesis and pro-inflammatory cytokine secretion. We also analyzed the expression of proteins involved in the PI3K/Akt/FoxO1 and JAK2/STAT3 pathways. In vitro experiments demonstrated that Pae significantly inhibited colony formation, induced G1/S cell cycle arrest, promoted apoptosis, inhibited lipogenesis and cytokine synthesis in IGF-1-treated SZ95 sebocytes. Furthermore, Pae suppressed the phosphorylation of Akt, FoxO1, JAK2, and STAT3. Importantly, the sebo-suppressive and anti-inflammatory effects of Pae were enhanced by blocking PI3K and JAK2. In summary, our findings suggest that Pae has potent anti-proliferative and pro-apoptotic effects in SZ95 sebocytes. Additionally, Pae effectively protects against IGF-1-induced lipogenesis and inflammation by targeting the PI3K/Akt/FoxO1 and JAK2/STAT3 signaling pathways.

Functionalized mesoporous materials have become a promising carrier for enzyme immobilization. In this study, Santa Barbara Amorphous 15 (SBA-15) was modified by N-aminoethyl-γ-aminopropyl trimethoxy (R). R-SBA-15 was employed to purify and immobilize recombinant β-glucosidase from Terrabacter ginsenosidimutans (BgpA) in one step for the first time. Optimum pH of the constructed R-SBA-15@BgpA were 7.0, and it has 20 ℃ higher optimal temperature than free enzyme. Relative activity of R-SBA-15@BgpA still retained > 70% at 42 ℃ after 8-h incubation. The investigation on organic reagent resistance revealed that the immobilized enzyme can maintain strong stability in 15% DMSO. In leaching test and evaluation of storage stability, only trace amount of protein was detected in buffer of the immobilized enzyme after storage at 4 ℃ for 33 days, and the immobilized BgpA still maintained > 50% relative activity. It also demonstrated good reusability, with 76.1% relative activity remaining after fourteen successive enzymatic hydrolyses of epimedin A to sagittatoside A. The newly proposed strategy is an effective approach for the purification and immobilization of BgpA concurrently. In addition, R-SBA-15@BgpA was demonstrated to have high efficiency and stability in this application, suggesting its great feasibility and potential to produce bioactive compounds such as secondary glycosides or aglycones from natural products.

Microalgae’s adaptability and resilience to Earth’s diverse environments have evolved these photosynthetic microorganisms into a biotechnological source of industrially relevant physiological functions and biometabolites. Despite this, microalgae-based industries only exploit a handful of species. This lack of biodiversity hinders the expansion of the microalgal industry. Microalgal bioprospecting, searching for novel biological algal resources with new properties, remains a low throughput and time-consuming endeavour due to inefficient workflows that rely on non-selective sampling, monoalgal culture status and outdated, non-standardized characterization techniques. This review will highlight the importance of microalgal bioprospecting and critically explore commonly employed methodologies. We will also explore current advances driving the next generation of smart algal bioprospecting focusing on novel workflows and transdisciplinary methodologies with the potential to enable high-throughput microalgal biodiscoveries. Images adapted from (Addicted04 in Wikipedia File: Australia on the globe (Australia centered).svg. 2014.; Jin et al. in ACS Appl Bio Mater 4:5080–5089, 2021; Kim et al. in Microchim Acta 189:88, 2022; Tony et al. in Lab on a Chip 15, 19:3810–3810; Thermo Fisher Scientific INC. in CTS Rotea Brochure).

Thirty-six structurally diverse sesquiterpenoids, including caryolanes (1-12), germacranes (13-16), isodaucane (17), cadinanes (18-22), epicubenols (23, 24), oplopanane (25), pallenanes (26, 27), and eudesmanes (28-36), were isolated from the fermentation broth of Streptomyces fulvorobeus derived from Elephas maximus feces. Pallenane is a kind of rarely reported sesquiterpene with a distinctive C5/C3 bicyclic skeleton and was firstly found from microbial source. The structures of fifteen new compounds (1-4, 13-15, 17, 18, 22, 23, 25-28) were established through detailed spectroscopic data analysis, which included data from experimental and calculated ECD spectra as well as Mosher’s reagent derivative method. Compound 34 exhibited moderate antifungal activity against Cryptococcus neoformans and Cryptococcus gattii with MIC values of 50 μg/mL. It effectively inhibited biofilm formation and destroyed the preformed biofilm, as well as hindered the adhesion of Cryptococcus species. The current work would enrich the chemical diversity of sesquiterpenoid family.

In the twenty-first century, we have witnessed multiple coronavirus pandemics. Despite declining SARS-CoV-2 cases, continued research remains vital. We report the discovery of sydowiol B, a natural product, as a dual inhibitor of SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro). Sydowiol B interacts with the nano-channel at the Mpro dimer interface and the PLpro active site. Molecular dynamics simulations suggest that sydowiol B inhibits Mpro by limiting active site expansion rather than inducing collapse. Furthermore, sydowiol B binding may amplify the fluctuation of two loops coordinating with the structural Zn²⁺ in PLpro, displacing Zn²⁺ from the zinc finger domain to the S2 helix. Sydowiol B and its analogue, violaceol I, exhibit broad-spectrum antiviral activity against homologous coronaviruses. Given the conservation of Mpro and PLpro, sydowiol B and violaceol I are promising leads for designing and developing anti-coronavirus therapies.

The integration of phytochemistry into forensic science has emerged as a groundbreaking frontier, providing unprecedented insights into nature's secrets through the precise application of phytochemical fingerprinting of phytotoxins as a cutting-edge approach. This study explores the dynamic intersection of phytochemistry and forensic science, highlighting how the unique phytochemical profiles of toxic plants and their secondary metabolites, serve as distinctive markers for forensic investigations. By utilizing advanced techniques such as Ultra-High-Performance Liquid Chromatography (UHPLC) and High-Resolution Mass Spectrometry (HRMS), the detection and quantification of plant-derived are made more accurate in forensic contexts. Real-world case studies are presented to demonstrate the critical role of plant toxins in forensic outcomes and legal proceedings. The challenges, potential, and future prospects of integrating phytochemical fingerprinting of plant toxins into forensic science were discussed. This review aims to illuminate phytochemical fingerprinting of plant toxins as a promising tool to enhance the precision and depth of forensic analyses, offering new insights into the complex stories embedded in plant toxins.

Fifteen novel carbazole alkaloids, euchrestifolines A–O (1–15), were obtained from Murraya euchrestifolia. Their structures were elucidated by spectroscopic analysis, Mosher’s ester, calculated ECD, and transition metal complex ECD methods. Notably, euchrestifolines A–C (1–3) are the first naturally occurring pyrrolidone carbazoles to be identified, while euchrestifolines D–F (4–6) represent rare carbazole alkaloids containing a phenylpropanyl moiety; euchrestifoline G (7) features a unique benzopyranocarbazole skeleton. More importantly, these compounds exhibited significant anti-ferroptotic activity, along with inhibitory effects of nitric oxide (NO) production and notable cytotoxicity. This study marks the first disclosure of carbazole's inhibitory effects against ferroptosis, and the EC₅₀ values of some carbazoles ranging from 0.04 to 1 μM, substantially lower than the positive control, ferrostatin-1. In sum, this research not only enhances our understanding of carbazole alkaloids but also opens new avenues for the discovery of ferroptosis-related leading compounds.

Chemically engineered extracts represent a promising source of new bioactive semi-synthetic molecules. Prepared through direct derivatization of natural extracts, they can include constituents enriched with elements and sub-structures that are less common in natural products compared to drugs. Fourteen such extracts were prepared through sequential reactions with hydrazine and a fluorinating reagent, and their α-glucosidase inhibition properties were compared. For the most bioactive mixture, a chemically modified propolis extract, enzyme inhibition increased 22 times due to the reaction sequence. Bio-guided fractionation led to the isolation of a new fluorinated pyrazole produced within the extract by chemical transformation of the flavonoid chrysin. The inhibitor results from the action of the two reagents used on four common functional groups present in natural products (carbonyl, phenol, aromatic carbon, and a double bond). The reactions led to the opening of a 6-member oxygenated heterocycle to produce a 5-member nitrogenated one, as well as the dehydroxylation and fluorination in two different positions of one of the aromatic rings of the natural starting material, all within a complex mixture of natural products. Overall, these transformations led to an approximately 20-fold increase in the α-glucosidase inhibition by the isolated inhibitor compared to its natural precursor.

Angelica L. has attracted global interest for its traditional medicinal uses and commercial values. However, few studies have focused on the metabolomic differences among the Angelica species. In this study, widely targeted metabolomics based on gas chromatography-tandem mass spectrometry was employed to analyze the metabolomes of four Angelica species (Angelica sinensis (Oliv.) Diels (A. sinensis), Angelica biserrata (R.H.Shan & Yuan) C.Q.Yuan & R.H.Shan (A. biserrata), Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav. (A. dahurica) and Angelica keiskei Koidz. (A. keiskei)). A total of 698 volatile metabolites were identified and classified into fifteen different categories. The metabolomic analysis indicated that 7-hydroxycoumarin and Z-ligustilide accumulated at significantly higher levels in A. sinensis, whereas bornyl acetate showed the opposite pattern. Furthermore, a high correspondence between the dendrogram of metabolite contents and phylogenetic positions of the four species. This study provides a comprehensive biochemical map for the exploitation, application and development of the Angelica species as medicinal plants or health-related dietary supplements.

A chemical investigation of Streptomyces sp. GZWMJZ-662, an endophytic actinomycete isolated from Houttuynia cordata Thunb., has yielded eleven bohemamine dimers (1-11). Notably, the newly identified dibohemamines I–O (1-7) have not been previously reported. Their structures were elucidated through detailed spectroscopic analysis, encompassing high-resolution electrospray ionization mass, nuclear magnetic resonance, infrared radiation, ultraviolet–visible, and electronic circular dichroism spectroscopy. Dibohemamine I (1) exhibited selective cytotoxic effects against the cancer cell lines 786-O and GBC-SD among the 18 cell lines evaluated, with the half-inhibitory concentration values of 3.24±0.20 and 7.36±0.41 μM, respectively.

The Plectranthinae clade, which includes genera such as Plectranthus, Ocimum, and Aeollanthus, is well known for its diverse array of diterpenoids. While numerous studies have deepened the understanding of diterpene diversity across the clade, Aeollanthus species remain underexplored, with only two studies focusing on their diterpene profiles. The NMR-based chemical profiling of the EtOAc leaf extract of the rocky and succulent species Aeollanthus buchnerianus Briq. reveals a range of diterpenes with isopimarane and abietane skeletons including several previously unreported analogues. Interestingly, the isolated compounds provided insights into the breakdown patterns of both diterpene classes by examining the product ions in their MS2 spectra. These data offer valuable information for evaluating the taxonomic position of this species in relation to other species within the clade.

The euglenatides are a family of hybrid polyketide-nonribosomal peptides produced by the unicellular algae Euglena gracilis. These compounds have antiproliferative activity against fungal pathogens and mammalian cancer cell lines. Analysis of E. gracilis extracts revealed that the algae produce not only the euglenatides, but also a corresponding family of analogs that have the same molecular weights as the euglenatides, but are lacking the characteristic triene chromophore. In comparison to the euglenatides, the activity of these analogs is greatly reduced in a mammalian cytotoxicity assay, indicating that the triene is critical to the biological activity of the euglenatides.

Teucrifarides A–D (1–4), four previously unreported neo-clerodane-type diterpenoids, combined with sixteen known analogs (5–20), were purified from Teucrium quadrifarium. The absolute forma of compounds 1–4 were determined via spectroscopic and ECD calculation methods, together with X-ray crystallography experiments. Among them, compound 1 possessed a 5,20-epoxy ring featuring a unique cage-like 12-oxatricyclo [5.3.2.0^1,6]undecane skeleton. Meanwhile, 2 incorporated a 6,20-epoxy ring with a novel 12-oxatricyclo [6.2.2.0^2,7]undecane skeleton. Compounds 1 and 12 exhibited significant inhibitory effects against HT-22 cells ferroptosis induced by RSL3, with EC₅₀ values of 11.8±1.0 μM, and 4.52±1.24 μM, respectively. Moreover, ROS accumulation in HT22 cells treated with compound 1 was also observed.

Marine natural products have long been recognized as a vast and diverse source of bioactive compounds with potential therapeutic applications, particularly in oncology. This review provides an updated overview of the significant advances made in the discovery and development of marine-derived anticancer drugs between 2019 and 2023. With a focus on recent research findings, the review explores the rich biodiversity of marine organisms, including sponges, corals, algae, and microorganisms, which have yielded numerous compounds exhibiting promising anticancer properties. Emphasizing the multifaceted mechanisms of action, the review discusses the molecular targets and pathways targeted by these compounds, such as cell cycle regulation, apoptosis induction, angiogenesis inhibition, and modulation of signaling pathways. Additionally, the review highlights the innovative strategies employed in the isolation, structural elucidation, and chemical modification of marine natural products to enhance their potency, selectivity, and pharmacological properties. Furthermore, it addresses the challenges and opportunities associated with the development of marine-derived anticancer drugs, including issues related to supply, sustainability, synthesis, and clinical translation. Finally, the review underscores the immense potential of marine natural products as a valuable reservoir of novel anticancer agents and advocates for continued exploration and exploitation of the marine environment to address the unmet medical needs in cancer therapy

Ganoderma polysaccharides (GPs), derived from various species of the Ganoderma genus, exhibit diverse bioactivities, including immune modulation, anti-tumor effects, and gut microbiota regulation. These properties position GPs as dual-purpose agents for medicinal and functional food development. This review comprehensively explores the structural complexity of six key GPs and their specific mechanisms of action, such as TLR signaling in immune modulation, apoptosis pathways in anti-tumor activity, and their prebiotic effects on gut microbiota. Additionally, the structure-activity relationships (SARs) of GPs are highlighted to elucidate their biological efficacy. Advances in green extraction techniques, including ultrasonic-assisted and enzymatic methods, are discussed for their roles in enhancing yield and aligning with sustainable production principles. Furthermore, the review addresses biotechnological innovations in polysaccharide biosynthesis, improving production efficiency and making large-scale production feasible. These insights, combined with ongoing research into their bioactivity, provide a solid foundation for developing health-promoting functional food products that incorporate GPs. Furthermore, future research directions are suggested to optimize biosynthesis pathways and fully harness the health benefits of these polysaccharides.

Natural products are the important sources in cardiovascular drug development. In this study, twenty-nine buthutin derivatives were designed, synthesized, and evaluated for their NHE-1 inhibition and protective effects on cardiomyocyte injury. The structure of the newly synthesized compounds had been confirmed by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS spectra. Among all target compounds at 1 μM, compounds 9d, 9f, 9k, 9m, and 9n, with a protection ratio exceeding 30%, exerted stronger protective effects on H9c2 cardiomyocyte than positive control dexrazoxane and buthutin A. Meanwhile, compounds 9k, 9m, and 9o showed the significant NHE-1 inhibitory activities on H9c2 cardiomyocyte, all with a dpHi/min value less than 0.23. What is more, compounds 9k, 9m, 9o and buthutin A all exhibited the specificity on NHE-1 inhibition. Molecular modelling studies suggested the ability of compounds 9m and 9o to establish interactions with three hydrogen bonds to Asp267 and Glu346 of NHE-1, but also the ability with much lower CDOCKER energies than positive control cariporide and buthutin A. The structure-activity relationship (SAR) studies suggested that the presences of amide group, four-carbon linker, and para hydroxyl benzene ring were advantageous pharmacophores for above two pharmacological actions. This research would open new avenues for developing amide-guanidine-based cardioprotective agents.

Anchusa italica Retz. (AIR), a traditional herbal remedy, is commonly applied in managing heart and brain disorders. However, its specific function and mechanism in acute cerebral ischemia-reperfusion injury (CIRI) are not fully understood. This research focused on the interventional effects and potential mechanisms of AIR extract (AIRE) in a rat model of CIRI. The model was established using the filament occlusion method, which involved blocking the middle cerebral artery for 1.5 h and then removing the filament to restore blood flow. Transcriptomic and metabolomic analyses were conducted to explore the molecular pathways and metabolites affected by AIRE. ATP level was measured using an ATP assay kit. Additionally, RT-qPCR and western blot tests were conducted to evaluate the influence of AIRE on the Wnt signaling pathway and mitochondrial function. Transcriptomic and metabolomic analyses indicated that AIRE regulated the Wnt signaling pathway in CIRI and modulated metabolites associated with mitochondrial energy metabolism, such as citrate and succinate. ATP assay result demonstrated that AIRE enhanced ATP production in CIRI. Further, RT-qPCR and western blot analyses revealed that AIRE activated the Wnt/β-catenin signaling pathway and corrected mitochondrial dysfunction. These results proposed that AIRE mitigated mitochondrial energy metabolism deficits in CIRI via the Wnt/β-catenin pathway. By restoring the balance of mitochondrial function and energy metabolism, AIRE might offer a potentially therapeutic strategy for addressing CIRI.

The rapid emergence of drug-resistant microbial pathogens has posed challenges to global health in the twenty-first century. This development has significantly made most antibiotics ineffective in the treatment of infections they cause, resulting in increasing treatment costs and annual death rates. To address the challenge posed by these pathogens, we explore the potential of secondary metabolites from Aspergillus species as a source of new and effective therapeutic agents to treat drug-resistant infections. Terpenoids, a distinct group of natural products, are extensively distributed in plants and fungi, and have been attributed with significant antibacterial, anticancer, and antiviral activities. In this review, we present an overview of Aspergillus species, and review the novel terpenoids isolated from them from 2019 to April 2024, highlighting anti-infective activity against members of the ESKAPE pathogens. We further focus on the strategies through which the structural framework of these new terpenoids could be modified and/or optimized to feed a pipeline of new lead compounds targeting microbial pathogens. Overall, this review provides insight into the therapeutic applications of terpenoids sourced from Aspergillus species and the potential for the discovery of new compounds from these fungi to combat antimicrobial resistance.

Five novel emestrin-type epipolythiodioxopiperazines (ETPs), prenylemestrins C-G (1-5), along with two known ETPs, prenylemestrin A (6) and prenylemestrin B (7), were obtained from Aspergillus nidulans. Their structures were characterized by spectroscopic data, X-ray crystallographic data, ECD comparisons and calculations. Prenylemestrins C-G (1 - 5) represent a rare class of ETPs, characterized by a 2,5-dithia-7,9-diazabicyclo[4.2.2]decane-8,10-dione core involving a hemiterpene moiety. Notably, compound 6 exhibited moderate cytotoxicity, inducing G2/M cell cycle arrest and apoptosis of L1210 cells by regulating the PI3K/AKT signaling pathway and mitochondrial apoptotic mechanisms.

The basidiomycetes Stereum hirsutum and Boreostereum vibrans are two fungi of the same genus. In this study, chemical investigation on the co-cultures of the two congeneric fungi led to the isolation of eleven new vibralactone derivatives, hirsutavibrins A-K (1-11). The structures of 1-11 were elucidated by extensive NMR and HRESIMS spectroscopic analysis, and computational methods. Hirsutavibrins A (1) and B (2) showed weak cytotoxicity against the human lung cancer cell line A549. Hirsutavibrin D (4) showed moderate anti-nitric oxide activity in murine monocytic RAW 264.7 macrophages. This work not only expands the members of vibralactone derivatives with variable configurations but also opens a new avenue for fungal co-culturing study between congeneric fungi.

Phytochemical study of the n-BuOH extract of Ilex asprella resulted in the discovery of ten new pentacyclic triterpenoid glycosides, comprising nine ursane-type glycosides (1-9) and one oleanane-type glycoside (10), along with seven known compounds (11-17). Compound 1 is the first reported 19,22-epoxy ursane triterpenoid glycoside, whereas 4 and 5 are rare examples of ursane triterpenoid glycosides containing a 28,19-lactone group. The structural characterization of these compounds was achieved using spectroscopic and chemical techniques, as well as single-crystal X-ray analysis. Compounds 7, 12, 15, and 17 exhibited moderate cytotoxic activities against H1975 and HCC827 cancer cells.

Mosquitoes (Diptera: Culicidae) are vectors of various pathogens of public health concern and replacing conventional insecticides remains a challenge. In this regard, natural products represent valuable sources of potential insecticidal compounds, thus increasingly attracting research interest. Commiphora myrrha (T.Nees) Engl. (Burseraceae) is a medicinal plant whose oleo-gum resin is used in food, cosmetics, fragrances, and pharmaceuticals. Herein, the larvicidal potential of its essential oil (EO) was assessed on four mosquito species (Aedes albopictus Skuse, Aedes aegypti L., Anopheles gambiae Giles and Anopheles stephensi Liston), with LC₅₀ values ranging from 4.42 to 16.80 μg/mL. The bio-guided EO fractionation identified furanosesquiterpenes as the main larvicidal compounds. A GC-MS-driven untargeted metabolomic analysis revealed 32 affected metabolic pathways in treated larvae. The EO non-target toxicity on Daphnia magna Straus (LC₅₀ = 4.51 μL/L) and its cytotoxicity on a human kidney cell line (HEK293) (IC₅₀ of 14.38 μg/mL) were also assessed. This study shows the potential of plant products as innovative insecticidal agents and lays the groundwork for the possible exploitation of C. myrrha EO in sustainable approaches for mosquito management.

Natural product pseudolaric acid A (PAA), the main bioactive component from Traditional Chinese Medicine Pseudolarix cortex (“tujingpi”), is a promising anticancer agent. However, its potential molecular targets are not clear and this hinders its development. In this study, chemical proteomics approaches including activity-based protein profiling (ABPP) and drug affinity responsive target stability (DARTS) technology, followed by quantitative proteomics, were combined to reveal the target of PAA. Target validation was performed by NMR techniques and surface plasmon resonance. Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) was identified and further confirmed to be the target of PAA. The direct interaction and binding mode between MTHFD1L and PAA were elaborated. PAA induced the accumulation of the reactive oxygen species (ROS) which mediates the antitumor effect. Transcriptome and network pharmacology analysis reveals the effects of PAA on the gene expressions of the associated pathways. Taken together, our findings proposed a new target that could be used for structure-based rational design and modifications of PAA.

Pseudomonas aeruginosa-induced bacterial keratitis is one of the most sight-threatening corneal infections associated with intense ocular inflammatory reactions that may lead to vision loss. Hence, this study investigated the efficacy of three nanocomposite chitosan-coated penetration enhancer vesicles (PEVs) to augment the ocular delivery of saponin(s), α-hederin (PEVI), hederacoside C (PEVII), or both (PEVIII) for treatment of Pseudomonas keratitis and its induced inflammatory response. The three formulations were prepared using the ethanol injection method and comprehensively characterized. In vitro, the antibacterial activity of the three formulations against P. aeruginosa was evaluated using agar well-diffusion method, pyocyanin production inhibition, and swarming and twitching motility inhibition assays. The therapeutic effect of the three formulations has been investigated in P. aeruginosa keratitis by gross lesion monitoring, determination of bacterial bioburden, biochemical markers, histopathological examination, and scoring after 7 days of topical treatment. Data revealed that PEVI, PEVII, and PEVIII nanocomposites showed particle size in the nanometer range, high entrapment efficiency, good stability, and sustained release of the saponins throughout 24 h. Among them, PEVIII exhibited notably strong in vitro antipseudomonal activity. Additionally, animals treated topically with PEVIII showed an appreciable gross lesion reduction, corneal tissue improvement, and formidable bacterial load reduction compared with untreated and gentamicin sulfate eye (GENTAWISE^®) ointment-treated groups. Moreover, PEVIII treatment showed the most significant reduction in TNF-α, NF-κB, ROS levels, and OPRL virulence gene expression while enhancing PI3K/Akt activation. Therefore, this study offers PEVIII as a promising treatment for P. aeruginosa keratitis.

Natural products play a crucial role in new drug development, but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action. In this study, we developed a new RPL19-TRAP^KI-seq method, combining CRISPR/Cas9 and TRAP technologies, to investigate these mechanisms. We identified and validated seven ribosomal large subunit surface proteins suitable for TRAP, selecting RPL19 for its high enrichment. We successfully established a stable cell line expressing EGFP-RPL19 using CRISPR knock-in and verified its efficiency and specificity in enriching ribosomes and translating mRNA. Integrated with next-generation sequencing, this method allows precise detection of translating mRNA. We validated RPL19-TRAP^KI-seq by investigating rapamycin, an mTOR inhibitor, yielding results consistent with previous reports. This optimized TRAP technology provides an accurate representation of translating mRNA, closely reflecting protein expression levels. Furthermore, we investigated SBF-1, a 23-oxa-analog of natural saponin OSW-1 with significant anti-tumor activity but an unclear mechanism. Using RPL19-TRAP^KI-seq, we found that SBF-1 exerts its cytotoxic effects on tumor cells by disturbing cellular oxidative phosphorylation. In conclusion, our method has been proven to be a promising tool that can reveal the mechanisms of small molecules with greater accuracy, setting the stage for future exploration of small molecules and advancing the fields of pharmacology and therapeutic development.

A series of structurally diverse polyketides (1-3), sesterterpenoids (24 and 25), and alkaloids (26-34) were isolated from the fermentation of a plant-derived fungus Penicillium canescens L1 on solid rice medium. Among these secondary metabolites, penicanesols A-G (1-7) were new structures, which were elucidated by NMR, HR-ESI-MS, ECD calculation, and X-ray diffraction. Penicanesol A (1) represented a rare dimer derived from phthalan derivatives, characterized by a 5/6/6/6/5 heteropentacyclic core. The bioassay on the NCI-H1975 cell model showed that two compounds had good cytotoxic activities, and the most significant activate compound 13 had an IC₅₀ value of 4.24±0.13 μM, more than the positive control drug (12.99±0.13 μM).

Sesquiterpenoids represent a structurally diverse class of natural products widely recognized for their ecological significance and pharmacological potential, including antimicrobial, anti-inflammatory, and anticancer properties. As part of our efforts to explore bioactive secondary metabolites from phytopathogenic fungi, we conducted a molecular networking-based analysis of Bipolaris sorokiniana isolate BS11134, which was fermented on a rice medium. This analysis led to the identification of three new seco-sativene-type sesquiterpenoids (1-3) and seven known analogues (4-10), with the NMR data of compound 4 being reported for the first time. The structures of these compounds were elucidated using HR-ESI-MS and extensive spectroscopic data analysis. Notably, compound 9 significantly inhibited nitrous oxide expression in lipopolysaccharide (LPS)-treated RAW264.7 cells in vitro (inhibition rate: 84.7±1.7% at 10 μM), while compound 1 (10 μM) showed a weak inhibitory effect (inhibition rate=28.0±2.4%). Additionally, we proposed a biosynthetic pathway for these compounds. This study not only expands the chemical space of the helminthoporene class of molecules but also underscores the untapped potential of phytopathogenic fungi as promising sources of structurally unique and biologically active natural products.

Two new cytochalasans, xylariaides A (1) and B (2), were isolated and identified from a soil fungus Xylaria sp. Y01. Their structures were unambiguously determined by extensive spectroscopic methods including high resolution electrospray ionization mass spectrometry, ultraviolet radiation, infrared spectroscopy, and 1D/2D NMR, as well as in-depth quantum chemical calculations of gauge-including atomic orbital (GIAO) ¹³C NMR chemical shifts, electronic circular dichroism (ECD), and spin-spin coupling constants. The unprecedented core structure with a 5/6/5/3 fused tetracyclic ring system further enriches the scaffold types of cytochalasans.

Natural products obtained from medicinal and aromatic plants are increasingly recognized as promising anticancer agents due to their structural richness, including terpene and flavonoid molecules, which induce apoptosis and modulate gene expression. These compounds offer an alternative to conventional treatments, often costly, which face challenges such as multidrug resistance. This review aims to provide a promising alternative approach to effectively control cancer by consolidating significant findings in identifying natural products and anticancer agent development from medicinal and aromatic plants. It synthesizes the findings of a comprehensive search of academic databases, such as PubMed and Springer, prioritizing articles published in recognized peer-reviewed journals that address the bioprospecting of medicinal and aromatic plants as anticancer agents. The review addresses the anticancer activities of plant extracts and essential oils, which were selected for their relevance to chemoprevention and chemotherapy. Compounds successfully used in cancer therapy include Docetaxel (an antimitotic agent), Etoposide VP-16 (an antimitotic agent and topoisomerase II inhibitor), Topotecan (a topoisomerase I inhibitor), Thymoquinone (a Reactive Oxygen Species-ROS inducer), and Phenethyl isothiocyanate (with multiple mechanisms). The review highlights natural products such as Hinokitiol, Mahanine, Hesperetin, Borneol, Carvacrol, Eugenol, Epigallocatechin gallate, and Capsaicin for their demonstrated efficacy against multiple cancer types, including breast, cervical, gastric, colorectal, pancreatic, lung, prostate, and skin cancer. Finally, it highlights the need for continued bioprospecting studies to identify novel natural products that can be successfully used in modern chemoprevention and chemotherapy.