Chlorogenic Acid: A Systematic Review on the Biological Functions, Mechanistic Actions, and Therapeutic Potentials.

Chlorogenic acid (CGA) is a type of polyphenol compound found in rich concentrations in many plants such as green coffee beans. As an active natural substance, CGA exerts diverse therapeutic effects in response to a variety of pathological challenges, particularly conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional functions, including neuroprotection for neurodegenerative disorders and diabetic peripheral neuropathy, anti-inflammation, anti-oxidation, anti-pathogens, mitigation of cardiovascular disorders, skin diseases, diabetes mellitus, liver and kidney injuries, and anti-tumor activities. Mechanistically, its integrative functions act through the modulation of anti-inflammation/oxidation and metabolic homeostasis. It can thwart inflammatory constituents at multiple levels such as curtailing NF-kB pathways to neutralize primitive inflammatory factors, hindering inflammatory propagation, and alleviating inflammation-related tissue injury. It concurrently raises pivotal antioxidants by activating the Nrf2 pathway, thus scavenging excessive cellular free radicals. It elevates AMPK pathways for the maintenance and restoration of metabolic homeostasis of glucose and lipids. Additionally, CGA shows functions of neuromodulation by targeting neuroreceptors and ion channels. In this review, we systematically recapitulate CGA's pharmacological activities, medicinal properties, and mechanistic actions as a potential therapeutic agent. Further studies for defining its specific targeting molecules, improving its bioavailability, and validating its clinical efficacy are required to corroborate the therapeutic effects of CGA.

Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline.

Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-ß peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials.

NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.

Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.

Perturbations of Glutathione and Sphingosine Metabolites in Port Wine Birthmark Patient-Derived Induced Pluripotent Stem Cells.

Port Wine Birthmarks (PWBs) are a congenital vascular malformation on the skin, occurring in 1-3 per 1000 live births. We have recently generated PWB-derived induced pluripotent stem cells (iPSCs) as clinically relevant disease models. The metabolites associated with the pathological phenotypes of PWB-derived iPSCs are unknown, and so we aim to explore them in this study. Metabolites were separated by ultra-performance liquid chromatography and screened with electrospray ionization mass spectrometry. Orthogonal partial least-squares discriminant, multivariate, and univariate analyses were used to identify differential metabolites (DMs). KEGG analysis was used to determine the enrichment of metabolic pathways. A total of 339 metabolites was identified. There were 22 DMs, among which nine were downregulated-including sphingosine-and 13 were upregulated, including glutathione in PWB iPSCs, as compared to controls. Pathway enrichment analysis confirmed the upregulation of glutathione and the downregulation of sphingolipid metabolism in PWB-derived iPSCs as compared to normal ones. We next examined the expression patterns of the key molecules associated with glutathione metabolism in PWB lesions. We found that hypoxia-inducible factor 1α (HIF1α), glutathione S-transferase Pi 1 (GSTP1), γ-glutamyl transferase 7 (GGT7), and glutamate cysteine ligase modulatory subunit (GCLM) were upregulated in PWB vasculatures as compared to blood vessels in normal skin. Other significantly affected metabolic pathways in PWB iPSCs included pentose and glucuronate interconversions; amino sugar and nucleotide sugars; alanine, aspartate, and glutamate; arginine, purine, D-glutamine, and D-glutamate; arachidonic acid, glyoxylate, and dicarboxylate; nitrogen, aminoacyl-tRNA biosynthesis, pyrimidine, galactose, ascorbate, and aldarate; and starch and sucrose. Our data demonstrated that there were perturbations in sphingolipid and cellular redox homeostasis in PWB vasculatures, which could facilitate cell survival and pathological progression. Our data implied that the upregulation of glutathione could contribute to laser-resistant phenotypes in some PWB vasculatures.

Perturbations of glutathione and sphingosine metabolites in Port Wine Birthmark patient-derived induced pluripotent stem cells.

Port Wine Birthmark (PWB) is a congenital vascular malformation in the skin, occurring in 1-3 per 1,000 live births. We recently generated PWB-derived induced pluripotent stem cells (iPSCs) as clinically relevant disease models. The metabolites associated with the pathological phenotypes of PWB-derived iPSCs are unknown, which we aimed to explore in this study. Metabolites were separated by ultra-performance liquid chromatography and were screened with electrospray ionization mass spectrometry. Orthogonal partial least-squares discriminant analysis, multivariate and univariate analysis were used to identify differential metabolites (DMs). KEGG analysis was used for the enrichment of metabolic pathways. A total of 339 metabolites were identified. There were 22 DMs confirmed with 9 downregulated DMs including sphingosine and 13 upregulated DMs including glutathione in PWB iPSCs as compared to controls. Pathway enrichment analysis confirmed the upregulation of glutathione and downregulation of sphingolipid metabolism in PWB-derived iPSCs as compared to normal ones. We next examined the expression patterns of the key factors associated with glutathione metabolism in PWB lesions. We found that hypoxia-inducible factor 1α (HIF1α), glutathione S-transferase Pi 1 (GSTP1), γ-glutamyl transferase 7 (GGT7), and glutamate cysteine ligase modulatory subunit (GCLM) were upregulated in PWB vasculatures as compared to blood vessels in normal skins. Our data demonstrate that there are perturbations in sphingolipid and cellular redox homeostasis in the PWB vasculature, which may facilitate cell survival and pathological progression. Our data imply that upregulation of glutathione may contribute to laser-resistant phenotypes in the PWB vasculature.

Mitochondrial genome of Leocrates chinensis Kinberg, 1866 (Annelida: Hesionidae).

We report the complete mitochondrial genome of Leocrates chinensis Kinberg, 1866 - the type species of the genus. It is 15061 bp long, and contains 13 protein-coding genes (PCGs), 22 tRNA genes (tRNAs), and 2 rRNA genes (rRNAs), and 1 putative control region. Phylogenetic analysis indicated that L. chinensis was placed as sister to Sirsoe methanicola (BS = 100) of the same family Hesionidae.

Harsh Sensitivity and Mechanism Exploration of an Antibacterial Peptide Extracted from Walnut Oil Residue Derived from Agro-Industrial Waste.

Walnut (Juglans regia L.) cake meal constitutes a significant amount of solid byproduct from the production of walnut oil, comprising more than 40% protein. However, it is usually not well utilized. Therefore, an antibacterial peptide was obtained by hydrolyzing walnut oil residue protein with pepsin based on the diameter parameters of the antibacterial zone in this research. The purified antibacterial peptide WRPH-II-6 was obtained by two-part purification (ultrafiltration and reversed-phase liquid chromatography) and possessed higher antibacterial activity against Escherichia coli (MIC = 1.33 mg/mL), Staphylococcus aureus (MIC = 0.33 mg/mL), and Bacillus subtilis (MIC = 0.66 mg/mL). The amino acid sequence of WRPH-II-6 was identified as TGSAVPSPRASATATMEMAAAMGLMPGSPSSVSAVMSPF, where the presence of a large proportion of hydrophobic amino acid residues, such as alanine, proline, and methionine, explained the marked antibacterial activity of WRPH-II-6. The harsh sensitivity experiment demonstrated that WRPH-II-6 retains the stability of antibacterial activity when exposed to broad-spectrum pH values, variable temperatures, and long-lasting UV irradiation. The antibacterial mechanism of the WRPH-II-6 peptide against S. aureus and B. subtilis involves nonmembrane disruption: the contact of anions and cations causes the folding and collapse of the bacterial cell membrane to achieve the inhibitory effect. The antibacterial mechanism against E. coli is membrane disruption, which markedly disrupts the bacterial cell membrane to achieve the bactericidal effect. Significantly, the walnut residual protein hydrolysate is a potent preservative and antibacterial agent.

Impact of UHT processing on volatile components and chemical composition of sea buckthorn (Hippophae rhamnoides) pulp: A prediction of the biochemical pathway underlying aroma compound formation.

The effects of ultrahigh-temperature sterilization (UHT) on the volatile components and chemical composition of sea buckthorn pulp (SBP) were evaluated firstly. UHT had significant effects on the volatiles of SBP (mainly occurring at 140 °C for 2 s and 4 s), in which 140 °C for 2 s resulted in a decrease of 3.48% and 14.60% in total volatiles and esters, and an increase of 6.73% in alcohols, while alcohols contents sharply decreased by 6.90% at 140 °C for 4 s. Moreover, 140 °C for 2 s and 4 s decreased the amino acid content by 35.39% and 29.75%, respectively, while UHT significantly promoted the increase of fatty acids, but only a small increase at 140 °C for 4 s. The speculation is that a large number of volatiles were formed during the 140 °C for 2 s and 4 s, mainly from amino acid reactions and lipid oxidation.

Inhibition of CHRM3 Alleviates Necrosis Via the MAPK-p38/miR-31-5p/RIP3 Axis in L-Arginine-Induced Severe Acute Pancreatitis.

OBJECTIVES: Pancreatic acinar necrosis is a typical feature in the early phase of severe acute pancreatitis (SAP). Muscarinic acetylcholine receptor M3 (CHRM3) has been reported to play important roles in promoting insulin secretion and tumor cell proliferation, but its effect on necrosis remains unknown. This study revealed the important role of CHRM3 in regulating L-arginine-induced SAP and the molecular mechanisms. METHODS: To verify the function of CHRM3, pancreatic tissues and primary acinar cells of CRISPR/Cas9-mediated Chrm3 knockout mice were used in CHRM3 knockdown experiments, and to ascertain the CHRM3 overexpression, PLV-EGFP-Chrm3 plasmids were transfected in acinar cells in vitro. RESULTS: In L-arginine-induced SAP, CHRM3 is activated and regulates SAP through the mitogen-activated protein kinase/p38 pathway. Moreover, the expression of miR-31-5p decreased in the SAP model both in vitro and in vivo. Mir-31-5p effects the necrosis of acinar cells in SAP by upregulating the target gene RIP3, and miR-31-5p is a downstream miRNA of CHRM3. CONCLUSIONS: Necrosis in L-arginine-induced SAP is promoted by CHRM3 through the mitogen-activated protein kinase-p38/miR-31-5p/RIP3 axis.

Overexpression of three P450 genes is responsible for resistance to novel pyrimidine amines in Magnaporthe oryzae.

BACKGROUND: A series of pyrimidine amine derivatives has been synthesized by modifying the pyrimidine ring group of diflumetorim-a mitochondrial complex I inhibiting fungicide. One derivative, code number SYP-34773, is investigated in this study involving Magnaporthe oryzae, the causal agent of rice blast, which is the most devastating disease in rice. The response, resistance profile and mechanism of M. oryzae to SYP-34773 were investigated, which provides or provide?? important data for the registration and rational use of pyrimidine amines. RESULTS: SYP-34773 showed greater control efficacy than fungicide isoprothiolane in the field. The baseline sensitivity was established at a mean 50% effective concentration (EC50 ) of 0.08 µg ml-1 . Four stable SYP-34773-resistant isolates with reduced sensitivity were generated from one (S118) of ten sensitive isolates with a resistance factor of EC50 ranging from 7.00 to 15.00. Conidia production and pathogenicity were similar to that of S118, although there was a significant decrease in mycelial growth and conidial germination in resistant isolates. Positive cross-resistance was observed between SYP-34773 and diflumetorim; and the SYP-34773-resistant isolates were still sensitive to isoprothiolane, carbendazim, fluazinam, azoxystrobin, or prochloraz. RNA-Seq analyses revealed three cytochrome P450 genes were upregulated in the resistant isolate under the treatment with SYP-34773, as confirmed by quantitative real-time PCR. The SYP-34773 content was significantly reduced in the resistant isolate when compared with the parental isolate. CONCLUSION: The study demonstrated that SYP-34773 exhibits high activity against M. oryzae. Overexpression of three cytochrome P450 genes has an important role in the resistance of M. oryzae to novel pyrimidine amines. © 2020 Society of Chemical Industry.

Lemon essential oil ameliorates age-associated cognitive dysfunction via modulating hippocampal synaptic density and inhibiting acetylcholinesterase.

The lemon essential oil (LEO), extracted from the fruit of lemon, has been used to treat multiple pathological diseases, such as diabetes, inflammation, cardiovascular diseases, depression and hepatobiliary dysfunction. The study was designed to study the effects of LEO on cognitive dysfunction induced by Alzheimer's disease (AD). We used APP/PS1 double transgene (APP/PS1) AD mice in the experiment; these mice exhibit significant deficits in synaptic density and hippocampal-dependent spatial related memory. The effects of LEO on learning and memory were examined using the Morris Water Maze (MWM) test, Novel object recognition test, and correlative indicators, including a neurotransmitter (acetylcholinesterase, AChE), a nerve growth factor (brain-derived neurotrophic factor, BDNF), a postsynaptic marker (PSD95), and presynaptic markers (synapsin-1, and synaptophysin), in APP/PS1 mice. Histopathology was performed to estimate the effects of LEO on AD mice. A significantly lowered brain AChE depression in APP/PS1 and wild-type C57BL/6L (WT) mice. PSD95/ Synaptophysin, the index of synaptic density, was noticeably improved in histopathologic changes. Hence, it can be summarized that memory-enhancing activity might be associated with a reduction in the AChE levels and is elevated by BDNF, PSD95, and synaptophysin through enhancing synaptic plasticity.

MicroRNA-23a suppresses the apoptosis of inflammatory macrophages and foam cells in atherogenesis by targeting HSP90.

In previous study, we have found that microRNA-23a is down regulated in atherosclerotic tissues. Here we demonstrate that miR-23a directly binds to 3'UTR of HSP90 mRNA to suppress the expression of HSP90. To investigate the potential roles of miR-23a in macrophage, THP-1 macrophages were transfected with miR-23a mimics or inhibitors. Our results showed inflammatory factors IL-6 and MCP-1 concentrations in cell culture medium of macrophage and foam cell transfected with miR-23a mimics were decreased. Furthermore, we find that apoptosis of macrophage and foam cells transfected with miR-23a mimics were inhibited. Over expression of miR-23a in foam cells could reduced lipid intake and accumulation in foam cells. Meanwhile, we found that in inflammatory macrophages and foam cells transfected with miR-23a mimcs, HSP90 and NF-κB proteins are significantly decreased. Our results have suggested a promising and potential therapeutic target for atherosclerosis.