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Exploring the genetic basis of congenital cataracts in two families identifies a molecule, lanosterol, which prevents intracellular protein aggregation of various cataract-causing mutant crystallins, and which can reduce cataract severity and increase lens transparency in vivo in dogs. Lanosterol counters cataract formation In a study of the genetic basis of congenital cataract formation in two families, Kang Zhang and colleagues demonstrate that lanosterol, a sterol present naturally in the lens, can prevent intracellular aggregation of various cataract-causing mutant crystallin proteins. The mutations identified in the genetic study impair the function of lanosterol synthase, an enzyme for synthesizing lanosterol. In dogs with naturally occurring cataracts, the application of eye drops containing lanosterol for six weeks reduced cataract severity and increased lens transparency, suggesting that lanosterol or molecules with similar activity might provide an alternative to surgery for the management of cataracts. The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people 1 , and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

The frequency of autoimmune diseases such as rheumatoid arthritis is increasing annually. Current treatments for these diseases cause new problems due to their side effects. In this study, we investigated the impact of Ganoderic Acid A (GAA), a potent anti-inflammatory herbal molecule, to evaluate the potential efficacy of GAA in alleviating Rheumatoid arthritis (RA)-associated clinical and histopathological manifestations. 40 Balb/c male mice were randomly divided into five groups (n = mice number per each group) as control (C), acetic acid (AA), rheumatoid arthritis (RA), low dose GAA (LGA) and high dose GAA (HGA) groups. Collagen emulsion was applied intra-articularly (ia), and complete Freund’s adjuvant (CFA) was applied subcutaneously (sc) to the RA and GA groups to induce an experimental model of rheumatoid arthritis. Other groups were given physiologic saline (PS) or AA at the same dose and in the same way. The procedures were repeated on the 22nd day; however, incomplete Freund’s adjuvant was applied to the RA and GA groups instead of CFA. PS was given to groups C, AA and RA for 9 days starting from the 22nd day; GAA was applied to the LGA (20 mg/kg) and HGA (40 mg/kg) groups by gavage. We evaluated body weight, arthritis score, knee temperature, knee circumference, behavioural assessment of pain, gait, tail-flick test, hot plate test, locomotor activity test, lower extremity index, spectrophotometric and histopathological evaluation methods, respectively. Compared to the RA group, the clinical arthritis score was reduced in the HGA group (p < 0.05). GAA significantly reduced knee temperatures and knee circumference, with changes in hot plate scores and tail flip test response. In the GAA groups, serum concentrations of AST, IL-6, TNF-α, NFkB were reduced, and joint damage and arthritis scores were also reduced histologically (p < 0.05). The results of this study suggest that the arthritis regressed with GAA treatment. Edema and inflammation were found to be reduced in the GAA groups compared with the RA group. GAA treatment resulted in significant improvements in behavioural activity, reduced inflammation and the damage to cartilage and bone structure and had an antinociceptive effect.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening monogenetic diseases characterized by progressive enlargement of fluid-filled renal cysts. Our previous study has shown that Ganoderma triterpenes (GT) retards PKD renal cyst development. In the present study we identified the effective ingredient of GT in suppression of kidney cyst development. Using an in vitro MDCK cystogenesis model, we identified ganoderic acid A (GA-A) as the most promising candidate among the 12 ganoderic acid (GA) monomers. We further showed that GA-A (6.25−100 μM) significantly inhibited cyst growth in MDCK cyst model and embryonic kidney cyst model in vitro, and the inhibitory effect was reversible. In kidney-specific Pkd1 knockout (kPKD) mice displaying severe cystic kidney disease, administration of GA-A (50 mg· kg −1  ·d −1 , sc) significantly attenuated renal cyst development. In both MDCK cells and kidney of kPKD mice, we revealed that GA-A dose-dependently downregulated the Ras/MAPK signaling pathway. The expression of proliferating cell nuclear antigen (PCNA) was also suppressed, suggesting a possible effect of GA-A on cell proliferation. These experimental data suggest that GA-A may be the main ingredient of GT as a potential therapeutic reagent for treating ADPKD.

Ganoderma lucidum, a species of the Basidiomycetes class, has been attracting international attention owing to its wide variety of biological activities and great potential as an ingredient in skin care cosmetics including “skin-whitening” products. However, there is little information available on its inhibitory effect against tyrosinase activity. Therefore, the objectives of this study were to investigate the chemical composition of G. lucidum and its inhibitory effects on melanogenesis. We isolated the active compound from G. lucidum using ethanol extraction and ethyl acetate fractionation. In addition, we assayed its inhibitory effects on tyrosinase activity and melanin biosynthesis in B16F10 melanoma cells. In this study, we identified a bioactive compound, ganodermanondiol, which inhibits the activity and expression of cellular tyrosinase and the expression of tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF), thereby decreasing melanin production. Furthermore, ganodermanondiol also affected the mitogen-activated protein kinase (MAPK) cascade and cyclic adenosine monophosphate (cAMP)-dependent signaling pathway, which are involved in the melanogenesis of B16F10 melanoma cells. The finding that ganodermanondiol from G. lucidum exerts an inhibitory effect on tyrosinase will contribute to the use of this mushroom in the preparation of skin care products in the future.

Recurrent meningiomas constitute an uncommon but significant problem after standard (surgery and radiation) therapy failure. Current chemotherapies (hydroxyurea, RU-486, and interferon-α) are only of marginal benefit. There is an urgent need for more effective treatments for meningioma patients who have failed surgery and radiation therapy. Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM are some of the plant derivatives that have anti-tumorgenic properties and cause cell death in meningioma cells in vitro. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining their efficacy in vitro against meningioma cells. Treatment effects were assessed using MTT assay, Western blot analysis, caspases assay, and DNA fragmentation assay. Results indicated that treatments of IOMM-Lee and CH157MN meningioma cells with Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM induced apoptosis with enhanced phosphorylation of glycogen synthase kinase 3 β (GSK3β) via inhibition of the Wnt5/β-catenin pathway. These drugs did not induce apoptosis in normal human neurons. Other events in apoptosis included downregulation of tetraspanin protein (TSPAN12), survival proteins (Bcl-XL and Mcl-1), and overexpression apoptotic factors (Bax and caspase-3). These results provide preliminary strong evidence that medicinal plants containing Limonin, Tangeritin, 6-Gingerol, Zerumbone, Ganoderic Acid A, and Ganoderic Acid DM can be applied to high-grade meningiomas as a therapeutic agent, and suggests that further in vivo studies are necessary to explore its potential as a therapeutic agent against malignant meningiomas.

Triterpene acids (TAs) are the major bioactive constituents in the medicinal fungus Ganoderma lingzhi. However, fermentative production of TAs has not been optimized for commercial use, and whether the TAs isolated from G. lingzhi submerged culture mycelia possess antitumor activity needs to be further proven. In this study, enhanced TA yield and productivity were attained with G. lingzhi using response surface methodology. The interactions of three variables were studied using a Box-Benhnken design, namely initial pH, dissolved oxygen (DO) and fermentation temperature. The optimum conditions were an initial pH of 5.9, 20.0% DO and 28.6 °C. These conditions resulted in a TA yield of 308.1 mg/L in a 5-L stirred bioreactor. Furthermore, the optimized conditions were then successfully scaled up to a production scale of 200 L, and maximum TA production and productivity of 295.3 mg/L and 49.2 mg/L/day were achieved, which represented 80.9% and 111.5% increases, respectively, compared with the non-optimized conditions. Additionally, the triterpene acid extract (TAE) from G. lingzhi mycelia was found to be cytotoxic to the SMMC-7721 and SW620 cell lines in vitro, and the TAE exhibited dose-dependent antitumor activity against the solid tumor sarcoma 180 in vivo. Chemical analysis revealed that the key active triterpene compounds, ganoderic acid T and ganoderic acid Me, predominated in the extract.

Background A substantial literature supports antidiabetic properties of the lanosteryl triterpene (methyl-3β-hydroxylanosta-9,24-dien-21-oate, RA-3) isolated from Protorhus longifolia stem bark. However, the molecular mechanism(s) associated with the antihyperglycemic properties of the triterpene remained to be explored. The current study aimed at investigating the molecular mechanism(s) through which RA-3 improves insulin signaling in streptozotocin-induced type 1 diabetic rats. Methods The type 1 diabetic rats were treated daily with a single oral dose of RA-3 (100 mg/kg) for 28 days. The rats were then sacrificed, and blood, skeletal muscle and pancreases were collected for biochemical, protein expression and histological analysis, respectively. Results Persistently high blood glucose levels in the diabetic control rats significantly increased expression of IRS-1Ser307 while the expression of p-Akt Ser473, p-GSK-3β Ser9, GLUT 4 and GLUT 2 were decreased. However, enhanced muscle insulin sensitivity, which was indicated by a decrease in the expression of IRS-1ser307 with a concomitant increase in the p-AktSer473, p-GSK-3β Ser9, GLUT 4 and GLUT 2 expression were observed in the diabetic rats treated with RA-3. The triterpene-treated animals also showed an improved pancreatic β-cells morphology, along with increased C-peptide levels. An increase in the levels of serum antioxidants such as catalase, superoxide dismutase, and reduced glutathione was noted in the rats treated with the triterpene, while their serum levels of interleukin-6 and malondialdehyde were reduced. Conclusions It is apparent that RA-3 is able to improve the insulin signaling in type 1 diabetic rats. Its beta (β)-cells protecting mechanism could be attributed to its ability to alleviate inflammation and oxidative stress in the cells.

Cataract caused by crystallin aggregation is the leading cause of vision impairment and blindness globally. The only available treatment option so far is surgery. In this study, we leverage lipid nanoparticles (LNPs)-formulated mRNA encoding human lanosterol synthase (hLSS) to elevate lanosterol levels in the lens as a potential anti-cataract therapy. hLSS mRNA delivered with aromatized LNPs can be avidly taken up and translated into hLSS proteins in mammalian cells. mRNA formulations administered via intravitreal, subconjunctival, intracameral, or subretinal injection in rats display distinct kinetics and bio-distribution profiles, among which intracameral injection achieves sustained and selective protein expression in the lens. In comparison to clinically used LNPs, aromatized LNPs show more than seven-fold higher mRNA delivery potency in rats upon intracameral injection, without inducing significant ocular lesions. Furthermore, ocular delivery of hLSS mRNA-loaded formulations leads to elevated levels of hLSS proteins and lanosterol within the lens and a remarkable improvement in cataract symptoms in two rat models of cataract. Collectively, topical delivery of hLSS mRNA-LNPs to the eyes offers a potential strategy to reduce intracellular aggregation of crystallins and ameliorate cataract development. Surgery is currently the only treatment option for cataract. Here, the authors report on ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase as a potential anti-cataract therapy, which ameliorates cataract development in two rat cataract models.

Chaga mushroom (Inonotus obliquus) comprises polyphenolic compounds, triterpenoids, polysaccharides, and sterols. Among the triterpenoid components, inotodiol has been broadly examined because of its various biological activities. The purpose of this study is to examine inotodiol from a safety point of view and to present the potential possibilities of inotodiol for medical usage. From chaga mushroom extract, crude inotodiol (INO20) and pure inotodiol (INO95) were produced. Mice were treated with either INO20 or INO95 once daily using oral administration for repeated dose toxicity evaluation. Serum biochemistry parameters were analyzed, and the level of pro-inflammatory cytokines in the serum was quantified. In parallel, the effect of inotodiol on food allergic symptoms was investigated. Repeated administration of inotodiol did not show any mortality or abnormalities in organs. In food allergy studies, the symptoms of diarrhea were ameliorated by administration with INO95 and INO20. Furthermore, the level of MCPT-1 decreased by treatment with inotodiol. In this study, we demonstrated for the first time that inotodiol does not cause any detrimental effect by showing anti-allergic activities in vivo by inhibiting mast cell function. Our data highlight the potential to use inotodiol as an immune modulator for diseases related to inflammation.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with no therapeutic consensus. Oxidation and inflammation are hallmarks in the progression of this complex disease, which also involves interactions between the genetic background and the environment. Mastiha is a natural nutritional supplement known to possess antioxidant and anti-inflammatory properties. This study investigated how a 6-month Mastiha supplementation (2.1 g/day) could impact the antioxidant and inflammatory status of patients with NAFLD, and whether genetic variants significantly mediate these effects. We recruited 98 patients with obesity (BMI ≥ 30 kg/m 2 ) and NAFLD and randomly allocated them to either the Mastiha or the placebo group for 6 months. The anti-oxidative and inflammatory status was assessed at baseline and post-treatment. Genome-wide genetic data was also obtained from all participants, to investigate gene-by-Mastiha interactions. NAFLD patients with severe obesity (BMI > 35kg/m 2 ) taking the Mastiha had significantly higher total antioxidant status (TAS) compared to the corresponding placebo group (P value=0.008). We did not observe any other significant change in the investigated biomarkers as a result of Mastiha supplementation alone. We identified several novel gene-by-Mastiha interaction associations with levels of cytokines and antioxidant biomarkers. Some of the identified genetic loci are implicated in the pathological pathways of NAFLD, including the lanosterol synthase gene ( LSS) associated with glutathione peroxidase activity (Gpx) levels, the mitochondrial pyruvate carrier-1 gene ( MPC1) and the sphingolipid transporter-1 gene ( SPNS1 ) associated with hemoglobin levels, the transforming growth factor‐beta‐induced gene ( TGFBI ) and the micro-RNA 129-1 ( MIR129-1) associated with IL-6 and the granzyme B gene ( GZMB ) associated with IL-10 levels. Within the MAST4HEALTH randomized clinical trial (NCT03135873, www.clinicaltrials.gov ) Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity. We identified several novel genome-wide significant nutrigenetic interactions, influencing the antioxidant and inflammatory status in NAFLD.