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Phytomedicine : International Journal... Jul 2023Macrophages M1 polarization involved in the process of renal inflammatory injury, is a well-established hallmark of chronic kidney disease (CKD). Paeoniflorin (PF), a...
BACKGROUND
Macrophages M1 polarization involved in the process of renal inflammatory injury, is a well-established hallmark of chronic kidney disease (CKD). Paeoniflorin (PF), a water-soluble monoterpene glycoside extracted from Paeonia lactiflora, revealed renal anti-inflammatory activities in our previous study. However, the potential molecular mechanism of PF on CKD remains unknown.
PURPOSE
The present study aims to investigate the regulation of PF on macrophage polarization in CKD.
METHODS
A CKD model was established by cationic bovine serum albumin and a murine macrophage cell line RAW264.7 induced with lipopolysaccharide (LPS) were used to clarify the underlying mechanisms of PF in CKD.
RESULTS
Results showed that PF exhibited favorable protective effects on CKD model mice by promoting renal function, ameliorating renal pathological injury and podocyte damage. Furthermore, PF inhibited the infiltration of M1 macrophage marker CD68 and iNOS in kidney tissue, but increased the proportion of M2 macrophage marker CD206. In RAW264.7 cells stimulated with LPS, the levels of cytokines including IL-6, IL-1β, TNF-α, MCP-1 were lessened under PF treatment, while the levels of Arg1, Fizz1, IL-10 and Ym-1 were augmented. These results indicated that PF promoted macrophage polarization from M1 to M2 in vivo and in vitro. More importantly, PF repaired the damaged mitochondria through increasing mitochondrial membrane potential and reducing ROS accumulation. The mitophagy-related proteins PINK1, Parkin, Bnip3, P62 and LC3 were up-regulated by PF, accompanied by the incremental expressions of Krüppel-like transcription factor 4 (KLF4). Moreover, the promotion of mitophagy and inhibition of M1 macrophage polarization owing to PF were reversed by mitophagy inhibitor Mdivi-1 or silencing KLF4.
CONCLUSION
Overall, PF suppressed renal inflammation by promoting macrophage polarization from M1 to M2 and inducing mitophagy via regulating KLF4. It is expected to provide a new strategy for exploring the effects of PF in treating CKD.
Topics: Mice; Animals; Lipopolysaccharides; Mitophagy; Macrophages; Nephritis; Kidney; Monoterpenes; Renal Insufficiency, Chronic; Inflammation
PubMed: 37247587
DOI: 10.1016/j.phymed.2023.154901 -
Medicinal Research Reviews Jul 2023Secoiridoids are natural products of cyclopentane monoterpene derivatives that are formed by splitting the rings of cyclomethene oxime compounds at C-7 and C-8, and only... (Review)
Review
Secoiridoids are natural products of cyclopentane monoterpene derivatives that are formed by splitting the rings of cyclomethene oxime compounds at C-7 and C-8, and only account for a small part of cyclic ether terpenoids. Because of the chemically active hemiacetal structure in their common basic skeleton, secoiridoids have a wide range of biological activities, such as neuroprotective, anti-inflammatory, antidiabetic, hepatoprotective, and antinociceptive activities. Phenolic secoiridoids can also act against multiple molecular targets involved in human tumorigenesis, making them potentially valuable precursors for antitumor drug development. This review provides a detailed update, covering relevant discoveries from January 2011 to December 2020, about the occurrence, structural diversity, bioactivities, and synthesis of naturally occurring secoiridoids. We aimed to resolve the lack of extensive, specific, and thorough review of secoiridoids, as well as open new areas for pharmacological investigation and better drugs based on these compounds.
Topics: Humans; Iridoids; Phenols; Antineoplastic Agents; Anti-Inflammatory Agents
PubMed: 36899490
DOI: 10.1002/med.21949 -
The Science of the Total Environment Dec 2023Cypermethrin is a pyrethroid insecticide that is used to control insects and protect crops. However, pesticide residues and their possible toxicity to non-target animals...
Cypermethrin is a pyrethroid insecticide that is used to control insects and protect crops. However, pesticide residues and their possible toxicity to non-target animals such as mammals are concerning. Although cypermethrin reduces testosterone levels, the molecular mechanisms involved, particularly those regarding endoplasmic reticulum (ER) stress and autophagy regulation, have not yet been fully elucidated. In this study, we demonstrated testicular toxicity of cypermethrin in mouse Leydig (TM3) and Sertoli (TM4) cells. Cypermethrin suppresses TM3 and TM4 cell proliferation and induces apoptosis. Moreover, it interrupted calcium homeostasis in intracellular organelles and dissipated mitochondrial membrane polarization in mouse testicular cells. Moreover, we verified the accumulation of Sqstm1/p62 protein in the mitochondria of cypermethrin-treated TM3 and TM4 cells. Furthermore, we confirmed that cypermethrin activated autophagy and the ER stress pathway in a time-dependent manner in both cell types. Finally, we determined that cypermethrin downregulated testicular function-related genes, steroidogenesis, and spermatogenesis in mouse testis cells. Therefore, we conclude that cypermethrin regulates autophagy and ER stress, leading to testicular dysfunction.
Topics: Male; Animals; Mice; Testis; Pyrethrins; Endoplasmic Reticulum Stress; Autophagy; Apoptosis; Mammals
PubMed: 37567297
DOI: 10.1016/j.scitotenv.2023.166167 -
Molecules (Basel, Switzerland) Oct 2023Plant products have been employed in medicine for centuries. As the world becomes more health-conscious, there is a growing interest in natural and minimally processed... (Review)
Review
Plant products have been employed in medicine for centuries. As the world becomes more health-conscious, there is a growing interest in natural and minimally processed products for oral health care. This has led to an increase in research into the bioactive compounds found in plant products, particularly monoterpenes. Monoterpenes are known to have beneficial biological properties, but the specific mechanisms by which they exert their effects are not yet fully understood. Despite this, some monoterpenes are already being used in oral health care. For example, thymol, which has antibacterial properties, is an ingredient in varnish used for caries prevention. In addition to this, monoterpenes have also demonstrated antifungal, antiviral, and anti-inflammatory properties, making them versatile for various applications. As research continues, there is potential for even more discoveries regarding the benefits of monoterpenes in oral health care. This narrative literature review gives an overview of the biological properties and current and potential applications of selected monoterpenes and their derivatives in oral health care. These compounds demonstrate promising potential for future medical development, and their applications in future research are expected to expand.
Topics: Monoterpenes; Oils, Volatile; Thymol; Antifungal Agents; Delivery of Health Care
PubMed: 37894657
DOI: 10.3390/molecules28207178 -
Arthropod Structure & Development Mar 2024The large abundance of termites is partially achieved by their defensive abilities. Stylotermitidae represented by a single extant genus, Stylotermes, is a member of a...
The large abundance of termites is partially achieved by their defensive abilities. Stylotermitidae represented by a single extant genus, Stylotermes, is a member of a termite group Neoisoptera that encompasses 83% of termite species and 94% of termite genera and is characterized by the presence of the frontal gland. Within Neoisoptera, Stylotermitidae represents a species-poor sister lineage of all other groups. We studied the structure of the frontal, labral and labial glands in soldiers and workers of Stylotermes faveolus, and the composition of the frontal gland secretion in S. faveolus and Stylotermes halumicus. We show that the frontal gland is a small active secretory organ in soldiers and workers. It produces a cocktail of monoterpenes in soldiers, and some of these monoterpenes and unidentified proteins in workers. The labral and labial glands are developed similarly to other termite species and contribute to defensive activities (labral in both castes, labial in soldiers) or to the production of digestive enzymes (labial in workers). Our results support the importance of the frontal gland in the evolution of Neoisoptera. Toxic, irritating and detectable monoterpenes play defensive and pheromonal functions and are likely critical novelties contributing to the ecological success of these termites.
Topics: Animals; Isoptera; Cockroaches; Pheromones; Monoterpenes
PubMed: 38520874
DOI: 10.1016/j.asd.2024.101346 -
Autophagy Dec 2023Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide...
Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide (TMZ) represent the standard of care, but, in most cases, the tumor develops resistance to further treatment and the patients succumb to disease. Therefore, there is a great need for the development of well-tolerated, effective drugs that specifically target chemoresistant gliomas. NEO214 was generated by covalently conjugating rolipram, a PDE4 (phosphodiesterase 4) inhibitor, to perillyl alcohol, a naturally occurring monoterpene related to limonene. Our previous studies in preclinical models showed that NEO214 harbors anticancer activity, is able to cross the blood-brain barrier (BBB), and is remarkably well tolerated. In the present study, we investigated its mechanism of action and discovered inhibition of macroautophagy/autophagy as a key component of its anticancer effect in glioblastoma cells. We show that NEO214 prevents autophagy-lysosome fusion, thereby blocking autophagic flux and triggering glioma cell death. This process involves activation of MTOR (mechanistic target of rapamycin kinase) activity, which leads to cytoplasmic accumulation of TFEB (transcription factor EB), a critical regulator of genes involved in the autophagy-lysosomal pathway, and consequently reduced expression of autophagy-lysosome genes. When combined with chloroquine and TMZ, the anticancer impact of NEO214 is further potentiated and unfolds against TMZ-resistant cells as well. Taken together, our findings characterize NEO214 as a novel autophagy inhibitor that could become useful for overcoming chemoresistance in glioblastoma. ATG: autophagy related; BAFA1: bafilomycin A; BBB: blood brain barrier; CQ: chloroquine; GBM: glioblastoma; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGMT: O-6-methylguanine-DNA methyltransferase; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; POH: perillyl alcohol; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TMZ: temozolomide.
Topics: Humans; Glioblastoma; Temozolomide; Autophagy; Rolipram; Cell Death; Monoterpenes; Glioma; TOR Serine-Threonine Kinases; Sirolimus; Chloroquine; Lysosomes
PubMed: 37545052
DOI: 10.1080/15548627.2023.2242696 -
International Journal of Molecular... Nov 2023Monoterpene thiols are one of the classes of natural flavors that impart the smell of citrus fruits, grape must and wine, black currants, and guava and are used as... (Review)
Review
Monoterpene thiols are one of the classes of natural flavors that impart the smell of citrus fruits, grape must and wine, black currants, and guava and are used as flavoring agents in the food and perfume industries. Synthetic monoterpene thiols have found an application in asymmetric synthesis as chiral auxiliaries, derivatizing agents, and ligands for metal complex catalysis and organocatalysts. Since monoterpenes and monoterpenoids are a renewable source, there are emerging trends to use monoterpene thiols as monomers for producing new types of green polymers. Monoterpene thioderivatives are also known to possess antioxidant, anticoagulant, antifungal, and antibacterial activity. The current review covers methods for the synthesis of acyclic, mono-, and bicyclic monoterpene thiols, as well as some investigations related to their usage for the preparation of the compounds with antimicrobial properties.
Topics: Monoterpenes; Sulfhydryl Compounds; Wine; Vitis
PubMed: 37958865
DOI: 10.3390/ijms242115884 -
Acta Pharmacologica Sinica Dec 2023Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, which has yet no curable medication. Neuroinflammation and mitochondrial dysfunction are...
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, which has yet no curable medication. Neuroinflammation and mitochondrial dysfunction are tightly linked to DPN pathology. G-protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells, but also in spinal dorsal horn and dorsal root ganglion (DRG) neurons, regulating neuropathic pain. We previously have reported that vincamine (Vin), a monoterpenoid indole alkaloid extracted from Madagascar periwinkle, is a GPR40 agonist. In this study, we evaluated the therapeutic potential of Vin in ameliorating the DPN-like pathology in diabetic mice. Both STZ-induced type 1 (T1DM) and db/db type 2 diabetic (T2DM) mice were used to establish late-stage DPN model (DPN mice), which were administered Vin (30 mg·kg·d, i.p.) for 4 weeks. We showed that Vin administration did not lower blood glucose levels, but significantly ameliorated neurological dysfunctions in DPN mice. Vin administration improved the blood flow velocities and blood perfusion areas of foot pads and sciatic nerve tissues in DPN mice. We demonstrated that Vin administration protected against sciatic nerve myelin sheath injury and ameliorated foot skin intraepidermal nerve fiber (IENF) density impairment in DPN mice. Moreover, Vin suppressed NLRP3 inflammasome activation through either β-Arrestin2 or β-Arrestin2/IκBα/NF-κB signaling, improved mitochondrial dysfunction through CaMKKβ/AMPK/SIRT1/PGC-1α signaling and alleviated oxidative stress through Nrf2 signaling in the sciatic nerve tissues of DPN mice and LPS/ATP-treated RSC96 cells. All the above-mentioned beneficial effects of Vin were abolished by GPR40-specific knockdown in dorsal root ganglia and sciatic nerve tissues. Together, these results support that pharmacological activation of GPR40 as a promising therapeutic strategy for DPN and highlight the potential of Vin in the treatment of this disease.
Topics: Animals; Mice; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Indole Alkaloids; Monoterpenes; Receptors, G-Protein-Coupled; Sciatic Nerve; Signal Transduction; Vincamine
PubMed: 37580494
DOI: 10.1038/s41401-023-01135-1 -
Biotechnology Advances 2023Terpenoids are a large class of plant-derived compounds, that constitute the main components of essential oils and are widely used as natural flavors and fragrances. The... (Review)
Review
Terpenoids are a large class of plant-derived compounds, that constitute the main components of essential oils and are widely used as natural flavors and fragrances. The biosynthesis approach presents a promising alternative route in terpenoid production compared to plant extraction or chemical synthesis. In the past decade, the production of terpenoids using biotechnology has attracted broad attention from both academia and the industry. With the growing market of flavor and fragrance, the production of terpenoids directed by synthetic biology shows great potential in promoting future market prospects. Here, we reviewed the latest advances in terpenoid biosynthesis. The engineering strategies for biosynthetic terpenoids were systematically summarized from the enzyme, metabolic, and cellular dimensions. Additionally, we analyzed the key challenges from laboratory production to scalable production, such as key enzyme improvement, terpenoid toxicity, and volatility loss. To provide comprehensive technical guidance, we collected milestone examples of biosynthetic mono- and sesquiterpenoids, compared the current application status of chemical synthesis and biosynthesis in terpenoid production, and discussed the cost drivers based on the data of techno-economic assessment. It is expected to provide critical insights into developing translational research of terpenoid biomanufacturing.
Topics: Monoterpenes; Odorants; Metabolic Engineering; Sesquiterpenes; Terpenes; Plants
PubMed: 37037288
DOI: 10.1016/j.biotechadv.2023.108151 -
Nature Chemical Biology Dec 2023Monoterpenoid indole alkaloids (MIAs) represent a large class of plant natural products with marketed pharmaceutical activities against a wide range of indications,...
Monoterpenoid indole alkaloids (MIAs) represent a large class of plant natural products with marketed pharmaceutical activities against a wide range of indications, including cancer, malaria and hypertension. Halogenated MIAs have shown improved pharmaceutical properties; however, synthesis of new-to-nature halogenated MIAs remains a challenge. Here we demonstrate a platform for de novo biosynthesis of two MIAs, serpentine and alstonine, in baker's yeast Saccharomyces cerevisiae and deploy it to systematically explore the biocatalytic potential of refactored MIA pathways for the production of halogenated MIAs. From this, we demonstrate conversion of individual haloindole derivatives to a total of 19 different new-to-nature haloserpentine and haloalstonine analogs. Furthermore, by process optimization and heterologous expression of a modified halogenase in the microbial MIA platform, we document de novo halogenation and biosynthesis of chloroalstonine. Together, this study highlights a microbial platform for enzymatic exploration and production of complex natural and new-to-nature MIAs with therapeutic potential.
Topics: Saccharomyces cerevisiae; Monoterpenes; Indole Alkaloids; Plants; Pharmaceutical Preparations; Catharanthus; Plant Proteins
PubMed: 37932529
DOI: 10.1038/s41589-023-01430-2