Explore the vast range of titles available.

Peanut (Arachis hypogaea L.) is a globally staple oilseed crop, extensively cultivated in tropical and subtropical regions. Due to its substantial oil (approximately 46%–58%) and protein (around 22%–32%) content, the peanut plays a pivotal role in addressing malnutrition and ensuring food security in many regions. The fatty acid profiles of vegetable oil and foods have recently garnered increased attention due to the potential impact on human health. Very long chain fatty acids (VLCFAs) are defined as fatty acids with a carbon chain length exceeding 18 atoms (Guyomarc'h et al., 2021). Peanut kernels contain various VLCFAs, such as arachidic acid (C20:0), eicosenoic acid (C20:1), behenic acid (C22:0) and lignoceric acid (C24:0), but most of them are saturated fatty acids (SFAs). It is well understood that high levels of very long chain saturated fatty acid (VLCSFA) are associated with prevalence of atherosclerosis and cardiovascular disease (Bloise et al., 2022). Therefore, reducing the VLCFA content in peanuts has gained more importance realizing its positive impact for improving the nutritional quality and health value.

3-ketoacyl-CoA synthases (KCSs), as components of a fatty acid elongase (FAE) complex, play key roles in determining the chain length of very-long-chain fatty acids (VLCFAs). KCS6, taking a predominate role during the elongation from C26 to C28, is well known to play an important role in wax synthesis. KCS5 is one paralog of KCS6 and its role in wax synthesis remains unknown. Wax phenotype analysis showed that in kcs5 mutants, the total amounts of wax components derived from carbon 32 (C32) and C34 were apparently decreased in leaves, and those of C26 to C32 derivatives were obviously decreased in flowers. Heterologous yeast expression analysis showed that KCS5 alone displayed specificity towards C24 to C28 acids, and its coordination with CER2 and CER26 catalyzed the elongation of acids exceeding C28, especially displaying higher activity towards C28 acids than KCS6. BiLC experiments identified that KCS5 physically interacts with CER2 and CER26. Wax phenotype analysis of different organs in kcs5 and kcs6 single or double mutants showed that KCS6 mutation causes greater effects on the wax synthesis than KCS5 mutation in the tested organs, and simultaneous repression of both protein activities caused additive effects, suggesting that during the wax biosynthesis process, KCS5 and KCS6 play redundant roles, among which KCS6 plays a major role. In addition, simultaneous mutations of two genes nearly block drought-induced wax production, indicating that the reactions catalyzed by KCS5 and KCS6 play a critical role in the wax biosynthesis in response to drought.

Cequa®, a unique and first-in-class preservative free cyclosporine-A (CsA) nanomicellar topical formulation was recently approved by US FDA for treatment of dry eye disease or keratoconjuntivitis sicca (KCS). Being highly hydrophobic, CsA is currently available as an oil based emulsion, which has its own shortcomings. Developing an aqueous and clear formulation of CsA is imperative yet a challenging need in the quest for a safe and better drug product. In this regard, a novel, clear, aqueous nanomicellar solution of CsA was developed which has the potential to deliver therapeutic concentrations of CsA with minimal discomfort to patients. Highly promising pre-clinical results of Cequa® (OTX-101), has led to its advancement to the clinical trials. Phase III clinical trials have demonstrated that OTX-101 is highly effective, safe, and has a rapid onset of action in treating KCS. This review presents a comprehensive insight on formulation development, preclinical and clinical pharmacokinetic results of Cequa®. Additionally, the translational development of Cequa® from the laboratory benchtop to patient bedside has been discussed.

Synovial sarcoma leads to pathological changes in multiple organs. To investigate the mechanism by which synovial sarcoma induces fatty liver through extracellular vesicles (EVs), the synovial sarcoma SW-982 cells were orthotopically implanted, or SW-982 derived EVs were extracted and used to \"educate\" nude mice. Liver tissues were then subjected to H&E and Oil-Red O (ORO) staining, and qPCR analysis. EVs were characterized using TEM and Nanosight. The bio-distribution of EVs was verified using the fluorescent dye Burgundy staining, followed by Odyssey imaging. Immunofluorescence (IF) and flow cytometry were used to confirm cellular uptake of EVs. Rab27a knockdown (KD) efficiency was validated by Western blot, and lipid droplet deposition in the liver from mice bearing with SW-982-Rab27a-KD cells was observed by staining with ORO. After three weeks of orthotopic implantation of SW-982 cells in nude mice, qPCR and H&E showed no tumor metastasis in liver tissues, while ORO staining revealed lipid deposition in the liver, and EVs diameters were confirmed by Nanosight and TEM to be approximately 141 nm in size. , EVs were taken up by liver Kupffer cells (KCs). After \"educating\" nude mice with EVs, lipid deposition in the liver was observed. In rescue experiments, Rab27a knockdown reduced EV secretion from the tumor, and KC inactivation led to decreased lipid deposition in the liver. It is shown that synovial sarcoma EVs mediate fatty liver through Kupffer cells.

Liver fibrosis is a highly conserved wound healing response to liver injury, characterized by excessive deposition of extracellular matrix (ECM) in the liver which might lead to loss of normal functions. In most cases, many types of insult could damage hepatic parenchymal cells like hepatocytes and/or cholangiocytes, and persistent injury might lead to initiation of fibrosis. This process is accompanied by amplified inflammatory responses, with immune cells especially macrophages recruited to the site of injury and activated, in order to orchestrate the process of wound healing and tissue repair. In the liver, both resident macrophages and recruited macrophages could activate interstitial cells which are responsible for ECM synthesis by producing a variety of cytokines and chemokines, modulate local microenvironment, and participate in the regulation of fibrosis. In this review, we will focus on the main pathological characteristics of liver fibrosis, as well as the heterogeneity on origin, polarization and functions of hepatic macrophages in the setting of liver fibrosis and their underlying mechanisms, which opens new perspectives for the treatment of liver fibrosis.

Very-long-chain fatty acids (VLCFA) are precursors for various lipids playing important physiological and structural roles in plants. Throughout plant tissues, VLCFA are present in multiple lipid classes essential for membrane homeostasis, and also stored in triacylglycerols. VLCFA and their derivatives are also highly abundant in lipid barriers, such as cuticular waxes in aerial epidermal cells and suberin monomers in roots. VLCFA are produced by the fatty acid elongase (FAE), which is an integral endoplasmic reticulum membrane multi-enzymatic complex consisting of four core enzymes. The 3-ketoacyl-CoA synthase (KCS) catalyzes the first reaction of the elongation and determines the chain-length substrate specificity of each elongation cycle, whereas the other three enzymes have broad substrate specificities and are shared by all FAE complexes. Consistent with the co-existence of multiple FAE complexes, performing sequential and/or parallel reactions to produce the broad chain-length-range of VLCFA found in plants, twenty-one KCS genes have been identified in the genome of Arabidopsis thaliana . Using CRISPR-Cas9 technology, we established an expression platform to reconstitute the different Arabidopsis FAE complexes in yeast. The VLCFA produced in these yeast strains were analyzed in detail to characterize the substrate specificity of all KCS candidates. Additionally, Arabidopsis candidate proteins were transiently expressed in Nicotiana benthamiana leaves to explore their activity and localization in planta . This work sheds light on the genetic and biochemical redundancy of fatty acid elongation in plants.

Cuticular wax, cutin and suberin polyesters covering the surface of some fleshy fruit are tightly associated with skin color and appearance. β-Ketoacyl-CoA synthase (KCS) is a rate-limiting enzyme participating in the synthesis of very-long-chain fatty acids (VLCFAs), the essential precursors of cuticular waxes and aliphatic monomers of suberin. However, information on the KCS gene family in pear genome and the specific members involved in pear fruit skin formation remain unclear. In the present study, we performed an investigation of the composition and amount of cuticular waxes, cutin and aliphatic suberin in skins of four sand pear varieties with distinct colors (russet, semi-russet, and green) and demonstrated that the metabolic shifts of cuticular waxes and suberin leading to the significant differences of sand pear skin color. A genome-wide identification of KCS genes from the pear genome was conducted and 35 KCS coding genes were characterized and analyzed. Expression profile analysis revealed that the KCS genes had diverse expression patterns among different pear skins and the transcript abundance of PbrKCS15, PbrKCS19, PbrKCS24, and PbrKCS28 were consistent with the accumulation of cuticular waxes and suberin in fruit skin respectively. Subcellular localization analysis demonstrated that PbrKCS15, PbrKCS19, PbrKCS24 and PbrKCS28 located on the endoplasmic reticulum (ER). Further, transient over-expression of PbrKCS15, PbrKCS19, and PbrKCS24 in pear fruit skins significantly increased cuticular wax accumulation, whereas PbrKCS28 notably induced suberin deposition. In conclusion, pear fruit skin color and appearance are controlled in a coordinated way by the deposition of the cuticular waxes and suberin. PbrKCS15, PbrKCS19, and PbrKCS24 are involved in cuticular wax biosynthesis, and PbrKCS28 is involved in suberin biosynthesis, which play essential roles in pear fruit skin formation. Moreover, this work provides a foundation for further understanding the functions of KCS genes in pear.Key messageThirty-five KCS genes were identified and analyzed in pear and functional characterization of PbrKCS15, PbrKCS19, PbrKCS24, and PbrKCS28 in cuticular wax and suberin synthesis and pear fruit skin formation.

Patients with metastatic colorectal cancer often have poor outcomes, primarily due to hepatic metastasis. Colorectal cancer (CRC) cells have the ability to secrete cytokines and other molecules that can remodel the tumor microenvironment, facilitating the spread of cancer to the liver. Kupffer cells (KCs), which are macrophages in the liver, can be polarized to M2 type, thereby promoting the expression of adhesion molecules that aid in tumor metastasis. Our research has shown that huachanshu (with bufalin as the main active monomer) can effectively inhibit CRC metastasis. However, the underlying mechanism still needs to be thoroughly investigated. We have observed that highly metastatic CRC cells have a greater ability to induce M2-type polarization of Kupffer cells, leading to enhanced metastasis. Interestingly, we have found that inhibiting the expression of IL-6, which is highly expressed in the serum, can reverse this phenomenon. Notably, bufalin has been shown to attenuate the M2-type polarization of Kupffer cells induced by highly metastatic Colorectal cancer (mCRC) cells and down-regulate IL-6 expression, ultimately inhibiting tumor metastasis. In this project, our aim is to study how high mCRC cells induce M2-type polarization and how bufalin, via the SRC-3/IL-6 pathway, can inhibit CRC metastasis. This research will provide a theoretical foundation for understanding the anti-CRC effect of bufalin.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic–lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.