Mitogen-activated Protein Kinase Signal Transduction Research Articles

Prevalence, incidence density and standardized morbidity rate of melanoma among patients with congenital melanocytic nevi: A systematic review.

Congenital melanocytic nevi (CMN) are the result of aberrations in the mitogen-activated protein kinase signal transduction pathway. The risk of melanoma is the most important concern among patients with CMN for its poor prognosis. However, due to the great variability between studies, the reported risk of melanoma varied considerably, making it difficult to provide reliable information. To evaluate the prevalence, incidence density and standardized morbidity ratio (SMR) of melanoma among patients with CMN, we conducted a systematic literature search of studies providing data on the risk of melanoma in CMN patients following our registered and published protocol (PROSPERO ID# CRD42022383009). Overall, twenty-seven studies with a total of 11480 CMN patients and 82 melanoma cases were included for analysis. The prevalence of melanoma was 1.84% [95% confidence interval (CI) 1.13%-2.99%] in CMN patients and 2.73% (95% CI 1.67%-4.33%) in patients with large CMN (LCMN). The incidence density of melanoma was 237.56 (95% CI 97.79-575.96) per 100,000 person-years (P-Y) in CMN patients and 585.73 (95% CI 315.39-1085.29) per 100,000 P-Y in the LCMN subgroup. The SMR of melanoma was 122.27 (95% CI 11.84-1262.88) among all CMN patients and 285.97 (95% CI 50.65-1614.59) in patients with LCMN. Our research suggests that the risk of melanoma in the CMN population seems to be overestimated by previous studies, but still significantly higher than that in the normal population. In addition to the risk of melanoma, aesthetic improvement and mental health should also be taken into account when making management decisions.

Patterns of change in regulatory modules of chemical reaction systems induced by network modification.

Cellular functions are realized through the dynamics of chemical reaction networks formed by thousands of chemical reactions. Numerical studies have empirically demonstrated that small differences in network structures among species or tissues can cause substantial changes in dynamics. However, a general principle for behavior changes in response to network structure modifications is not known. The chemical reaction system possesses substructures called buffering structures, which are characterized by a certain topological index being zero. It was proven that the steady-state response to modulation of reaction parameters inside a buffering structure is localized in the buffering structure. In this study, we developed a method to systematically identify the loss or creation of buffering structures induced by the addition of a single degradation reaction from network structure alone. This makes it possible to predict the qualitative and macroscopic changes in regulation that will be caused by the network modification. This method was applied to two reaction systems: the central metabolic system and the mitogen-activated protein kinases signal transduction system. Our method enables identification of reactions that are important for biological functions in living systems.

Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis.

Thromboembolism resulting from platelet dysfunction constitutes a significant contributor to the development of cardiovascular disease. Sirtuin 6 (SIRT6), an essential NAD+-dependent enzyme, has been linked to arterial thrombosis when absent in endothelial cells. In the present study, we have confirmed the presence of SIRT6 protein in anucleated platelets. However, the precise regulatory role of platelet endogenous SIRT6 in platelet activation and thrombotic processes has remained uncertain. Herein, we present compelling evidence demonstrating that platelets isolated from SIRT6-knockout mice (SIRT6-/-) exhibit a notable augmentation in thrombin-induced platelet activation, aggregation, and clot retraction. In contrast, activation of SIRT6 through specific agonist treatment (UBCS039) confers a pronounced protective effect on platelet activation and arterial thrombosis. Moreover, in platelet adoptive transfer experiments between wild-type (WT) and SIRT6-/- mice, the loss of SIRT6 in platelets significantly prolongs the mean thrombus occlusion time in a FeCl3-induced arterial thrombosis mouse model. Mechanistically, we have identified that SIRT6 deficiency in platelets leads to the enhanced expression and release of proprotein convertase subtilisin/kexin type 9 (PCSK9), subsequently activating the platelet activation-associated mitogen-activated protein kinase (MAPK) signaling pathway. These findings collectively unveil a novel protective role of platelet endogenous SIRT6 in platelet activation and thrombosis. This protective effect is, at least in part, attributed to the inhibition of platelet PCSK9 secretion and mitogen-activated protein kinase signaling transduction. Our study provides valuable insights into the intricate interplay between SIRT6 and platelet function, shedding light on potential therapeutic avenues for managing thrombotic disorders.

A clinical and biologic review of congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are the result of aberrations in the mitogen-activated protein kinase signal transduction pathway caused by postzygotic somatic mutations. The estimated incidence of newborns with CMN is 1%-2%. The main complications of CMN include proliferative nodules, melanomas, and neurocutaneous melanosis, and the latter two are the most troublesome issues to address. Treatments are primarily taken into account for aesthetic purposes and the reduction of melanoma risk. Due to the much lower incidence of malignant transformation observed in recent studies than in previous data, clinical management paradigms for CMN patients have gradually shifted towards conservative observation and close monitoring. Surgery and lasers are still the main treatments, and targeted therapy may be a promising strategy to help manage complications. With the increase in awareness of mental health, increasing focus has been placed on the quality of life (QoL) and psychological issues of both CMN patients and their parents. Recent studies have revealed that families coping with CMN might endure intense pressure, a major loss in QoL, and psychological problems after diagnosis and during treatment. Here, we sought to present an overview of genetic basis, complications, treatments, and psychological issues related to CMN and hope to provide better management for patients with CMN.

The role of epidermal growth factor and cholinergic receptor agonists and antagonists in MAPK signal transduction in K562 cells

Objective: Muscarinic receptors (M1-M5) are members of the G protein-coupled receptor superfamily and are effective in physiological
 functions through G proteins. Recent studies suggested that cholinergic receptors mediate cellular activities in hematopoietic cells.
 The aim of this study was to investigate the potential role of mitogen-activated protein kinases (MAPK) signaling extracellular signalregulated
 kinases 1 and 2 (ERK1/2)/phosphorylated ERK1/ (pERK1/2) pathways in chronic myeloid leukemia (K562) cells.
 Materials and Methods: Chronic myeloid leukemia cells were cultured. Cells were incubated in the presence of muscarinic receptor
 agonist, antagonist and epidermal growth factor (EGF). To detect MAPK activation, ERK/pERK protein expression levels were
 determined by western blot method techniques.
 Results: Our study results showed that cholinergic agents and EGFs affect the MAPK pathway in the human K562 cell line.
 Conclusion: Cholinergic and EGF receptors may affect the MAPK pathway in K562 cells.
 Conclusion: Cholinergic and EGF receptors may affect the MAPK pathway in K562 cells.

Synthesis and Biological Properties of Pyranocoumarin Derivatives as Potent Anti-Inflammatory Agents.

This study aimed to synthesize 23 coumarin derivatives and analyze their anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. A cytotoxicity test performed on LPS-induced RAW264.7 macrophages revealed that none of the 23 coumarin derivatives were cytotoxic. Among the 23 coumarin derivatives, coumarin derivative 2 showed the highest anti-inflammatory activity by significantly reducing nitric oxide production in a concentration-dependent manner. Coumarin derivative 2 inhibited the production of proinflammatory cytokines, including tumor necrosis factor alpha and interleukin-6, and decreased the expression level of each mRNA. In addition, it inhibited the phosphorylation of extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase, nuclear factor kappa-B p65 (NF-κB p65), and inducible nitric oxide synthase. These results indicated that coumarin derivative 2 inhibited LPS-induced mitogen-activated protein kinase and NF-κB p65 signal transduction pathways in RAW264.7 cells, as well as proinflammatory cytokines and enzymes related to inflammatory responses, to exert anti-inflammatory effects. Coumarin derivative 2 showed potential for further development as an anti-inflammatory drug for the treatment of acute and chronic inflammatory diseases.

Anlotinib Enhances the Therapeutic Effect of Bladder Cancer with GSDMB Expression: Analyzed from TCGA Bladder Cancer Database & Mouse Bladder Cancer Cell Line.

The mitogen-activated protein kinase (MAPK) pathway is inhibited by the pan-target inhibitor Anlotinib, which induces tumor cell death. In addition to the common apoptosis and necrosis, there is also a pyroptosis mode of cancer cell death in recent years, which is mainly manifested by the cleavage of gasdermin proteins (GSDMs). Gasdermin B (GSDMB) participates in the progression and outcome of bladder cancer. The efficacy and mechanism of Anlotinib in the treatment of GSDMB-positive bladder tumors have not been studied to date. The relationship between GSDMB expression and tumor stage, overall survival rate, immunotherapy response, tumor recurrence and progression rate was analyzed from the TCGA bladder cancer database. Anlotinib was used to treat GSDMB-positive bladder cancer in mice followed by flow analysis of the secretion of inflammatory factors related to pyroptosis and the level of anti-tumor factors. Western blot analysis detected which MAPK and MEK signal transduction pathways. TCGA data analysis showed that the overall survival rate of bladder cancer patients with high GSDMB expression was better than that of patients with low GSDMB expression. In vivo experiments showed that Anlotinib was more effective in the treatment of GSDMB-positive bladder cancer than GSDMB-negative bladder cancer. Anlotinib can increase the secretion of antitumor-related factors in GSDMB-positive bladder cancer such as TNF-a and CD107a. In addition, Anlotinib also induced an increase in GSDMB protein expression. Anlotinib treatment of GSDMB-positive bladder cancer decreased AKT and MEK protein expression, which were involved in Anlotinib signal transduction pathway. Anlotinib has a strong antitumor effect on GSDMB-positive bladder tumors. This effect is mainly achieved by anlotinib stimulating the secretion of relevant antitumor factors by lymphocytes. The PI3K/AKT and MEK signal transduction pathways were inhibited by Anlotinib in bladder cancer expressing GSDMB protein.

Effect of shading on physiological attributes and comparative transcriptome analysis of Camellia sinensis cultivar reveals tolerance mechanisms to low temperatures.

Tea is a vital beverage crop all over the world, including in China. Low temperatures restrict its growth, development, and terrestrial distribution, and cold event variability worsens cold damage. However, the physiological and molecular mechanisms of Camellia sinensis under shade in winter remain unclear. In our study, tea leaves were utilized for physiological attributes and transcriptome analysis in November and December in three shading groups and no-shade control plants. When compared to the no-shade control plants, the shading group protected tea leaves from cold damage, increased photochemical efficiency (Fv/Fm) and soil plant analysis development (SPAD), and sustained chlorophyll a, chlorophyll b, chlorophyll, and carotenoid contents by physiological mean. Then, transcriptome analysis revealed 20,807 differentially expressed genes (DEGs) and transcription factors (TFs) in November and December. A comparative study of transcriptome resulted in 3,523 DEGs and many TFs under SD0% vs. SD30%, SD0% vs. SD60%, and SD0% vs. SD75% of shading in November and December. Statistically, 114 DEGs were downregulated and 72 were upregulated under SD0% vs. SD30%. SD0% vs. SD60% resulted in 154 DEGs, with 60 downregulated and 94 upregulated. Similarly, there were 505 DEGs of which 244 were downregulated and 263 were upregulated under SD0% vs. SD75% of shading throughout November. However, 279 DEGs were downregulated and 105 were upregulated under SD0% vs. SD30%. SD0% vs. SD60% resulted in 296 DEGs, with 172 downregulated and 124 upregulated. Finally, 2,173 DEGs were regulated in December, with 1,428 downregulated and 745 upregulated under SD0% vs. SD75%. These indicate that the number of downregulated DEGs in December was higher than the number of upregulated DEGs in November during low temperatures. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of differentially expressed genes were highly regulated in the photosynthesis, plant hormone signal transduction, and mitogen-activated protein kinase (MAPK) signaling pathways. However, qRT-PCR and RNA-seq relative expression of photosynthetic (DEGs) Lhcb2 in both November and December, plant hormone (DEGs) BRI1 and JAZ in November and IAA and ERF1 in December, and key DEGs of MAPK signal transduction FLS2, CHIB, and MPK4 in November and RBOH, MKK4_5, and MEKK1 in December in three shading groups and no-shade control plants responded to tea cold tolerance. The enhanced expression of light-harvesting photosystem I gene Lhca5, light-harvesting photosystem II gene Lhcb2, and mitogen-activated protein kinases MEKK1 and MPK4/6 enhance the cold-tolerance mechanism of C. sinensis. These comprehensive transcriptomic findings are significant for furthering our understanding of the genes and underlying regulatory mechanisms of shade-mediated low-temperature stress tolerance in horticultural crops.

Metabolomic and Transcriptome Analysis of the Inhibitory Effects of Bacillus subtilis Strain Z-14 against Fusarium oxysporum Causing Vascular Wilt Diseases in Cucumber

Controlling cucumber Fusarium wilt caused by Fusarium oxysporum f. sp. cucumerinum (FOC) with Bacillus strains is a hot research topic. However, the molecular mechanism of Bacillus underlying the biocontrol of cucumber wilt is rarely reported. In this study, B. subtilis strain Z-14 showed significant antagonistic activity against FOC, and the control effect reached 88.46% via pot experiment. Microscopic observations showed that strain Z-14 induced the expansion and breakage of FOC hyphae. The cell wall thickness was uneven, and the organelle structure was degraded. The combined analysis of metabolome and transcriptome showed that strain Z-14 inhibited the FOC infection by inhibiting the synthesis of cell wall and cell membrane, energy metabolism, and amino acid synthesis of FOC mycelium, inhibiting the clearance of reactive oxygen species (ROS) and the secretion of cell wall-degrading enzymes (CWDEs), thereby affecting mitogen-activated protein kinase (MAPK) signal transduction and inhibiting the transport function.

Effect on MAPK Signal Path of Lead, Nickel, Mercury, Cadmium and Chromium in Breast Cancer Cell Line

The harms of heavy metals such as cadmium and lead on human health have been identified in the literature. However, genetic mechanisms that show the relationship between heavy metals and cancer have not been identified up to now. In the proposed project, the effects of lead, nickel, mercury, cadmium, and chrome on the expression levels of mitogen-activated protein kinase signal transduction pathways in breast cancer cell lines will be quantified by the Real Time-Polymerase Chain Reaction method, comparatively. Mitogen-activated protein kinase signal transduction pathway, found in eukaryotic organisms, plays a significant role in information transfer from the cell membrane to the nucleus. Genes in this signal transfer regulate embryogenesis, reproduction, diversification, survival, and apoptosis functions. Most of these genes are well-known oncogenes and each of these is an important subject in cancer treatment. The changes of gene expression levels in this transduction pathway can be the reason of breast and some other cancer types. According to the findings, when the heavy metal-treated cells were compared with the heavy metal-untreated cells, significant changes were observed in the level of expression of 47 genes in the signal pathway. It has been determined that heavy metals cause changes in the expression level of genes in the signaling pathway according to the obtained data.

Natural Compound Allicin Containing Thiosulfinate Moieties as Transmembrane Protein 16A (TMEM16A) Ion Channel Inhibitor for Food Adjuvant Therapy of Lung Cancer.

Cancer is one of the most serious malignant diseases, and chemotherapy is cancer's main clinical treatment method. However, chemotherapy inevitably produces drug resistance, and side effects accompany them. Adjuvant therapy is an effective way to enhance chemotherapeutic drug sensitivity and reduce side effects. This study found allicin, garlic's active ingredient, is an inhibitor of transmembrane protein 16A (TMEM16A), a novel drug target of lung adenocarcinoma. Allicin concentration-dependently inhibited TMEM16A currents with an IC50 of 24.35 ± 4.14 μM. Allicin thiosulfinate moieties bound with R535A/E624A/E633A residues of TMEM16A blocked the ion transport function and downregulated TMEM16A protein expression affecting the mitogen-activated protein kinase signal transduction. Then, allicin reduced the viability and migration of LA795 cells, and induced cell apoptosis. Moreover, multitarget combination administration results indicated that the therapeutic effect of 3.56 mg/kg allicin and 3 mg/kg cisplatin combined administration was superior to the superposition of the two drugs alone, demonstrating that the anticancer effects of allicin and cisplatin were synergistic. In addition, low-concentration combined administration also avoided the side effects of cisplatin in mice. Based on the good tumor suppressor effect and high biosafety of allicin and cisplatin combination in vivo, allicin can be used for food adjuvant therapy of cisplatin chemotherapy.

Stress signaling boosts interferon-induced gene transcription in macrophages.

Promoters of antimicrobial genes function as logic boards, integrating signals of innate immune responses. One such set of genes is stimulated by interferon (IFN) signaling, and the expression of these genes [IFN-stimulated genes (ISGs)] can be further modulated by cell stress-induced pathways. Here, we investigated the global effect of stress-induced p38 mitogen-activated protein kinase (MAPK) signaling on the response of macrophages to IFN. In response to cell stress that coincided with IFN exposure, the p38 MAPK-activated transcription factors CREB and c-Jun, in addition to the IFN-activated STAT family of transcription factors, bound to ISGs. In addition, p38 MAPK signaling induced activating histone modifications at the loci of ISGs and stimulated nuclear translocation of the CREB coactivator CRTC3. These actions synergistically enhanced ISG expression. Disrupting this synergy with p38 MAPK inhibitors improved the viability of macrophages infected with Listeria monocytogenes. Our findings uncover a mechanism of transcriptional synergism and highlight the biological consequences of coincident stress-induced p38 MAPK and IFN-stimulated signal transduction.

Enhanced Resistance to Sclerotinia sclerotiorum in Brassica rapa by Activating Host Immunity through Exogenous Verticillium dahliae Aspf2-like Protein (VDAL) Treatment.

Sclerotinia stem rot caused by Sclerotinia sclerotiorum is one of the most destructive diseases in Brassica rapa. Verticillium dahliae Aspf2-like protein (VDAL) is a secretory protein of V. dahliae which has been shown to enhance the resistance against fungal infections in several plants. Nonetheless, the molecular mechanisms of VDAL-primed disease resistance are still poorly understood. In this study, we performed physiological, biochemical, and transcriptomic analyses of Brassica rapa in order to understand how VDAL confers resistance to S. sclerotiorumn infections in plants. The results showed that foliar application of VDAL significantly reduced the plaque area on leaves inoculated with S. sclerotiorum. It also enhanced antioxidant capacity by increasing activities of superoxide dismutase (SOD), peroxidase (POD), peroxidase (APX), glutathione reductase (GR), protoporphyrinogen oxidase (PPO), and defense-related enzymes β-1,3-glucanase and chitinase during the infection periods. This occurred in parallel with significantly reduced relative conductivity at different periods and lower malondialdehyde (MDA) content as compared to sole S. sclerotiorum inoculation. Transcriptomic analysis showed a total of 146 (81 up-regulated and 65 down-regulated) differentially expressed genes (DEGs) in VDAL-treated leaves compared to the control. The most enriched three Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were the mitogen-activated protein kinase (MAPK) signaling pathway, plant hormone signal transduction, and plant-pathogen interaction, all of which were associated with plant immunity. DEGs associated with MAPK and hormone signal transduction pathways were ethylene response sensor ERS2, EIN3 (Ethylene Insensitive3)-binding F-box protein 2 (EBF2), ethylene-responsive transcription factor ERF94, MAPK 9 (MKK9), protein phosphatase 2C (PP2C37), auxin-responsive proteins (AUX/IAA1 and 19), serine/threonine-protein kinase CTR1, and abscisic acid receptors (PLY 4 and 5). Among the DEGs linked with the plant-pathogen interaction pathway were calmodulin-like proteins (CML5, 24, 27), PTI1-like tyrosine protein kinase 3 (Pti13) and transcription factor MYB30, all of which are known to play key roles in pathogen-associated molecular pattern (PAMP)-triggered immunity and effector-triggered immunity (ETI) for hypersensitive response (HR), cell wall reinforcement, and stomatal closure in plants. Overall, VDLA treatment triggered repression of the auxin and ABA signaling pathways and de-repression of the ethylene signaling pathways in young B. rapa seedlings to increase plant innate immunity. Our results showed that VDAL holds great potential to enhance fungal disease resistance in B. rapa crop.

Selenium ameliorates inflammation by decreasing autophagic flux and mitogen-activated protein kinase signalling on experimentally induced rat periapical lesions.

To reveal the molecular mechanisms that targets mitogen-activated protein kinase (MAPK) signalling and the autophagic flux and to investigate the possible effects of the systemic administration of selenium (Se) on experimentally induced rat periapical lesions. Thirty adult Sprague-Dawley rats were divided equally into negative control, positive control and Se groups. In the positive control and Se groups, the pulp chambers of their mandibular first molars were exposed to the oral environment to induce periapical lesions The Se group received daily intraperitoneal injections of Se at a dose of 0.1mg kg-1 . After 28 days, the amount of bone destruction; severity of inflammation; penetration of microorganisms along the root canal; collagen degradation in periodontal ligament; interleukin (IL)-6, hypoxia-inducible factor-1 (HIF-1), cyclooxygenase-2 (COX-2) and caspase-3 expression; autophagic flux; and p38 MAPK signalling were evaluated using radiographic, histopathological, Gram staining, picrosirius red stain, immunohistochemical, quantitative real-time polymerase chain (qRT-PCR) and Western blot methods, respectively. These data were analysed through the Kruskal-Wallis and Dunnett's tests (p < .05). The area of radiographic periapical bone loss, histopathological scores, the area of periapical bone loss and the scores for the bacteria localisation, the intensity of immunohistochemical staining for IL-6, HIF-1, COX-2 and caspase-3 in the Se group was significantly less than those of the positive control group (p < .01). The mRNA expression levels of Beclin-1, Atg3, Atg5, Atg7 and Atg16L1 were lower in the Se group than in the positive control group (p < .01). The protein expressions of Beclin-1, Atg5 and LC3-II, the phosphorylation ratio of the p38 MAPK and the ratios of LC3II/LC3I were significantly higher (p < .05) in the positive control and Se groups. On the contrary, the expression of the p62/SQSTM1 protein was significantly lower (p < .05) in the positive control and Se groups than in the negative control group. The induction of periapical lesions in rats increased autophagic flux and activated p38 MAPK signal transduction processes. Se suppressed the inflammatory process, reduced bone destruction and both the autophagic flux and p38 MAPK activation.

Nitric oxide alleviates salt stress through protein S-nitrosylation and transcriptional regulation in tomato seedlings.

NO enhances the resistance of tomato seedlings to salt stress through protein S-nitrosylation and transcriptional regulation, which involves the regulation of MAPK signaling and carbohydrate metabolism. Nitric oxide (NO) regulates various physiological and biochemical processes and stress responses in plants. We found that S-nitrosoglutathione (GSNO) treatment significantly promoted the growth of tomato seedling under NaCl stress, indicating that NO plays a positive role in salt stress resistance. Moreover, GSNO pretreatment resulted in an increase of endogenous NO level, S-nitrosothiol (SNO) content, S-nitrosoglutathione reductase (GSNOR) activity and GSNOR expression under salt stress, implicating that S-nitrosylation might be involved in NO-alleviating salt stress. To further explore whether S-nitrosylation is a key molecular mechanism of NO-alleviating salt stress, the biotin-switch technique and liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS) were conducted. Atotal of 1054 putative S-nitrosylated proteins have been identified, which were mainly enriched in chloroplast, cytoplasm and mitochondrion. Among them, 15 and 22 S-nitrosylated proteins were involved in mitogen-activated protein kinase (MAPK) signal transduction and carbohydrate metabolism, respectively. In MAPK signaling, various S-nitrosylated proteins, SAM1, SAM3, SAM, PP2C and SnRK, were down-regulated and MAPK, MAPKK and MAPKK5 were up-regulated at the transcriptional level by GSNO treatment under salt stress compared to NaCl treatment alone. The GSNO pretreatment could reduce ethylene production and ABA content under NaCl stress. In addition, the activities of enzyme identified in carbohydrate metabolism, their expression at the transcriptional level and the metabolite content were up-regulated by GSNO supplication under salt stress, resulting in the activation of glycolysis and tricarboxylic acid cycle (TCA) cycles. Thus, these results demonstrated that NO might beneficially regulate MAPK signaling at transcriptional levels and activate carbohydrate metabolism at the post-translational and transcriptional level, protecting seedlings from energy deficiency and salinity, thereby alleviating salt stress-induced damage in tomato seedlings. It provides initial insights into the regulatory mechanisms of NO in response to salt stress.

Reprisal of Schima superba to Mn stress and exploration of its defense mechanism through transcriptomic analysis.

One of the most diverse protein families, ATP-binding cassette (ABC) transporters, play a role in disease resistance, heavy metal tolerance, and food absorption.Differentially expressed genes contribute in the investigation of plant defense mechanisms under varying stress conditions. To elucidate the molecular mechanisms involved in Mn metal stress, we performed a transcriptomic analysis to explore the differential gene expression in Schima superba with the comparison of control. A total of 79.84 G clean data was generated and 6558 DEGs were identified in response to Mn metal stress. Differentially expressed genes were found to be involved in defense, signaling pathways, oxidative burst, transcription factors and stress responses. Genes important in metal transport were more expressive in Mn stress than control plants. The investigation of cis-acting regions in the ABC family indicated that these genes might be targeted by a large variety of trans-acting elements to control a variety of stress circumstances. Moreover, genes involved in defense responses, the mitogen-activated protein kinase (MAPK) signaling and signal transduction in S. superba were highly induced in Mn stress. Twenty ABC transporters were variably expressed on 1st, 5th, and 10th day of Mn treatment, according to the qRT PCR data. Inclusively, our findings provide an indispensable foundation for an advanced understanding of the metal resistance mechanisms. Our study will enrich the sequence information of S. superba in a public database and would provide a new understanding of the molecular mechanisms of heavy metal tolerance and detoxification.

Transcriptome and metabolome profiling of interspecific CSSLs reveals general and specific mechanisms of drought resistance in cotton.

In order to understand the molecular mechanism of cotton's response to drought during the flowering and boll stage, transcriptomics and metabolomics were carried out for two introgression lines (drought-tolerant line: T307; drought-sensitive line: S48) which were screened from Gossypium hirsutum cv. 'Emian22' with some gene fragments imported from Gossypium barbadense acc. 3-79, under drought stress by withdrawing water at flowering and boll stage. Results showed that the basic drought response in cotton included a series of broad-spectrum responses, such as amino acid synthesis, hormone (abscisic acid, ABA) signal transduction, and mitogen-activated protein kinases signal transduction pathway, which activated in both drought-tolerant and drought-sensitive lines. However, the difference of their imported fragments and diminished sequences triggers endoplasmic reticulum (ER) protein processing, photosynthetic-related pathways (in leaves), and membrane solute transport (in roots) in drought-tolerant line T307, while these are missed or not activated in drought-sensitive line S48, reflecting the different drought tolerance of the two genotypes. Virus-induced gene silencing assay of drought-tolerant differentially expressed heat shock protein (HSP) genes (mainly in leaf) and ATP-binding cassette (ABC) transporter genes (mainly in roots) indicated that those genes play important role in cotton drought tolerant. Combined analysis of transcriptomics and metabolomics highlighted the important roles of ER-stress-related HSP genes and root-specific ABC transporter genes in plants drought tolerance. These results provide new insights into the molecular mechanisms underlying the drought stress adaptation in cotton.

Therapeutic application of carvacrol: A comprehensive review.

Carvacrol is a major natural constituent and is significantly present as an essential oil in aromatic plants and is well known for its numerous biological activities. Therapeutic properties of carvacrol have been demonstrated as anti-oxidant, anticancer, diabetes prevention, cardioprotective, anti-obesity, hepatoprotective and reproductive role, antiaging, antimicrobial, and immunomodulatory properties. The carvacrol biosynthesis has been mediated through mevalonate pathway. Carvacrol has the anticancer ability against malignant cells via decreasing the expressions of matrix metalloprotease 2 and 9, inducing apoptosis, enhancing the expression of pro-apoptotic proteins, disrupting mitochondrial membrane, suppressing extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signal transduction, and also decreasing the phosphoinositide 3-kinase/protein kinase B. It also decreased the concentrations of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase, and gamma-glutamyl transpeptidase as well as also restored liver function, insulin level, and plasma glucose level. Carvacrol also has been found to exert antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Coagulase-negative staphylococcus, Salmonella spp., Enterococcus sp. Shigella, and Escherichia coli. The current review article summarizes the health-promoting perspectives of carvacrol through various pathways.

A curcumin-induced assembly of a transferrin nanocarrier system and its antitumor effect

To increase the solubility and targeting efficiency of curcumin (CCM) to tumors, transferrin (Tf)-CCM nanoparticles (NPs-CCM) with a CCM loading capacity of 5.2% were fabricated by Tf denaturation with hydrochloric acid, a denaturing agent, to open the hydrophobic cavity of Tf. The NPs-CCM were approximately 160 nm in size with a spherical shape. The solubility of the CCM in the nanoparticles was approximately 100,000 times greater than that of CCM alone (11 ng mL−1 vs 1.11 mg mL−1, respectively). The changes in the fluorescence spectra of Tf and 1-(anilinon)-aphthalene-8-sulfonic acid (ANS) in the NP-CCM preparation indicated that the polarity of certain hydrophobic and hydrophilic groups of Tf changed. CCM treatment of A549 cells resulted in a decrease in the mitochondrial membrane potential (MMP) and induced apoptosis through mitochondrial dependence. CCM increased the expression of phosphorylated c-Jun N-terminal kinase (JNK), P38, and extracellular signal-regulated kinase (ERK) but had a weak effect on the expression of nonphosphorylated JNK, P38, and ERK, which showed that the mitogen-activated protein kinase signaling (MAPK) transduction pathway is involved in CCM-mediated apoptosis. The half maximal inhibitory concentration (IC50) of NPs-CCM was higher than that of free CCM in A549 (16.41 ± 0.86 vs 12.51 ± 3.9 (μg mL−1), p = 0.036) and MCF-7 (9.31 ± 0.11 vs 2.44 ± 3.76 (μg mL−1), p < 0.0037) tumor cells, however the former had a greater tumor-targeting in vivo. Without the side effects of polyoxyethylene castor oil/ethanol as solvent, the hemolysis effect of NPs-CCM (0.05–1 mg mL−1) was notably lower than that of free CCM (p < 0.05). It was estimated that the half maximal lethal dose (LD50) of NPs-CCM was approximately two times that of CCM (100 mg kg−1 vs 50 mg kg−1), and the former had many advantages over that of free CCM in terms of lower toxicity and better targeting; thus, NPs-CCM can be administered at higher doses to acquire better antitumor effects than CCM alone, indicating that NPs-CCM are an effective and safe carrier for CCM delivery.

Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy.

Cisplatin and other platinum-based drugs, such as carboplatin, ormaplatin, and oxaliplatin, have been widely used to treat a multitude of human cancers. However, a considerable proportion of patients often relapse due to drug resistance and/or toxicity to multiple organs including the liver, kidneys, gastrointestinal tract, and the cardiovascular, hematologic, and nervous systems. In this study, we sought to provide a comprehensive review of the current state of the science highlighting the use of cisplatin in cancer therapy, with a special emphasis on its molecular mechanisms of action, and treatment modalities including the combination therapy with natural products. Hence, we searched the literature using various scientific databases., such as MEDLINE, PubMed, Google Scholar, and relevant sources, to collect and review relevant publications on cisplatin, natural products, combination therapy, uses in cancer treatment, modes of action, and therapeutic strategies. Our search results revealed that new strategic approaches for cancer treatment, including the combination therapy of cisplatin and natural products, have been evaluated with some degree of success. Scientific evidence from both in vitro and in vivo studies demonstrates that many medicinal plants contain bioactive compounds that are promising candidates for the treatment of human diseases, and therefore represent an excellent source for drug discovery. In preclinical studies, it has been demonstrated that natural products not only enhance the therapeutic activity of cisplatin but also attenuate its chemotherapy-induced toxicity. Many experimental studies have also reported that natural products exert their therapeutic action by triggering apoptosis through modulation of mitogen-activated protein kinase (MAPK) and p53 signal transduction pathways and enhancement of cisplatin chemosensitivity. Furthermore, natural products protect against cisplatin-induced organ toxicity by modulating several gene transcription factors and inducing cell death through apoptosis and/or necrosis. In addition, formulations of cisplatin with polymeric, lipid, inorganic, and carbon-based nano-drug delivery systems have been found to delay drug release, prolong half-life, and reduce systemic toxicity while other formulations, such as nanocapsules, nanogels, and hydrogels, have been reported to enhance cell penetration, target cancer cells, and inhibit tumor progression.