Mixed porokeratosis with a novel mevalonate kinase gene mutation:A case report

BACKGROUND Porokeratosis is a rare,acquired,or inherited disorder of keratinization.There are numerous clinical types of porokeratosis and they can coexist in one patient and multiple members of an affected family.However,coexistence of disseminated superficial actinic porokeratosis(DSAP)and porokeratosis ptychotropica(Ppt)is rare.CASE SUMMARY A 45-year-old man presented with long-standing skin lesions.Physical examination identified numerous small,brown 2-mm to 4-mm patches on his face and several hyperkeratotic,verrucous plaques on his trunk and extremities.His father and one of his brothers also had similar lesions for years.Skin biopsies indicated a cornoid lamella in the epidermis.We identified c.155G>A mutation in the mevalonate kinase(MVK)gene,which converted a serine residue to asparagine(p.Ser52Asn)and was causative for porokeratosis in this family.A clinicopathologic diagnosis of DSAP and Ppt with a novel MVK gene mutation was made.The hyperkeratotic plaques on the patient’s scrotum were completely removed more than 10 times using a microwave knife.CONCLUSION An unusual case of DSAP coexisting with Ppt harbored a novel MVK gene mutation also present in the patient’s family.

Efficient Production of δ-Guaiene, an Aroma Sesquiterpene Compound Accumulated in Agarwood, by Mevalonate Pathway-Engineered Escherichia coli Cells

Mevalonate pathway for isoprenoid biosynthesis was constructed in Escherichia coli cells by the transformation with a gene cluster isolated from Streptomyces sp., and farnesyl diphosphate synthase and δ-guaiene synthase genes were coexpressed in this strain. This transformant was capable of liberating an appreciable amount of δ-guaiene, an aroma sesquiterpene compound accumulated in agarwood, and its concentration was elevated to more than 30 μg/ml culture by the incubation with mevalonolactone as an isoprene precursor in a nutrient-enriched Terrific broth. Coexpression of type 1 isopentenyl diphosphate isomerase plus acetoacetyl-CoA ligase genes also enhanced δ-guaiene production, and the concentration of the compound was approximately 38 - 42 μg/ml culture in the presence of mevalonolactone or lithium acetoacetate. These results clearly indicate that mevalonate pathway-engineered E. coli cells showed an appreciable δ-guaiene producing activity in the en- riched medium in the presence of appropriate isoprene precursors.

The mevalonate pathway promotes the metastasis of osteosarcoma by regulating YAP 1 activity via RhoA

Osteosarcoma is the most common malignant bone tumour,and the metastasis of osteosarcoma is an important cause of death.Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new target for tumour therapy.In this study,we investigated the effect of mevalonate signalling on osteosarcoma metastasis and its molecular mechanism.First,we found that the key rate-limiting enzyme of mevalonate signalling,3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR),was highly expressed in osteosarcoma cells,and inhibition of HMGCR with simvastatin significantly inhibited the motility of 143B cells.Next,we found that YAP1 activity was significantly upregulated in osteosarcoma cells and that YAP1 knockdown inhibited the motility of 143B cells.We also found that the mevalonate pathway regulated the motility of 143B cells by modulating YAP1 phosphorylation and cellular localization.Moreover,we found that the activity of YAP1 was regulated by the mevalonate pathway by modulating the cell membrane localization of RhoA.Finally,we demonstrated that inhibition of the mevalonate pathway notably reduced the lung metastasis of 143B cells,as reflected by the decreased incidence and number of metastatic nodules and the increased survival time of the nude mice.Taken together,our findings suggest that the mevalonate pathway can promote the metastasis of osteosarcoma by activating YAP1 via RhoA.Inhibition of the mevalonate pathway may be a promising therapeutic strategy for osteosarcoma metastasis.

Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA

Mevalonate metabolism plays an important role in regulating tumor growth and progression;however,its role in immune evasion and immune checkpoint modulation remains unclear.Here,we found that non-small cell lung cancer(NSCLC)patients with higher plasma mevalonate response better to antiPD-(L)1 therapy,as indicated by prolonged progression-free survival and overall survival.Plasma mevalonate levels were positively correlated with programmed death ligand-1(PD-L1)expression in tumor tissues.In NSCLC cell lines and patient-derived cells,supplementation of mevalonate significantly upregulated the expression of PD-L1,whereas deprivation of mevalonate reduced PD-L1 expression.Mevalonate increased CD274 mRNA level but did not affect CD274 transcription.Further,we confirmed that mevalonate improved CD274 mRNA stability.Mevalonate promoted the affinity of the AU-rich elementbinding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA.By in vivo study,we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1,increased the infiltration of CD8^(+)T cells,and improved cytotoxic function of T cells.Collectively,our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody,and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

Response of the Ginseng C_(2)H_(2)-Type Zinc Finger Protein Family PgZFPs Gene to Methyl Jasmonate Regulation

The main active components of ginseng are ginsenosides,which play significant roles in treating cardiovascular diseases,cancer,and providing antioxidant effects.Ginsenosides are primarily synthesized through the mevalo-nate pathway and the methylerythritol phosphate pathway.Many key enzyme genes involved in this biosynthetic process have been cloned and validated,yet the regulatory functions of transcription factors remain unclear.The C_(2)H_(2)-type zincfinger protein family,one of the largest families of transcription factors,is crucial in plant growth and development,response to biotic and abiotic stresses,and regulation of secondary metabolism.This study,based on the ginseng transcriptome database from Jilin,conducted a correlation analysis between the expression levels of PgZFPs genes in the Jilin ginseng C_(2)H_(2)-type zincfinger protein family and ginsenoside content,a gen-ome-wide association study of PgZFPs,and co-expression analysis of PgZFPs with validated key enzyme genes.Ultimately,five candidate genes involved in ginsenoside biosynthesis were identified.The involvement of PgZFP27 and PgZFP-59-02 genes from the PgZFPs family in the biosynthesis of ginsenosides was validated through in vitro methyl jasmonate(MeJA)induction experiments.This result provides new genetic resources for the biosynthesis of ginsenosides.

Statins in risk-reduction and treatment of cancer

Statins,which are competitive inhibitors of 3-hydroxy-3-methyl-glutarylcoenzyme A reductase,reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications.In addition to this main activity,statins show pleiotropic effects such as antioxidant,anti-inflammatory and antiproliferative properties,with applications in many pathologies.Based on their antiproliferative properties,in vitro and in vivo studies have investigated their effects on various types of cancer(i.e.,breast cancer,prostate cancer,colorectal cancer,ovarian cancer,lung cancer)with different genetic and molecular characteristics.Many positive results were obtained,but they were highly dependent on the physiochemical properties of the statins,their dose and treatment period.Combined therapies of statins and cytotoxic drugs have also been tested,and synergistic or additive effects were observed.Moreover,observational studies performed on patients who used statins for different pathologies,revealed that statins reduced the risk of developing various cancers,and improved the outcomes for cancer patients.Currently,there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk.All these results are the foundation of new treatment directions in cancer therapy.

The Effect of Methylation Modification of MDD on the Expression of Key Genes in the Process of Saponin Synthesis in Eleutherococcus senticosus

Mevalonate pyrophosphate decarboxylase is a kind of key enzyme in the terpenoid synthesis pathway in Eleutherococcus senticosus.The results of bisulfite sequencing showed that there were three kinds of samples with a low(0.68%),medium(0.72%)and high(0.79%)DNA methylation ratio in the promoter of MDD in E.senticosus,respectively.The transcriptome sequencing results showed that the expression of MDD in E.senticosus was significantly up-regulated in the types with low DNA methylation ratios of MDD(P<0.05).There was a significant negative correlation between the saponin content in E.senticosus and the DNA methylation ratio of MDD promoter(P<0.05).The screening results of differentially expressed transcription factors among the three groups with different DNA methylation ratio showed that a total of 4 transcription factors could bind to 6 CpG sites.Protein-protein interaction analysis showed that E.senticosus MDD could interacted with other key enzymes in the process of terpenoid synthesis.In addition,it was found that the DNA methylation of MDD promoter was mainly regulated by DNA methyltransferase.These results demonstrated that under the action of DNA methyltransferase,the changes of DNA methylation of MDD promoter could regulate its own expression level by affecting the combination ability of transcription factors,and then affected the expression of other genes in terpenoid synthesis pathway.The synthesis and accumulation of saponins in E.senticosus was also changed.

Statin as a therapeutic agent in gastroenterological cancer

Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase,the rate-limiting enzyme of the mevalonate pathway,and are widely used as an effective and safe approach handle hypercholesterolemia.The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression.Multiple studies have indicated that statins improve patient prognosis in various carcinomas.Basic research on the mechanisms underlying the antitumor effects of statins is underway.The development of new anti-cancer drugs is progressing,but increasing medical costs from drug development have become a major obstacle.Readily available,inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment.Identifying the cancer patients that may benefit from statins is key to improved patient treatment.This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.

Towards Application of Bioactive Natural Products Containing Isoprenoids for the Regulation of HMG-CoA Reductase—A Review

Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynthetic origins, natural products can be divided into three major groups: the isoprenoids, alkaloids, and phenolic compounds. Isoprenoids are structurally the most diverse group of secondary natural metabolites with different roles in the growth, development, and reproduction of a diverse range of prokaryotic and eukaryotes cells. Mevalonate and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways are known to be responsible for biosynthesis of numerous isoprenoids. HMG-CoA reductase is a rate-determining enzyme in mevalonate pathway, producing intermediates such as farnesyl and geranylgeranyl pyrophosphates, which lead to by-products such as cholesterol. Earlier studies have demonstrated that the inhibition of HMG-CoA reductase is one of the most effective approaches for treating hypercholesterolemia and eventually cardiovascular disease (CVD). Statins are HMG-CoA reductase inhibitors and the most prescribed group of drugs worldwide in treating hypercholesterolemia;however the application of this group of drugs may be expensive and has side effects including rashes and gastrointestinal symptoms. For these reasons, there is an important need to examine the viability of natural products as an alternative to statin treatment. This article is a review of different aforementioned areas with a focus on isoprenoids that can be used for the regulation of HMG-CoA reductase.

Review of the Mechanisms of Action of the Statins and Their Pleiotropic Effects in the Treatment of Hypercholesterolemia and Atherosclerosis

Statins are lipid-lowering agents widely used in the treatment of hypercholesterolemia and atherosclerosis. They act by inhibiting of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme responsible for the conversion of HMG-CoA to mevalonate in cholesterol biosynthesis. Due to their ability to reduce low-density lipoproteins (LDL) levels more than other cholesterol-lowering drugs, they have become the drugs most often prescribed in the treatment of atherosclerosis.

Zoledronate-loaded aluminum salt nanovaccines amplify cellular immune response by enhancing cross-presentation

Being a Th2 stimulator,classic aluminum salt-based adjuvants only stimulate weak cellular immune responses that are required for vaccination against intracellular viruses or cancerous cells.As a thirdgeneration bisphosphonate,zoledronate(ZOL)can enhance antigen crosspresentation by inhibiting key enzymes of the mevalonate pathway.Here,we developed the subunit antigen ovalbumin(OVA)and ZOL co-loaded aluminum hydroxide nanoparticles(APN-OVA-ZOL)and investigated their capacity for inducing cellular immune responses against the antigen.Our results showed that the developed nanovaccines could successfully encapsulate OVA and ZOL,and enabled efficient lymph node delivery.Benefited by the mevalonate pathway inhibition effect of ZOL,APN-OVA-ZOL significantly promoted crosspresentation.As a result,APN-OVA-ZOL induced robust cellular immunity,including the activation of T and B cells.In a EG7-OVA tumor-bearing murine model,APN-OVA-ZOL significantly inhibited the tumor growth and prolonged mice survival.This work provided a strong empirical foundation indicating that zoledronate-loaded aluminum salt nanovaccines had a strong potency for cancer immunotherapy.

Engineering metabolic pathways in Amycolatopsis japonicum for the optimization of the precursor supply for heterologous brasilicardin congeners production

The isoprenoid brasilicardin A is a promising immunosuppressant compound with a unique mode of action,high potency and reduced toxicity compared to today's standard drugs.However,production of brasilicardin has been hampered since the producer strain Nocardia terpenica IFM0406 synthesizes brasilicardin in only low amounts and is a biosafety level 2 organism.Previously,we were able to heterologously express the brasilicardin gene cluster in the nocardioform actinomycete Amycolatopsis japonicum.Four brasilicardin congeners,intermediates of the BraA biosynthesis,were produced.Since chemical synthesis of the brasilicardin core structure has remained elusive we intended to produce high amounts of the brasilicardin backbone for semi synthesis and derivatization.Therefore,we used a metabolic engineering approach to increase heterologous production of brasilicardin in A.japonicum.Simultaneous heterologous expression of genes encoding the MVA pathway and expression of diterpenoid specific prenyltransferases were used to increase the provision of the isoprenoid precursor isopentenyl diphosphate(IPP)and to channel the precursor into the direction of diterpenoid biosynthesis.Both approaches contributed to an elevated heterologous production of the brasilicardin backbone,which can now be used as a starting point for semi synthesis of new brasilicardin congeners with better properties.

The role of cholesterol metabolism in leukemia

Leukemia is a common hematological malignancy with overall poor prognosis.Novel therapies are needed to improve the outcome of leukemia patients.Cholesterol metabolism reprogramming is a featured alteration in leukemia.Many metabolic-related genes and metabolites are essential to the progress and drug resistance of leukemia.Exploring potential therapeutical targets related to cholesterol homeostasis is a promising area.This review summarized the functions of cholesterol and its derived intermediate metabolites,and also discussed potential agents targeting this metabolic vulnerability in leukemia.

Statins markedly potentiate aminopeptidase inhibitor activity against(drug-resistant)human acute myeloid leukemia cells

Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) cells.Methods: U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and in vitro non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR activation.Results: A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents;and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation;this was experimentally confirmed by impaired Rheb prenylation by simvastatin.Conclusion: These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.

Old and new damage‐associated molecular patterns (DAMPs) in autoimmune diseases

All organisms living in complex environments have evolved effective mechanisms of dynamic responses to extracellular stimuli.The immune system activates when damaged or injured cells release damage‐associated molecular patterns(DAMPs).In addition to well‐characterized DAMPs such as high‐mobility group box 1 and adenosine triphosphate,studies on new classes of DAMPs have emerged.Here,we review recent reports of a new class of isoprenoid‐derived DAMPs,including farnesyl pyrophosphate and geranylgeranyl pyrophosphate,both of which are pivotal metabolic inter-mediates of the mevalonate pathway.We also explore the roles of old and new DAMPs in autoimmune diseases that result from dysregulated inflammation.The findings highlight that understanding the functional mechanisms of DAMPs is important to enrich the DAMP family and decipher their immunoregulatory mechanisms to provide new therapeutics for the prevention and treatment of autoimmune diseases.