Effects of phosphorylation on CsTT12 transport function: A comparative phosphoproteomic analysis of flavonoid biosynthesis in tea plants (Camellia sinensis).

Monomeric flavan-3-ols and their oligomeric forms, proanthocyanidins (PAs), are closely related to the bitterness of tea beverages. Monomeric flavan-3-ols are characteristic flavor compounds in tea. Increasing the content of PAs and anthocyanins enhances the resistance of tea plants to pathogen invasion but decreases the quality of tea beverages. MATE family transporters play a critical role in transferring monomeric flavan-3-ols and anthocyanins into vacuoles for storage or subsequent condensation into PAs. Their activities modulate the ratio of monomeric flavan-3-ols to PAs and increase anthocyanin content in tea plants. In this study, it was observed that the gene expression and protein phosphorylation level of the MATE transporter CsTT12, a vacuole-localized flavonoid transporter, were notably upregulated following exogenous sucrose treatment, promoting PA synthesis in tea plants. Further analysis revealed that overexpression of CsTT12 and CsTT12S17D significantly increased the content of anthocyanins and PAs in plants, whereas CsTT12S17A did not. In CsTT12 knockdown plants, PA's accumulation decreased significantly, while monomeric catechin content increased. Moreover, phosphorylation modification enhanced the vacuolar membrane localization of CsTT12, whereas dephosphorylation weakened its vacuolar membrane localization. This study uncovers the crucial role of phosphorylation in flavonoid biosynthesis and provides insights into balancing quality improvements and resistance enhancement.

Assessment of antioxidant properties in selected pigmented and non-pigmented rice (Oryza sativa L.) germplasm and determination of its association with Rc gene haplotypes.

BACKGROUND: Antioxidant properties of rice provide various health benefits due to its ability to inhibit cellular oxidation. Antioxidant content of rice is known to be linked with the pericarp pigmentation. The Rc gene of rice (Os07g0211500) codes for a basic helix-loop-helix (bHLH) protein, acting as a transcriptional factor in regulating proanthocyanidin biosynthesis. The current study was carried out to evaluate the variation of antioxidant properties in a selected panel of rice accessions and assess the possibility of using haplotypes defined based on the Rc gene to predict pericarp pigmentation and antioxidant content in rice. RESULTS: Thirty-two rice accessions were evaluated for grain pericarp colour and antioxidant properties; total phenolic content (TPC), total flavonoids (TFC), proanthocyanidins (PAC) and radical scavenging activity (RSA). The parameters TPC, TFC and PAC showed significant positive correlation with RSA (r > 0.69; P < 0.01). The study panel showed a wide variation for antioxidant properties and rice accessions such as Sudu Heenati, Deweraddiri, Madathawalu, Masuran, Ld 368, At 311, Kalu Heenati, Bw 272-6B, Pokkali, At 362 and Wanni Dahanala exhibited profound potential with respect to antioxidant properties. Based on three-target sites previously reported as critical for the function of the coded bHLH protein (an A/C SNP at 1,353-bp, a 1-bp insertion/deletion at 1,388-bp, and a 14-bp insertion/deletion at 1,408-1,421-bp positioned in the mRNA corresponding to the exon 6 of rice Rc gene), three haplotypes were defined (H1-H3). Pigmentation of the rice pericarp could be successfully explained based on the defined haplotypes (H1 (C/G/+): red, and H2 (A/G/+) and H3 (C/G/-): white), and the H1 haplotype corresponded to a significantly (P < 0.05) higher TPC, TFC, PAC and RSA compared to the other haplotypes. CONCLUSIONS: The studied rice accessions showed a significant variation with respect to antioxidant properties. Haplotype H1 defined based on the three-target sites in the exon 6 of Rc gene can detect rice accessions with red pigmented pericarp and high antioxidant properties effectively. Hence, its use can be recommended as an alternative to biochemical assays for screening during rice breeding programs.

Combined treatment with Aronia berry extract and oligomeric proanthocyanidins exhibit a synergistic anticancer efficacy through LMNB1-AKT signaling pathways in colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and highly recurrent malignancies worldwide and currently ranks as the second leading cause of cancer-related deaths. The high degree of morbidity and mortality associated with CRC is primarily attributed to the limited effectiveness of current therapeutic approaches and the emergence of chemoresistance to standard treatment modalities. Recent research indicates that several natural products, including Aronia berry extracts (ABE) and oligomeric proanthocyanidins (OPCs), might offer a safe, cost-effective, and multitargeted adjunctive role to cancer treatment. Herein, we hypothesized a combined treatment with ABE and OPCs could synergistically modulate multiple oncogenic pathways in CRC, thereby enhancing their anticancer activity. We initially conducted a series of in vitro experiments to assess the synergistic anticancer effects of ABE and OPCs on CRC cell lines. We demonstrate that these two compounds exhibited a superior synergistic anticancer potential versus individual treatments in enhancing the ability to inhibit cell viability, suppress colony formation, and induce apoptosis (p < 0.05). Consistent with our in vitro findings, we validated this combinatorial anticancer effect in tumor-derived 3D organoids (PDOs; p < 0.01). Using genome-wide transcriptomic profiling, we identified that a specific gene, LMNB1, associated with the cell apoptosis pathway, was found to play a crucial role in exhibiting anticancer effects with these two products. Furthermore, the combined treatment of ABE and OPCs significantly impacted the expression of key proteins involved in apoptosis, including suppressed expression levels of LMNB1 in CRC cell lines (p < 0.05), which resulted in inhibiting downstream AKT phosphorylation. In conclusion, our study provides novel evidence of the synergistic anticancer effects of ABE and OPCs in CRC cells, partially mediated through the regulation of apoptosis and the oncogene LMNB1 within the AKT signaling pathway. These findings have the potential to better appreciate the anticancer potential of natural products in CRC and help improve treatment outcomes in this malignancy.

Antimicrobial and antibiofilm properties of procyanidins: potential for clinical and biotechnological applications.

Procyanidins (PCs) have emerged as agents with potential antimicrobial and antibiofilm activities, although their mechanisms of action and structure-activity relationships remain poorly understood. This review assessed the potential mechanisms of action and applications of these compounds to explore these aspects. Studies on the antimicrobial properties of PCs suggest that they are involved in osmotic imbalance, DNA interactions and metabolic disruption. Although less studied, their antibiofilm activities include antiadhesive effects and the modulation of mobility and quorum sensing. However, most research has used uncharacterized plant extracts for in vitro assays, limiting the understanding of the structure-activity relationships of PCs and their in vivo mechanisms. Clinical trials on the antimicrobial and antibiofilm properties of PCs have not clarified these issues due to nonstandardized methodologies, inadequate chemical characterization, and the limited number of studies, preventing a consensus and evaluation of the in vivo effects. Additionally, patent analysis revealed that technological developments in the antimicrobial and antibiofilm uses of PCs are concentrated in health care and dental care, but new biotechnological uses are emerging. Therefore, while PCs are promising antimicrobial and antibiofilm compounds, further research into their chemical structures and mechanisms of action is crucial for evidence-based applications in biotechnology and health care.

The impact of CYP3A4 genetic polymorphism on crizotinib metabolism and drug-drug interactions.

To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC50 values were 24.53 ± 0.32 µM in rat liver microsomes and 18.24 ± 0.12 µM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC(0-t), Cmax of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism.

Randomized, placebo-controlled, double-blinded study of prophylactic cranberries use in women with recurrent uncomplicated cystitis.

BACKGROUND: Τhe adherence of p-fimbriated Escherichia coli (E. coli) to urothelial cells leading to recurrent urinary tract infections (rUTIs) may be prevented by proanthocyanidins (PACs) contained in American cranberries. PURPOSE: The purpose of this clinical trial was to assess the clinical utility of prophylactic use of high-dose PACs daily in women with a history of rUTIs. MATERIALS AND METHODS: 172 adult women with a history of rUTIs, defined as ≥ 2 within a 6-month period or ≥ 3 within a 12-month period were enrolled and randomized in two groups to receive either Cysticlean™ 240 mg or placebo for a 12-month period. Urine samples, vaginal and rectal swabs were collected at initial and quarterly study visits. The primary study endpoints were the number of urinary tract infections (UTIs) and changes in Quality of Life (QoL), assessed by the 36-Item Short Form Survey (SF-36) questionnaire. RESULTS: 160 adult women of median age 40 years old (range 19-82) were finally analyzed in this randomized, placebo-controlled, double-blinded clinical trial. In response to intervention, the number of UTIs was significantly lower (Incidence rate ratio IRR 0.49, p < 0.001) and QoL was slightly improved. The numbers of E. coli isolates detected in vaginal (IRR 0.71, p value < 0.001) and in rectal swabs (IRR 0.87, p value < 0.001) were also significantly decreased. No adverse events were reported. CONCLUSION: The daily use of Cysticlean™ 240 mg was associated with a reduction of UTIs and a prolongation of UTI-free survival compared to placebo treatment, supporting its use as prophylaxis in this patient population. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT03032003.

Purification of proanthocyanidins from nut seeds and study on its bactericidal mechanism against Streptococcus mutans.

AIM: The aim of this study was to purify proanthocyanidins from areca nut seeds (P-AN) and to investigate the bactericidal activity and mechanism of the purified products against Streptococcus mutans. METHODS AND RESULTS: Ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry, Fourier transform infrared, Matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MADLI-TOF-MS), and thiolysis experiment were used for P-AN chemical analysis. Time-kill analysis and glycolytic pH drop were used to evaluate the activity of S. mutans in vitro. Meanwhile, the investigation of the bacteriostatic mechanism included membrane protein, fluidity, permeability, and integrity tests. The results showed that P-AN was a kind of proanthocyanidin mainly composed of B-type proanthocyanidins and their polymers. Moreover, MADLI-TOF-MS and thiolysis experiments demonstrated that the degree of polymerization of P-AN was 13. The time-kill analysis showed that P-AN had strong bactericidal activity against S. mutans. P-AN at minimum inhibitory concentration (MIC) concentrations was able to induce S. mutans death, while complete lethality occurred at 2 MIC. Glycolysis test showed that P-AN significantly inhibited S. mutans acid production (P < .01). The morphological changes of S. mutans were observed by scanning electron microscopy and transmission electron microscopy experiments, which indicated that P-AN destroyed the cellular structure of S. mutans. At the same time, significant changes were observed in membrane proteins, fluidity, permeability, and integrity. CONCLUSION: P-AN can effectively inhibit the activity of S. mutans. P-AN can reduce the erosion of the tooth surface by the acid of S. mutans. P-AN could break the structure of the cell membrane protein of S. mutans. P-AN could destroy the integrity of membrane, resulting in the death of S. mutans.

Proanthocyanidins alleviate Henoch-Schönlein purpura by mitigating inflammation and oxidative stress through regulation of the TLR4/MyD88/NF-κB pathway.

OBJECTIVE: Investigate Proanthocyanidins (PCs) efficacy and mechanisms in treating Henoch-Schönlein purpura (HSP)-like rat models, focusing on inflammatory and oxidative stress (OS) responses. METHODS: An HSP-like rat model was established using ovalbumin (OVA) injection, leading to symptoms mimicking HSP. The study measured inflammatory markers (IL-4, IL-17, TNF-α), OS markers (MDA, SOD, CAT), and assessed the TLR4/MyD88/NF-κB signaling pathway's involvement via histopathological and immunofluorescence analyses. RESULTS: PCs treatment significantly improved HSP-like symptoms, reduced inflammatory cell infiltration, and decreased IgA deposition in renal mesangial areas. Serum analyses revealed that PCs effectively lowered IL-4, IL-17, TNF-α, and MDA levels while increasing SOD and CAT levels (p < 0.05). Crucially, PCs also downregulated TLR4, MyD88, and NF-κB expressions, highlighting the blockage of the TLR4-mediated signaling pathway as a key mechanism. CONCLUSION: PCs show promising therapeutic effects in HSP-like rats by mitigating inflammatory responses and oxidative damage, primarily through inhibiting the TLR4/MyD88/NF-κB pathway. These findings suggest PCs as a potential treatment avenue for HSP, warranting further investigation.

Proanthocyanidins isolated from lotus seed skin mitigate glycolipid metabolism disorder through the p38/Nrf2/NF-κB signaling pathway.

Lotus seed skin extract is rich in flavonoids, making it a promising candidate for developing health products. In a previous study, we found that proanthocyanidins from lotus seed skin, particularly proanthocyanidin B1 (PB1), can indirectly activate the Nrf2 signaling pathway, exerting an antioxidant effect. In this study, we isolate proanthocyanidins from lotus seed skin (PLS) using ethanol extraction and RP-HPLC identification, and investigate its effects on glycolipid metabolism both in vivo and in vitro. Our results demonstrate that PLS reduces body weight in high-fat diet (HFD) mice by decreasing feed efficiency. PLS also normalizes serum glucose, insulin secretion, glycosylated hemoglobin (HbA1c), and intraperitoneal glucose tolerance (IPGTT). Furthermore, PLS significantly improves blood lipid parameters and inhibits the expressions of six proinflammatory factors, including IL-1α, IL-1ß, IL-3, IL-6, IFN-γ and TNF-α in HFD mice. Additionally, analysis of fresh liver tissues reveals that PLS and PB1 induce the expressions of antioxidant proteins such as HO-1 and NQO1 by activating the p38-Nrf2 signaling pathway and inhibiting the NF-κB signaling pathway. In conclusion, proanthocyanidins from lotus seed skin regulate glycolipid metabolism disorders by targeting the p38/Nrf2/NF-κB signaling pathway. Our study offers a new approach for the high-value comprehensive utilization of lotus seed skin by-products and precise dietary intervention for metabolic syndrome.

Proanthocyanidins and volatile aroma of cranberry juice are modulated by its microbiota and processing environment.

The quality and sensory attributes of juices are influenced by their natural microbiota and the microorganisms found on filtration membranes. This study aimed to assess the influence of natural microbiota and specific contaminants, including Candida krusei, Rhodotorula mucilaginosa, Debaryomyces prosopidis, Ralstonia insidiosa, and Lactiplantibacillus paraplantarum, isolated from cranberry juice and its associated industrial filtration membranes, on the characteristics of cranberry juice. Their growth kinetics and impacts on total phenols, total anthocyanins, total proanthocyanins, total organic acids, pH, titratable acidity, and volatile compounds were assessed. During the 42 h fermentation period, Candida krusei and Ralstonia insidiosa exhibited significant growth, increasing by 1-log and 3-log, respectively. The natural microbiota led to a 7% and 6% reduction in anthocyanins and proanthocyanidins, while Candida krusei and Rhodotorula mucilaginosa caused losses of 10% and 7% in proanthocyanidins, respectively. Organic acid content remained stable, except for an 8% decrease caused by Ralstonia insidiosa. Volatile compounds underwent significant increases, particularly in green (703%), winey (100%), mushroom (306%), and fusel (2678%) notes. These findings underscore the rapid impact of microorganisms from natural microbiota and filtration membranes on cranberry juice characteristics, highlighting the importance for beverage industries to prioritize customer safety and satisfaction.

Co-assembled whey protein and proanthocyanidins as a promising biocarrier for hydrophobic pterostilbene: Fabrication, characterization, and cellular antioxidant potential.

The usage of food-derived polyphenols with different polarities has been limited by their instability and incompatibility. Therefore, a biocarrier was developed by co-assembly of whey protein isolate (WPI) and hydrophilic proanthocyanidin (PC) for loading hydrophobic pterostilbene (PTE). Such biocarrier has superior affinity for PTE than WPI alone, as determined by encapsulation efficiency and loading capacity assay, fluorescence quenching analysis, and molecular docking, whereas the assembly process was characterized by particle size and zeta potential, 3-dimensional fluorescence, and scanning electron microscopy. Circular dichroism and Fourier transform infrared spectroscopy spectra confirmed the α-helix to ß-sheet and random coil transition of proteins during the formation of nanocomplexes. Whey protein isolate acted as a mediator through altering the binding mode of PC and PTE, allowing them to perform significant synergistic effects in enhancing 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl radical scavenging and reducing H2O2-induced cell damage. This research may serve to develop new protein/polyphenol co-loading systems and offer a reliable nutritional fortification.

Effect of proanthocyanidins on blood lipids: A systematic review and meta-analysis.

Proanthocyanidins (PCs) are natural antioxidant polyphenols and their effect on the regulation of blood lipids is still controversial. This study was conducted to evaluate the effect of PCs on lipid metabolism. We searched PubMed, Embase, Web of Science, Chinese biomedical literature service system, China National Knowledge Internet, and Wanfang Data with no time restriction until March 18, 2022, using various forms of "proanthocyanidins" and "blood lipid" search terms. Randomized controlled trials investigating the relationship between PCs and lipid metabolism were included. The standard system of Cochrane Collaboration was used to assess the quality of studies. We standardized mean differences (SMDs) with 95% confidence interval (CI) using the random-effects model, Cohen approach. Seventeen studies (17 trials, N = 1138) fulfilled the eligibility criteria. PCs significantly reduced triglyceride, and increased recombinant apolipoprotein A1. Subgroup analysis showed a significant reduction in triglycerides in older adults (≥60 years) and total cholesterol for participants who were not overweight or obese (body mass index <24). An intervention duration of greater than 8 weeks reduced triglyceride and low-density lipoprotein cholesterol levels but increased high-density lipoprotein cholesterol. Different doses of PCs could regulate triglycerides, high-density lipoprotein cholesterol and total cholesterol. PCs have beneficial effects on circulating lipids and may represent a new approach for treating or preventing lipid metabolism disorders. However, more high-quality studies are needed to confirm these results.

Anti-inflammatory effect of proanthocyanidins from blueberry through NF-κß/NLRP3 signaling pathway in vivo and in vitro.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is an uncontrolled systemic inflammatory response. Proanthocyanidins (PC) is a general term of polyphenol compounds widely existed in blueberry fruits and can treat inflammation-related diseases. This study aimed to explore the regulatory effect of PC on lipopolysaccharide (LPS)-induced systemic inflammation and its potential mechanism, providing effective strategies for the further development of PC. METHODS: Here, RAW264.7 macrophages were stimulated with LPS to establish an inflammation model in vitro, while endotoxin shock mouse models were constructed by LPS in vivo. The function of PC was investigated by MTT, ELISA kits, H&E staining, immunohistochemistry, and Western blot analysis. RESULTS: Functionally, PC could demonstrate the potential to mitigate mortality in mice with endotoxin shock, as well as attenuated the levels of inflammatory cytokines (IL-6, TNF-α) and biochemical indicators (AST, ALT, CRE and BUN). Moreover, it had a significant protective effect on lung and kidney tissues damage. Mechanistically, PC exerted anti-inflammatory effects by inhibiting the activation of the NF-κB/NLRP3 signaling pathway. CONCLUSION: PC might have the potential ability of anti-inflammatory effects via modulation of the NF-κB/NLRP3 signaling pathway.

Exploration of the anthocyanin and proanthocyanidin profile of Greek red grape skins belonging to Vradiano, Limnio, and Kotsifali cultivars, analyzed by a novel LC-QTOF-MS/MS method.

INTRODUCTION: Winegrape varieties Kotsifali, Limnio, and Vradiano OBJECTIVE: The aim of this study was to develop a liquid chromatographic quadrupole time-of-flight tandem mass spectrometric (LC-QTOF-MS/MS) method for the investigation of the anthocyanin and proanthocyanidin content of Greek grape varieties employing target and suspect screening strategies. METHODOLOGY: A novel LC-QTOF-MS/MS method was developed and validated to assess the anthocyanin content of Kotsifali, Limnio, and Vradiano grape varieties. Sixteen grape samples were collected from the main growing areas of each variety in Greece. The influence of the grape variety on the anthocyanin and proanthocyanidin composition of three Greek winegrapes was investigated using chemometrics. RESULTS: Excellent linearity (R2 > 0.99) was achieved for all the target analytes, and recoveries ranged between 90.1% and 119.1%. The limits of quantification (LOQs) and limits of detection (LODs) were calculated over the range of 0.020-0.40 mg/g and 0.010-0.13 mg/g, respectively. The RSD% was lower than 9.1% and 7.3% for intra-day and inter-day studies, respectively, indicating satisfactory trueness and precision. Target and suspect screening resulted in the identification of 5 and 26 anthocyanins, respectively. CONCLUSIONS: Kotsifali variety exhibited a higher concentration of anthocyanins compared with Vradiano and Limnio. Higher levels of mean degree of polymerization (mDp) and different percentage levels of prodelphinidins (%P) were established among the varieties.

Proanthocyanidins as the marker of amomum fruit from three botanical origins based on comprehensive profiling with LC-MS and GC-MS combined with chemometrics.

INTRODUCTION: Amomum fruit, also known as Sharen, serves as both a functional food and a traditional Chinese medicine with significant pharmacological activities. However, there are three botanical origins of Amomum fruit: Amomum villosum Lour. (AVL), Amomum villosum Lour. var. xanthioides T. L. (AVX), and Amomum longiligulare T. L. Wu (ALW). OBJECTIVE: Conducting a comprehensive chemical composition analysis of Amomum fruit from three botanical origins aims to identify potential differences in metabolic characteristics. METHODS: To annotate the metabolic characteristic ions of multi-origin Amomum fruit, we employed metabolomic techniques, including ultra-high-performance liquid chromatography (LC) coupled with linear ion trap-Orbitrap-tandem mass spectrometry (MS) and gas chromatography-MS, in conjunction with feature-based molecular networking technology. Additionally, chemometrics was utilized to examine the correlations between the various botanical origins. RESULTS: A total of 201 non-volatile and 151 volatile metabolites were annotated, and most of the proanthocyanidins and flavonoids were identified by feature-based molecular networking. Additionally, 61 non-volatile and 45 volatile feature ions were screened out for classification. Principal component analysis, orthogonal projection to latent structures discrimination analysis, and heat map analysis were employed to clearly distinguish the metabolite profiles of Amomum fruit from different origins. Hierarchical clustering analysis indicated that proanthocyanidins C1 and C2, as well as proanthocyanins oligomers, show significant differential expression between AVX and AVL, which could be the new quality markers for the classification. CONCLUSION: Classification of the botanical origin of Amomum fruit based on LC-MS characteristic ions proved to be more advantageous. This study introduces new strategies and technical support for the quality control of Amomum fruit and facilitates the identification of unknown compounds for future research.

Proanthocyanidins Ameliorate LPS-Inhibited Osteogenesis of PDLSCs by Restoring Lysine Lactylation.

Periodontitis is a bacteria-induced inflammatory disease characterized by the progressive destruction of periodontal supporting tissues. Periodontal ligament stem cells (PDLSCs) are capable of differentiating into osteoblasts, which is an important stem cell source for endogenous periodontal tissue regeneration. Lysine lactylation (Kla) is a novel post-translational modification of proteins that is recently thought to be associated with osteogenic differentiation. Here, we found that lactylation levels are reduced both in the periodontal tissue of rats with periodontitis and lipopolysaccharide (LPS)-stimulated human PDLSCs. Proanthocyanidins were able to promote the osteogenesis of inflamed PDLSCs by restoring lactylation levels. Mechanistically, proanthocyanidins increased lactate production and restored the lactylation levels of PDLSCs, which recovered osteogenesis of inflamed PDLSCs via the Wnt/ß-catenin pathway. These results provide evidence on how epigenetic regulation by pharmacological agents influence the osteogenic phenotype of stem cells and the process of periodontal tissue repair. Our current study highlights the valuable potential of natural product proanthocyanidins in the regenerative engineering of periodontal tissues.

Effects of UV-B Radiation Exposure on Transgenerational Plasticity in Grain Morphology and Proanthocyanidin Content in Yuanyang Red Rice.

The effect of UV-B radiation exposure on transgenerational plasticity, the phenomenon whereby the parental environment influences both the parent's and the offspring's phenotype, is poorly understood. To investigate the impact of exposing successive generations of rice plants to UV-B radiation on seed morphology and proanthocyanidin content, the local traditional rice variety 'Baijiaolaojing' was planted on terraces in Yuanyang county and subjected to enhanced UV-B radiation treatments. The radiation intensity that caused the maximum phenotypic plasticity (7.5 kJ·m-2) was selected for further study, and the rice crops were cultivated for four successive generations. The results show that in the same generation, enhanced UV-B radiation resulted in significant decreases in grain length, grain width, spike weight, and thousand-grain weight, as well as significant increases in empty grain percentage and proanthocyanidin content, compared with crops grown under natural light conditions. Proanthocyanidin content increased as the number of generations of rice exposed to radiation increased, but in generation G3, it decreased, along with the empty grain ratio. At the same time, biomass, tiller number, and thousand-grain weight increased, and rice growth returned to control levels. When the offspring's radiation memory and growth environment did not match, rice growth was negatively affected, and seed proanthocyanidin content was increased to maintain seed activity. The correlation analysis results show that phenylalanine ammonialyase (PAL), cinnamate-4-hydroxylase (C4H), dihydroflavonol 4-reductase (DFR), and 4-coumarate:CoA ligase (4CL) enzyme activity positively influenced proanthocyanidin content. Overall, UV-B radiation affected transgenerational plasticity in seed morphology and proanthocyanidin content, showing that rice was able to adapt to this stressor if previous generations had been continuously exposed to treatment.

Non-Mature miRNA-Encoded Micropeptide miPEP166c Stimulates Anthocyanin and Proanthocyanidin Synthesis in Grape Berry Cells.

The phenylpropanoid and flavonoid pathways exhibit intricate regulation, not only influenced by environmental factors and a complex network of transcription factors but also by post-transcriptional regulation, such as silencing by microRNAs and miRNA-encoded micropeptides (miPEPs). VviMYBC2-L1 serves as a transcriptional repressor for flavonoids, playing a crucial role in coordinating the synthesis of anthocyanin and proanthocyanidin. It works in tandem with their respective transcriptional activators, VviMYBA1/2 and VviMYBPA1, to maintain an equilibrium of flavonoids. We have discovered a miPEP encoded by miR166c that appears to target VviMYBC2-L1. We conducted experiments to test the hypothesis that silencing this transcriptional repressor through miPEP166c would stimulate the synthesis of anthocyanins and proanthocyanidins. Our transcriptional analyses by qPCR revealed that the application of exogenous miPEP166c to Gamay Fréaux grape berry cells resulted in a significant upregulation in flavonoid transcriptional activators (VviMYBA1/2 and VviMYBPA1) and structural flavonoid genes (VviLDOX and VviDFR), as well as genes involved in the synthesis of proanthocyanidins (VviLAR1 and VviANR) and anthocyanins (VviUFGT1). These findings were supported by the increased enzyme activities of the key enzymes UFGT, LAR, and ANR, which were 2-fold, 14-fold, and 3-fold higher, respectively, in the miPEP166c-treated cells. Ultimately, these changes led to an elevated total content of anthocyanins and proanthocyanidins.

Therapeutic Effects of Proanthocyanidins on Diabetic Erectile Dysfunction in Rats.

The rising occurrence of erectile dysfunction related to diabetes mellitus (DMED) has led to the creation of new medications. Proanthocyanidins (PROs) is a potential agent for DMED. In this study, the DMED rat model was established using streptozotocin (STZ) and erectile function was assessed using apomorphine (APO) in rats. Following this, the rats were subjected to oral treatment with PRO. Then, we evaluated the influence of PROs on DMED rats. The findings suggest that PROs significantly enhance erectile function in DMED rats. PROs modulated glucose and lipid metabolism in DMED rats by decreasing blood glucose and lipid levels while increasing liver glycogen and serum insulin levels. Furthermore, PROs enhanced vascular endothelial function in DMED rats by augmenting nitric oxide (NO) levels and reducing the levels of endothelin-1 (ET-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Additionally, PROs have been shown to elevate testosterone (T) levels, mitigate pathological testicular damage, and enhance sperm concentration and survival rates. Finally, the core targets were screened using network pharmacology, followed by validation through molecular docking, enzyme-linked immunoassay (ELISA), and real-time PCR methodologies. Our findings imply that PROs may treat DMED by elevating AKT1 levels while concurrently diminishing CASP3 levels, thereby effectively regulating the PI3K-Akt signaling pathway. Overall, these results support using PROs as a potential candidate for the treatment of DMED.

The Novel A-Type Proanthocyanidin-Rich Phytocomplex SP4™ Acts as a Broad-Spectrum Antiviral Agent against Human Respiratory Viruses.

The appearance of new respiratory virus infections in humans with epidemic or pandemic potential has underscored the urgent need for effective broad-spectrum antivirals (BSAs). Bioactive compounds derived from plants may provide a natural source of new BSA candidates. Here, we investigated the novel phytocomplex formulation SP4™ as a candidate direct-acting BSA against major current human respiratory viruses, including coronaviruses and influenza viruses. SP4™ inhibited the in vitro replication of SARS-CoV-2, hCoV-OC43, hCoV-229E, Influenza A and B viruses, and respiratory syncytial virus in the low-microgram range. Using hCoV-OC43 as a representative respiratory virus, most of the antiviral activity of SP4™ was observed to stem primarily from its dimeric A-type proanthocyanidin (PAC-A) component. Further investigations of the mechanistic mode of action showed SP4™ and its PAC-A-rich fraction to prevent hCoV-OC43 from attaching to target cells and exert virucidal activity. This occurred through their interaction with the spike protein of hCoV-OC43 and SARS-CoV-2, thereby interfering with spike functions and leading to the loss of virion infectivity. Overall, these findings support the further development of SP4™ as a candidate BSA of a natural origin for the prevention of human respiratory virus infections.