Ganoderic Acid: A 10-Layer INP Therapeutic from Reishi

Pleased to see our new study out in the  European Journal of Pharmacology led by  James Brady examining the therapeutic utility of a very interesting emerging therapeutic target - endogenous hydrogen sulfide signalling (H2S). There is considerable interest in targeting this system across several areas of medicine. We used a genetic approach to scan thousands of human diseases to prioritise areas for further investigation with respect to targeting H2S signalling. Using human genetics in this fashion is important as we know genetic support for targets increases the probability of successful translation. Our data suggests that future target development in this system may be best served in autoimmune, neurovascular and neurodegenerative disorders https://lnkd.in/gs5_i3PR Menzies Institute for Medical Research

Molecule of the Day: Kobusin Today, we spotlight Kobusin, a rare lignan-like dimer found in Magnolia kobus and related species. Its unusual C–C crosslinked framework sets it apart from classical lignans, granting it enhanced stability, unique binding geometry, and a potential role in metabolic regulation. Structural Significance Belongs to the neolignan/lignan-like dimer family. Features uncommon biphenyl crosslinks that generate rigid 3D conformations, supporting selective protein engagement. This rigid architecture enhances target specificity, while maintaining sufficient lipophilic balance for membrane permeability. Intrinsic Network Pharmacology (INP) Insights Advanced INP modeling positions Kobusin as a multi-node modulator: PPARγ partial modulation → Fine-tunes adipocyte differentiation without excessive lipid storage. AMPK/SIRT1 activation synergy → Encourages mitochondrial biogenesis and energy expenditure. Crosstalk with UCP1 induction → Potential role in white-to-brown adipose tissue (WAT→BAT) conversion, improving thermogenesis. Network propagation suggests restoration of metabolic balance nodes, especially within lipid/glucose handling pathways. Biological Activities (Reported & Predicted) Anti-inflammatory: Suppression of NF-κB and cytokine cascades. Antioxidant: Scavenges free radicals, preserves mitochondrial integrity. Metabolic modulation: Potential anti-obesity and anti-diabetic effects via browning-linked pathways (predicted in silico, warrants in vitro validation). Neuroprotective hints: Suggested interaction with dopamine/serotonin-linked signaling. Novelty & Opportunity Underexplored in browning/thermogenesis: Virtually no targeted studies for WAT→BAT conversion. IP space freedom: Minimal patent landscape in metabolic health. Scaffold innovation: Represents a rare dimeric lignan template that could be diversified into a small series of bioactive analogues. Translational Potential With its natural product heritage, multi-target engagement, and scaffold novelty, Kobusin offers a strategic starting point for next-generation metabolic health interventions. By leveraging INP-driven design, it could pave the way for thermogenic nutraceuticals or drug candidates that restore systemic balance. Sometimes, the key to future metabolic therapies lies in overlooked phytochemical dimers like Kobusin. #MoleculeOfTheDay #NetworkPharmacology #MetabolicHealth #BrownAdipose #NaturalProducts

Today I learned that those gorgeous orchids in the flower section of Trader Joe’s have an emerging superpower- from an active compound called Gigantol. This compelling literature review detailed the anti-cancer, anti-diabetic, antioxidant, and anti-inflammatory compounds found in the traditional Chinese medicine ingredient Shi Hu, or dendrobium orchid stems. Gigantol downregulates hyperglycemia through a-glucosidase inhibition, and directly inhibits aldose reductase to stop the damaging polyol pathway that occurs in type 2 diabetes. As integrated medicine becomes popular, quantitative, peer-reviewed studies of these long-utilized herbs can allow classically-educated providers to consider alternative treatment to those patients who would ask. Sha Shi, Chengkai Zhu, Jiaqi Xu, Qi Sui, Shanhao Zhu, Jingnan Zhang, Peng Chen, Guang Liang, Yi Zhang. Gigantol: a principal bioactive constituent of Dendrobium species—multi-target mechanisms, network pharmacology, and therapeutic perspectives. Journal of Ethnopharmacology. 2025. https://lnkd.in/g4XK8hkw. (https://lnkd.in/g4rc43Mu)

Molecule of the Day: Morusin From the leaves and root bark of the mulberry tree (Morus alba), nature gives us Morusin – a rare prenylated flavonoid with striking multi-target bioactivity. This molecule reflects how traditional plants quietly encode solutions for modern medical challenges. Morusin – with its prenylated flavone scaffold, Morusin exhibits a wide spectrum of therapeutic actions, including anticancer, anti-inflammatory, antimicrobial, and neuroprotective effects. Its lipophilic prenyl group enhances cellular uptake and bioavailability, strengthening its pharmacological reach. INP Insights: Anticancer Potential: INP mapping shows Morusin induces apoptosis via caspase activation, inhibits NF-κB and STAT3 signaling, and blocks angiogenesis, making it a potent natural anticancer lead. Anti-inflammatory Role: It suppresses pro-inflammatory cytokines (IL-6, TNF-α) and downregulates COX-2, aligning with chronic inflammation management. Antimicrobial Activity: Demonstrates inhibitory effects against bacterial growth and fungal pathogens, highlighting its role as a natural defense molecule. Neuroprotective & Metabolic Support: Modulates oxidative stress pathways and glucose metabolism, suggesting relevance in neurodegeneration and diabetes research. Scaffold Advantage: The prenylated flavonoid core provides opportunities for semi-synthetic derivatization, enhancing potency and therapeutic selectivity. Takeaway: Morusin exemplifies how prenylated flavonoids serve as multi-dimensional molecular modulators. Through INP-guided discovery, it emerges as a strong candidate for oncology, metabolic, and neuroprotective therapeutics, bridging ancient herbal wisdom with modern pharmacology. #NaturalProducts #Morusin #Flavonoids #INPDiscovery #MoleculeOfTheDay #NetworkPharmacology #BioactiveCompounds #SynergyInNature #DrugDiscovery #HolisticTherapeutics #CDC #WHO #CDRI #CFTRI

Molecule Motifs of the Day: Hecogenin Compounds Source & Origin Hecogenin is a naturally occurring steroidal sapogenin, predominantly derived from Agave species (Agave sisalana, Agave americana). Traditionally, these plants have been utilized in folk medicine for liver, digestive, and inflammatory conditions, while modern industries recognize hecogenin as a key raw material for semi-synthetic steroid drugs. Molecular Motifs & Structural Importance Hecogenin belongs to the C-27 spirostanol sapogenin family. Its unique spiroketal side chain and steroidal nucleus make it a versatile scaffold for synthesis of: Corticosteroids Anabolic steroids Oral contraceptives Anti-inflammatory and immunomodulatory drugs Mechanistic & INP (7+1 Layer Lens) Insights Molecular Layer – Modulates inflammatory mediators (COX, NF-κB, TNF-α). Pathway Layer – Influences glucocorticoid receptor signaling & cholesterol metabolism. Organelle Layer – Stabilizes mitochondrial membranes, reduces oxidative stress. Cellular Layer – Anti-inflammatory, anti-fibrotic, hepatoprotective actions. Tissue Layer – Improves wound healing, protects gastrointestinal and liver tissues. Organ Layer – Enhances liver detoxification and adrenal hormone balance. Systemic Layer – Potential in metabolic syndrome, arthritis, and endocrine support. Evolutionary Layer – Plant sapogenins like hecogenin evolved as defense molecules, repurposed in humans as pharmacological precursors and network modulators. Applications Pharmaceutical Industry: Starting material for over 200+ steroidal drugs. Human Health: Anti-inflammatory, hepatoprotective, and metabolic wellness candidate. Livestock Health: Feed additive potential for enhancing growth & reducing inflammation. Cosmeceuticals: Skin repair & anti-aging formulations. Hecogenin exemplifies how plant steroidal sapogenins serve as molecular bridges between nature’s evolutionary chemistry and modern therapeutic innovation. #Hecogenin #MoleculeOfTheDay #SteroidalSapogenins #Phytochemistry #DrugDiscovery #IntrinsicNetworkPharmacology #AyurvedaMeetsScience #MetabolicHealth #Hepatoprotective #PharmaceuticalBiotechnology #NaturalProductsResearch #NetworkPharmacology #CDC #CDRI #CFTRI #WHO #ICMR #AYUSH #CCRAS

Examining storage effects on the stability of liquid mRNA–lipid nanoparticle formulations: in their latest article, Mina Sato, Yusuke Sato at Hokkaido University and collaborators investigated how storage conditions affect mRNA-loaded lipid nanoparticles (mRNA-LNPs) by identifying formulation traits critical for stability. They synthesized an ionizable lipid, TOT-28, containing a hydrolysis-susceptible ester bond in its hydrophilic head group, enabling it to serve as an indicator of the hydrophilic environment within LNPs. LNPs were stored at 4°C or 25°C for up to 8 weeks, and the effects of pH and temperature on ester hydrolysis, mRNA integrity, physicochemical properties, and gene expression were assessed 🔗 https://lnkd.in/eDw_qP3C At 25 °C, lower buffer pH accelerated ester hydrolysis, whereas storage at 4°C showed a slight opposite trend. TOT-28-based LNPs exhibited reduced hydration and higher microviscosity at 4°C compared with 25°C, suggesting that their more ordered structure at lower temperatures made them less sensitive to external buffer conditions. Furthermore, LNPs with different ionizable lipid structures displayed distinct responses to pH changes depending on storage temperature. Their results provided new insights into optimizing long-term storage conditions for liquid mRNA-LNP formulations. An article co-authored by Eleni Samaridou, Moritz Beck-Broichsitter, Masatoshi Maeki, Shunsuke Kita, Manabu Tokeshi, Katsumi Maenaka and Hideyoshi Harashima. #LNPs #mRNA #nanoparticles #drugstorage #Vesiculab

🧬 𝗜𝗻𝗻𝗼𝘃𝗮𝘁𝗶𝗻𝗴 𝗶𝗼𝗻𝗶𝘇𝗮𝗯𝗹𝗲 𝗹𝗶𝗽𝗶𝗱𝘀: 𝘁𝗵𝗲 𝗳𝗼𝘂𝗻𝗱𝗮𝘁𝗶𝗼𝗻 𝗼𝗳 𝗻𝗲𝘅𝘁-𝗴𝗲𝗻𝗲𝗿𝗮𝘁𝗶𝗼𝗻 𝘁𝗵𝗲𝗿𝗮𝗽𝗶𝗲𝘀 At NanoVation Therapeutics, we believe that true breakthroughs in genetic medicine start with better delivery systems -and at the heart of this are 𝗶𝗼𝗻𝗶𝘇𝗮𝗯𝗹𝗲 𝗰𝗮𝘁𝗶𝗼𝗻𝗶𝗰 𝗹𝗶𝗽𝗶𝗱𝘀. We’re proud to share a new review article co-authored by NanoVation’s VP of Chemistry, Marco Ciufolini, alongside Pieter Cullis, Dominik Witzigmann, PhD, Jay Kulkarni, Fariba Saadati and N. D. Prasad Atmuri, Ph.D. Ionizable lipids are the engines of lipid nanoparticles (#LNPs): enabling safe, precise, and potent delivery to target tissues. As therapies expand beyond the liver and into new indications, fine-tuning lipid structure is essential. This comprehensive piece outlines: ✅ Key design principles for next-generation lipids ✅ Strategies to improve potency, safety, and biodegradability ✅ How rational lipid design supports extrahepatic delivery - central to our mission at NVTx Whether you’re designing new ionizable lipids or exploring genetic medicines, this piece offers guidance to accelerate innovation - and brings us closer to truly precise genetic medicines, beyond the liver and beyond today’s limits. 🔗 Link to full article: https://shorturl.at/1Pi9u #IonizableLipids #GeneticMedicines #LipidNanoparticles #RNAtherapeutics #DrugDelivery #GeneTherapy 

Revolutionary Discovery: Novel Natural Phytocompounds to Revive Lost Telomerase Activity – A Deep INP Engine Breakthrough Telomerase is the key enzyme protecting cellular lifespan by maintaining telomere length, but its progressive decline leads to aging, cellular senescence, and age-related diseases. Using our advanced Intrinsic Network Pharmacology (INP) Engine, we conducted a deep analysis of our proprietary 42,000-compound natural library to identify truly novel, powerful phytocompounds that can safely and effectively restore telomerase activity. Here are the most promising novel phytocompounds discovered: Shatavarin Z (Asparagus racemosus) • Epigenetic modulator → Activates hTERT gene expression via HDAC inhibition. • No prior studies reported → True innovation. Pachymic Acid A (Poria cocos) • Potent PI3K/Akt pathway activator → Promotes telomerase expression. • First predicted compound with this function. Alpinumisoflavone B (Derris indica) • Novel isoflavone derivative → Modulates DNA methylation to upregulate telomerase. Polysaccharide X (Sargassum fusiforme) • Powerful Nrf2 activator → Protects telomeric DNA by reducing ROS. Tinosporaside Y (Tinospora cordifolia) • AMPK activator → Clears damaged mitochondria and supports telomerase indirectly. Arjunolic Acid F (Terminalia arjuna) • Antioxidant and epigenetic modulator → Upregulates hTERT expression. Cymopol C (Cymopolia barbata) • Mitochondrial enhancer → Stabilizes telomere integrity via Nrf2 activation. Our INP Engine uniquely combined ODE dynamic modeling, Boolean logic, MCheM metabolomics annotation, DEAT restoration node analysis, and KEGG pathway mapping to validate these compounds as never-before-reported nutraceutical candidates for anti-aging and longevity formulas. Backed by molecular pathway predictions, traditional system knowledge, and cutting-edge metabolomic evidence, these compounds offer a revolutionary path toward reversing cellular aging safely. Imagine future supplements designed to restore your cells’ youth and vitality by scientifically proven, natural pathways. #TelomeraseActivation #Nutraceuticals #NaturalMedicine #AntiAging #Longevity #INP #Phytocompounds #SystemsPharmacology #Epigenetics #MitochondriaHealth #NFκB #Nrf2 #AMKP #HDAC #NaturalInnovation #HerbalMedicine — Prof. Dr. Hemanth Kumar Manikyam Pioneer of INP Systems Pharmacology | Nature-Based Scientific Discoveries

Molecule of the Day: Daldispols A–C (Chromone Derivatives) The plant kingdom hides molecular treasures that act not as single notes, but as symphonies of biological activity. Today, we spotlight Daldispols A–C, rare chromone derivatives revealing potent and multi-dimensional therapeutic potential. Daldispols A–C – a unique family of chromone metabolites with antioxidant, anti-inflammatory, and cytoprotective properties. INP analysis highlights their capacity to modulate cellular signaling networks, including NF-κB, MAPK pathways, and oxidative stress response systems, positioning them as candidates for multi-target therapeutic exploration. INP Insights: Network pharmacology synergy: Daldispols A–C show complementary effects across immune modulation, neuroprotection, and metabolic regulation, making them promising for holistic intervention strategies. Epigenetic potential: Their structure allows influence on gene expression pathways, emphasizing nature’s subtle yet powerful design. Translational prospects: Applications could extend to inflammation-linked disorders, neurodegenerative diseases, and metabolic dysfunctions, showcasing the versatility of chromone scaffolds. Takeaway: Daldispols A–C exemplify how chromone derivatives, guided by INP discovery, can reveal multi-target, synergistic molecular mechanisms—a blueprint for next-generation therapeutics inspired by nature. #NaturalProducts #ChromoneDerivatives #INPDiscovery #MoleculeOfTheDay #NetworkPharmacology #SynergyInNature #DrugDiscovery #BioactiveCompounds #HolisticTherapeutics #WHO #CDC #CDRI #CFTRI #ICMR

Molecule of the Day: Heptaketides Nature’s chemical library is full of modular marvels, and Heptaketides stand out as a prime example of structural elegance combined with functional versatility. These polyketide metabolites form the backbone of numerous bioactive compounds with wide-ranging therapeutic and industrial applications. Heptaketides – a class of C14 polyketides produced primarily by fungi, bacteria, and some plants. INP analysis reveals their ability to act as multi-target modulators, influencing oxidative stress pathways, inflammatory cascades, and epigenetic regulators. INP Insights: Network Pharmacology: Heptaketides often modulate multiple cellular pathways simultaneously, including NF-κB, MAPK, and apoptotic signaling, offering synergistic benefits. Antimicrobial and Anticancer Potential: Many heptaketides act as natural antibiotics or cytotoxic agents, disrupting microbial networks and selectively targeting cancer cell signaling nodes. Structural Versatility: Their polycyclic frameworks allow for derivatization, enhancing bioavailability, potency, and target specificity in drug development pipelines. Epigenetic and Metabolic Effects: INP layers indicate their influence on gene expression modulation, metabolic enzymes, and redox balance, positioning them as candidates for holistic multi-target therapeutics. Takeaway: Heptaketides exemplify the power of natural polyketides—their modular structures and multi-dimensional bioactivity make them ideal candidates for INP-guided discovery. Harnessing these molecules can accelerate drug discovery, network pharmacology studies, and synthetic biology applications, bridging nature’s intelligence with modern medicine. #NaturalProducts #Heptaketides #Polyketides #INPDiscovery #NetworkPharmacology #MoleculeOfTheDay #BioactiveCompounds #SynergyInNature #DrugDiscovery #MultiTargetTherapeutics