Piceatannol Alleviates Deoxynivalenol-Induced Damage in Intestinal Epithelial Cells via Inhibition of the NF-κB Pathway.

Deoxynivalenol (DON) is a common mycotoxin that is widely found in various foods and feeds, posing a potential threat to human and animal health. This study aimed to investigate the protective effect of the natural polyphenol piceatannol (PIC) against DON-induced damage in porcine intestinal epithelial cells (IPEC-J2 cells) and the underlying mechanism. The results showed that PIC promotes IPEC-J2 cell proliferation in a dose-dependent manner. Moreover, it not only significantly relieved DON-induced decreases in cell viability and proliferation but also reduced intracellular reactive oxygen species (ROS) production. Further studies demonstrated that PIC alleviated DON-induced oxidative stress damage by increasing the protein expression levels of the antioxidant factors NAD(P)H quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase modifier subunit (GCLM), and the mRNA expression of catalase (CAT), Superoxide Dismutase 1 (SOD1), peroxiredoxin 3 (PRX3), and glutathione S-transferase alpha 4 (GSTα4). In addition, PIC inhibited the activation of the nuclear factor-B (NF-κB) pathway, downregulated the mRNA expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) to attenuate DON-induced inflammatory responses, and further mitigated DON-induced cellular intestinal barrier injury by regulating the protein expression of Occludin. These findings indicated that PIC had a significant protective effect against DON-induced damage. This study provides more understanding to support PIC as a feed additive for pig production.

The importance of strigolactone transport regulation for symbiotic signaling and shoot branching.

MAIN CONCLUSION: This review presents the role of strigolactone transport in regulating plant root and shoot architecture, plant-fungal symbiosis and the crosstalk with several phytohormone pathways. The authors, based on their data and recently published results, suggest that long-distance, as well local strigolactone transport might occur in a cell-to-cell manner rather than via the xylem stream. Strigolactones (SLs) are recently characterized carotenoid-derived phytohormones. They play multiple roles in plant architecture and, once exuded from roots to soil, in plant-rhizosphere interactions. Above ground SLs regulate plant developmental processes, such as lateral bud outgrowth, internode elongation and stem secondary growth. Below ground, SLs are involved in lateral root initiation, main root elongation and the establishment of the plant-fungal symbiosis known as mycorrhiza. Much has been discovered on players and patterns of SL biosynthesis and signaling and shown to be largely conserved among different plant species, however little is known about SL distribution in plants and its transport from the root to the soil. At present, the only characterized SL transporters are the ABCG protein PLEIOTROPIC DRUG RESISTANCE 1 from Petunia axillaris (PDR1) and, in less detail, its close homologue from Nicotiana tabacum PLEIOTROPIC DRUG RESISTANCE 6 (PDR6). PDR1 is a plasma membrane-localized SL cellular exporter, expressed in root cortex and shoot axils. Its expression level is regulated by its own substrate, but also by the phytohormone auxin, soil nutrient conditions (mainly phosphate availability) and mycorrhization levels. Hence, PDR1 integrates information from nutrient availability and hormonal signaling, thus synchronizing plant growth with nutrient uptake. In this review we discuss the effects of PDR1 de-regulation on plant development and mycorrhization, the possible cross-talk between SLs and other phytohormone transporters and finally the need for SL transporters in different plant species.

Petunia hybrida PDR2 is involved in herbivore defense by controlling steroidal contents in trichomes.

As a first line of defense against insect herbivores many plants store high concentrations of toxic and deterrent secondary metabolites in glandular trichomes. Plant Pleiotropic Drug Resistance (PDR)-type ABC transporters are known secondary metabolite transporters, and several have been implicated in pathogen or herbivore defense. Here, we report on Petunia hybrida PhPDR2 as a major contributor to trichome-related chemical defense. PhPDR2 was found to localize to the plasma membrane and be predominantly expressed in multicellular glandular trichomes of leaves and stems. Down-regulation of PhPDR2 via RNA interference (pdr2) resulted in a markedly higher susceptibility of the transgenic plants to the generalist foliage feeder Spodoptera littoralis. Untargeted screening of pdr2 trichome metabolite contents showed a significant decrease in petuniasterone and petuniolide content, compounds, which had previously been shown to act as potent toxins against various insects. Our findings suggest that PhPDR2 plays a leading role in controlling petuniasterone levels in leaves and trichomes of petunia, thus contributing to herbivory resistance.

Molecular identification and functional analysis of a maize (Zea mays) DUR3 homolog that transports urea with high affinity.

MAIN CONCLUSION: Successful molecular cloning and functional characterization of a high-affinity urea permease ZmDUR3 provide convincing evidence of ZmDUR3 roles in root urea acquisition and internal urea-N-remobilization of maize plants. Urea occurs ubiquitously in both soils and plants. Being a major form of nitrogen fertilizer, large applications of urea assist cereals in approaching their genetic yield potential, but due to the low nitrogen-use efficiency of crops, this practice poses a severe threat to the environment through their hypertrophication. To date, except for paddy rice, little is known about the biological basis for urea movement in dryland crops. Here, we report the molecular and physiological characterization of a maize urea transporter, ZmDUR3. We show using gene prediction, PCR-based cloning and yeast complementation, that a functional full-length cDNA encoding a 731 amino acids-containing protein with putative 15 transmembrane α-helixes for ZmDUR3 was successfully cloned. Root-influx studies using (15)N-urea demonstrated ZmDUR3 catalyzes urea transport with a K m at ~9 µM when expressed in the Arabidopsis dur3-mutant. qPCR analysis revealed that ZmDUR3 mRNA in roots was significantly upregulated by nitrogen depletion and repressed by reprovision of nitrogen after nitrogen starvation, indicating that ZmDUR3 is a nitrogen-responsive gene and relevant to plant nitrogen nutrition. Moreover, detection of higher urea levels in senescent leaves and obvious occurrence of ZmDUR3 transcripts in phloem-cells of mature/aged leaves strongly implies a role for ZmDUR3 in urea vascular loading. Significantly, expression of ZmDUR3 complemented atdur3-mutant of Arabidopsis, improving plant growth on low urea and increasing urea acquisition. As it also targets to the plasma membrane, our data suggest that ZmDUR3 functions as an active urea permease playing physiological roles in effective urea uptake and nitrogen remobilization in maize.

Trichostatin A relieves anxiety-and depression-like symptoms in APP/PS1 mice.

Background: Cognitive deficits and behavioral disorders such as anxiety and depression are common manifestations of Alzheimer's disease (AD). Our previous work demonstrated that Trichostatin A (TSA) could alleviate neuroinflammatory plaques and improve cognitive disorders. AD, anxiety, and depression are all associated with microglial inflammation. However, whether TSA could attenuate anxiety- and depression-like behaviors in APP/PS1 mice through anti-inflammatory signaling is still unclearly. Methods: In the present study, all mice were subjected to the open field, elevated plus maze, and forced swim tests to assess anxiety- and depression-related behaviors after TSA administration. To understand the possible mechanisms underlying the behavioral effects observed, CST7 was measured in the hippocampus of mice and LPS-treated BV2 microglia. Results: The results of this study indicated that TSA administration relieved the behaviors of depression and anxiety in APP/PS1 mice, and decreased CST7 levels in the hippocampus of APP/PS1 mice and LPS-induced BV2 cells. Conclusion: Overall, these findings support the idea that TSA might be beneficial for reducing neurobehavioral disorders in AD and this could be due to suppression of CST7-related microglial inflammation.

Refining the optimal CAF cluster marker for predicting TME-dependent survival expectancy and treatment benefits in NSCLC patients.

The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we have systematically screened multiple databases to identify the most robust marker for distinguishing CAFs in lung cancer, with a particular focus on their potential use in early diagnosis, staging, and treatment response evaluation. Our investigation revealed that COL1A1, COL1A2, FAP, and PDGFRA are effective markers for characterizing CAF subgroups in most lung adenocarcinoma datasets. Through comprehensive analysis of treatment responses, we determined that COL1A1 stands out as the most effective indicator among all CAF markers. COL1A1 not only deciphers the TME signatures related to CAFs but also demonstrates a highly sensitive and specific correlation with treatment responses and multiple survival outcomes. For the first time, we have unveiled the distinct roles played by clusters of CAF markers in differentiating various TME groups. Our findings confirm the sensitive and unique contributions of CAFs to the responses of multiple lung cancer therapies. These insights significantly enhance our understanding of TME functions and drive the translational application of extensive scRNA sequence results. COL1A1 emerges as the most sensitive and specific marker for defining CAF subgroups in scRNA analysis. The CAF ratios represented by COL1A1 can potentially serve as a reliable predictor of treatment responses in clinical practice, thus providing valuable insights into the influential roles of TME components. This research marks a crucial step forward in revolutionizing our approach to cancer diagnosis and treatment.

Agomelatine: a potential novel approach for the treatment of memory disorder in neurodegenerative disease.

Agomelatine is a selective agonist of melatonin receptor 1A/melatonin receptor 1B (MT1/MT2) and antagonist of 5-hydroxytryptamine 2C receptors. It is used clinically to treat major depressive episodes in adults. The pro-chronobiological activity of agomelatine reconstructs sleep-wake rhythms and normalizes circadian disturbances via its agonistic effect of melatonin receptor 1A/melatonin receptor 1B, which work simultaneously to counteract depression and anxiety disorder. Moreover, by antagonizing neocortical postsynaptic 5-hydroxytryptamine 2C receptors, agomelatine enhances the release of dopamine and noradrenaline in the prefrontal cortex, increases the activity of dopamine and noradrenaline, and thereby reduces depression and anxiety disorder. The combination of these two effects means that agomelatine exhibits a unique pharmacological role in the treatment of depression, anxiety, and disturbance of the circadian rhythm. Emotion and sleep are closely related to memory and cognitive function. Memory disorder is defined as any forms of memory abnormality, which is typically evident in a broad range of neurodegenerative diseases, including Alzheimer's disease. Memory impairment and cognitive impairment are common symptoms of neurodegenerative and psychiatric diseases. Therefore, whether agomelatine can improve memory and cognitive behaviors if used for alleviating depression and circadian-rhythm sleep disorders has become a research "hotspot". This review presents the latest findings on the effects of agomelatine in the treatment of psychologic and circadian-rhythm sleep disorders in clinical trials and animal experiments. Our review evaluates recent studies on treatment of memory impairment and cognitive impairment in neurodegenerative and psychiatric diseases.

Rice DUR3 mediates high-affinity urea transport and plays an effective role in improvement of urea acquisition and utilization when expressed in Arabidopsis.

• Despite the great agricultural and ecological importance of efficient use of urea-containing nitrogen fertilizers by crops, molecular and physiological identities of urea transport in higher plants have been investigated only in Arabidopsis. • We performed short-time urea-influx assays which have identified a low-affinity and high-affinity (K(m) of 7.55 µM) transport system for urea-uptake by rice roots (Oryza sativa). • A high-affinity urea transporter OsDUR3 from rice was functionally characterized here for the first time among crops. OsDUR3 encodes an integral membrane-protein with 721 amino acid residues and 15 predicted transmembrane domains. Heterologous expression demonstrated that OsDUR3 restored yeast dur3-mutant growth on urea and facilitated urea import with a K(m) of c. 10 µM in Xenopus oocytes. • Quantitative reverse-transcription polymerase chain reaction (qPCR) analysis revealed upregulation of OsDUR3 in rice roots under nitrogen-deficiency and urea-resupply after nitrogen-starvation. Importantly, overexpression of OsDUR3 complemented the Arabidopsis atdur3-1 mutant, improving growth on low urea and increasing root urea-uptake markedly. Together with its plasma membrane localization detected by green fluorescent protein (GFP)-tagging and with findings that disruption of OsDUR3 by T-DNA reduces rice growth on urea and urea uptake, we suggest that OsDUR3 is an active urea transporter that plays a significant role in effective urea acquisition and utilisation in rice.

Endovascular Thrombectomy Versus Bridging Thrombolysis: Real-World Efficacy and Safety Analysis Based on a Nationwide Registry Study.

Background It was uncertain if direct endovascular thrombectomy (ET) was superior to bridging thrombolysis (BT) for patients with acute ischemic stroke caused by large-vessel occlusions. We aimed to examine real-world clinical outcomes of ET using nationwide registry data in China and to compare the efficacy and safety between BT and direct ET. Methods and Results Patients treated with ET from a nationwide registry study in China were included. Rapid neurological improvement, intracranial hemorrhage, and in-hospital mortality were compared between the 2 groups using multivariate logistic models and propensity-score matching analyses. A total of 7674 patients from 592 stroke centers were included. The median onset-to-puncture time, onset-to-door time, and door to puncture time were 290, 170, and 99 minutes, respectively. A total of 2069 (27.0%) patients received BT treatment. Patients in the BT group had a significantly shorter onset-to-puncture time (235 versus 323 minutes; P<0.001) and onset-to-door time (90 versus 222 minutes; P<0.001) compared with the direct ET group. The prior use of intravenous thrombolysis was associated with a higher rate of rapid neurological improvement (adjusted odds ratio [OR], 0.83; 95% CI, 0.71-0.96) and higher risk of intracranial hemorrhage (adjusted OR, 1.46; 95% CI, 1.18-1.80) in multivariate analyses and propensity-score matching analyses. Conclusions This study reflects the current application of ET in China. More patients received direct ET than BT. Our results suggested that favorable short-term outcomes could be achieved with BT compared with direct ET. Higher risk of intracranial hemorrhage was observed in the BT group.

Effect of traditional Chinese medicine compounds on rumen fermentation, methanogenesis and microbial flora in vitro.

This study was conducted to investigate the effects of traditional Chinese medicine compounds (TCMC) on rumen fermentation, methane emission and populations of ruminal microbes using an in vitro gas production technique. Cablin patchouli herb (CPH), Atractylodes rhizome (AR), Amur Cork-tree (AC) and Cypsum were mixed with the weight ratios of 1:1:1:0.5 and 1:1:1:1 to make up TCMC1 and TCMC2, respectively. Both TCMC were added at level of 25 g/kg of substrate dry matter. In vitro gas production was recorded and methane concentration was determined at 12 and 24 h of incubation. After 24 h, the incubation was terminated and the inoculants were measured for pH, ammonia nitrogen, volatile fatty acids (VFA). Total deoxyribonucleic acid of ruminal microbes was extracted from the inocula, and populations were determined by a real-time quantitative polymerase chain reaction. Populations of total rumen methanogens, protozoa, total fungi, Ruminococcus albus, Fibrobacter succinogenes and Ruminococcus flavefaciens were expressed as a proportion of total rumen bacterial 16S ribosomal deoxyribonucleic acid. Compared with the control, the 2 TCMC decreased (P ≤ 0.05) total VFA concentration, acetate molar proportion, acetate to propionate ratio, gas and methane productions at 12 and 24 h, hydrogen (H) produced and consumed, and methanogens and total fungi populations, while the 2 TCMC increased (P ≤ 0.05) propionate molar proportion. Traditional Chinese medicine compound 1 also decreased (P ≤ 0.05) R. flavefaciens population. From the present study, it is inferred that there is an effect of the TCMC in suppressing methanogenesis, probably mediated via indirect mode by channeling H2 utilized for methanogenesis to synthesis of propionate and direct action against the rumen microbes involved in methane formation. In addition, the relative methane reduction potential (RMRP) of TCMC2 was superior to that of TCMC1.

Wenxia Changfu Formula () induces apoptosis of lung adenocarcinoma in a transplanted tumor model of drug-resistance nude mice.

OBJECTIVE: To explore the apoptosis mechanism of Wenxia Changfu Formula (, WCF) in reversing drug resistance of lung cancer in vivo. METHODS: Thirty model mice were randomly assigned to three groups: control group, cisplatin (CDDP) group, and WCF group. A transplanted tumor model of lung adenocarcinoma was established in all groups. Mice in the WCF group received intragastric administration of WCF (0.2 mL/10 g body weight) everyday in addition to CDDP intraperitoneally (5 mg/kg body weight) twice a week. The mice in the CDDP group received CDDP intraperitoneally (5 mg/kg body weight) twice a week, while the control group received normal saline intraperitoneally (0.2 mL/10 g body weight) everyday. The weight of the nude mice and respective tumors, tumor volume and tumor-inhibiting rate were measured. Electron microscopy was used to observe the existence of apoptosis body. Apoptosis index (AI) was detected by TdT-mediated dUTP nick end labeling staining. The expression of Fas and FasL mRNA was investigated by reverse transcription polymerase chain reaction, while immunohistochemistry was applied to detect the protein expression of Fas and FasL, caspase-3 and caspase-activated DNase (CAD), respectively. RESULTS: Compared with CDDP group and control group, WCF could significantly reduce the tumor volume from the 19th day and alleviate the tumor weight (P <0.05), and the apoptosis body was found in tumor cells in the WCF group. WCF could also enhance the level of AI, up-regulate the expression of caspase apoptosis pathway related protein caspase-3 and CAD, as well as the expression of Fas, FasL mRNA and protein (P <0.05). CONCLUSION: WCF could improve the sensitivity of tumor cells to CDDP and reverse the drug resistance by inducing the apoptosis.

Asymmetric localizations of the ABC transporter PaPDR1 trace paths of directional strigolactone transport.

Strigolactones, first discovered as germination stimulants for parasitic weeds [1], are carotenoid-derived phytohormones that play major roles in inhibiting lateral bud outgrowth and promoting plant-mycorrhizal symbiosis [2-4]. Furthermore, strigolactones are involved in the regulation of lateral and adventitious root development, root cell division [5, 6], secondary growth [7], and leaf senescence [8]. Recently, we discovered the strigolactone transporter Petunia axillaris PLEIOTROPIC DRUG RESISTANCE 1 (PaPDR1), which is required for efficient mycorrhizal colonization and inhibition of lateral bud outgrowth [9]. However, how strigolactones are transported through the plant remained unknown. Here we show that PaPDR1 exhibits a cell-type-specific asymmetric localization in different root tissues. In root tips, PaPDR1 is co-expressed with the strigolactone biosynthetic gene DAD1 (CCD8), and it is localized at the apical membrane of root hypodermal cells, presumably mediating the shootward transport of strigolactone. Above the root tip, in the hypodermal passage cells that form gates for the entry of mycorrhizal fungi, PaPDR1 is present in the outer-lateral membrane, compatible with its postulated function as strigolactone exporter from root to soil. Transport studies are in line with our localization studies since (1) a papdr1 mutant displays impaired transport of strigolactones out of the root tip to the shoot as well as into the rhizosphere and (2) DAD1 expression and PIN1/PIN2 levels change in plants deregulated for PDR1 expression, suggestive of variations in endogenous strigolactone contents. In conclusion, our results indicate that the polar localizations of PaPDR1 mediate directional shootward strigolactone transport as well as localized exudation into the soil.

In vitro and in vivo inhibitory effect of the combination of Wenxia Changfu formula [see text] with cisplatin in non-small cell lung cancer.

OBJECTIVE: To observe the effect of the combination of Wenxia Changfu Formula ([see text], WCF) with cisplatin (CDDP) on inhibiting non-small cell lung cancer (NSCLC) in vitro and In Vivo and explore its mechanism from its effect on cell cycle. METHODS: In vitro, WCF-containing serum was prepared and the rhubarb b1, emodin, and aconitine were detected qualitatively by high-performance liquid chromatogram (HPLC). A549 cell lines were treated with blank control (dimethyl sulfoxide), normal serum, normal serum with CDDP (1.25, 2.5, and 5.0 µg/mL, respectively), WCF-containing serum plus different doses of CDDP (1.25, 2.5, and 5.0 µg/mL, respectively). The inhibitory effect was detected by 3-(4,5)-dimethylthiazo(-zy1)-3,5-diphenylterazolium bromide (MTT). The cell cycle was detected by flow cytometry. The protein and mRNA expressions of cyclin D1, proliferating cell nuclear antigen (PCNA), retinoblastoma (Rb), and p16 were observed with immunofluorescence and RT-PCR, respectively. In Vivo, nude mice xenograft model was established and grouped into the control, CDDP, WCF, and combination groups. The combination's inhibition of tumor growth and influence on the weight, spleen, and thymus gland were observed. RESULTS: The inhibitory rate of the combination against A549 cell lines excelled the CDDP alone significantly (P <0.05); the combination showed a synergism inhibitory effect (Q=1.19). Compared with the monotherapy, the combination increased the cell percentage in G(0)/G(1) phase and decreased the cell percentage in S phase significantly (P <0.05); the protein and mRNA expressions of cyclin D1, PCNA, and Rb were significantly reduced; the protein and mRNA expressions of p16 were significantly enhanced. Compared with the monotherapy, the combination inhibited the tumor growth significantly In Vivo and reduced the weight of tumor (P <0.05); compared with the CDDP group, the spleen and thymus gland index of the combination group were enhanced significantly (P <0.05). CONCLUSIONS: The combination of WCF with CDDP significantly inhibited the A549 cell lines proliferation in vitro and the growth of the tumor In Vivo; it inhibited effectively the atrophy of the immune organ caused by chemotherapy. The combination inhibited overproliferation of A549 cell lines by arresting the G(0) /G(1) phase of cell cycle and affecting the protein and mRNA expressions of cell cycle-related proteins, cyclin D1, etc.