Asymmetric Carbene-Alkyne Metathesis-Mediated Cascade: Synthesis of Benzoxazine Polychiral Polyheterocycles and Discovery of a Novel Pain Blocker.

This study introduces a novel approach for synthesizing Benzoxazine-centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene-alkyne metathesis-triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis-mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co-catalysis, ensuring precise stereo control as validated by X-ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo- and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy-induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1-Nav1.7 connection in the context of CIPN.

Aging-Accelerated Mouse Prone 8 (SAMP8) Mice Experiment and Network Pharmacological Analysis of Aged Liupao Tea Aqueous Extract in Delaying the Decline Changes of the Body.

Aging and metabolic disorders feedback and promote each other and are closely related to the occurrence and development of cardiovascular disease, type 2 diabetes, neurodegeneration and other degenerative diseases. Liupao tea is a geographical indication product of Chinese dark tea, with a "red, concentrated, aged and mellow" flavor quality. In this study, the aqueous extract of aged Liupao tea (ALPT) administered by continuous gavage significantly inhibited the increase of visceral fat and damage to the intestinal-liver-microbial axis in high-fat modeling of SAMP8 (P8+HFD) mice. Its potential mechanism is that ALPT significantly inhibited the inflammation and aggregation formation pathway caused by P8+HFD, increased the abundance of short-chain fatty acid producing bacteria Alistipes, Alloprevotella and Bacteroides, and had a calorie restriction effect. The results of the whole target metabolome network pharmacological analysis showed that there were 139 potential active components in the ALPT aqueous extract, and the core targets of their actions were SRC, TP53, AKT1, MAPK3, VEGFA, EP300, EGFR, HSP90AA1, CASP3, etc. These target genes were mainly enriched in cancer, neurodegenerative diseases, glucose and lipid metabolism and other pathways of degenerative changes. Molecular docking further verified the reliability of network pharmacology. The above results indicate that Liupao tea can effectively delay the body's degenerative changes through various mechanisms and multi-target effects. This study revealed that dark tea such as Liupao tea has significant drinking value in a modern and aging society.

Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Nav1.7 Voltage-Gated Sodium Channel.

Neuropathic pain is a refractory chronic disease affecting millions of people worldwide. Given that present painkillers have poor efficacy or severe side effects, developing novel analgesics is badly needed. The multiplex structure of active ingredients isolated from natural products provides a new source for phytochemical compound synthesis. Here, we identified a natural product, Narirutin, a flavonoid compound isolated from the Citrus unshiu, showing antinociceptive effects in rodent models of neuropathic pain. Using calcium imaging, whole-cell electrophysiology, western blotting, and immunofluorescence, we uncovered a molecular target for Narirutin's antinociceptive actions. We found that Narirutin (i) inhibits Veratridine-triggered nociceptor activities in L4-L6 rat dorsal root ganglion (DRG) neurons, (ii) blocks voltage-gated sodium (NaV) channels subtype 1.7 in both small-diameter DRG nociceptive neurons and human embryonic kidney (HEK) 293 cell line, (iii) does not affect tetrodotoxin-resistant (TTX-R) NaV channels, and (iv) blunts the upregulation of Nav1.7 in calcitonin gene-related peptide (CGRP)-labeled DRG sensory neurons after spared nerve injury (SNI) surgery. Identifying Nav1.7 as a molecular target of Narirutin may further clarify the analgesic mechanism of natural flavonoid compounds and provide an optimal idea to produce novel selective and efficient analgesic drugs.

Synergistic effects of epigallocatechin gallate and l-theanine in nerve repair and regeneration by anti-amyloid damage, promoting metabolism, and nourishing nerve cells.

Green tea has significant protective activity on nerve cells, but the mechanism of action is unclear. Epigallocatechin gallate (EGCG) and N-ethyl-L-glutamine (L-theanine) are the representative functional components of green tea (Camellia sinensis). In this study, an AD model of Aß25-35-induced differentiated neural cell line PC12 cells was established to study the synergistic effect of EGCG and L-theanine in protecting neural cells. The results showed that under Aß25-35 stress conditions, mitochondria and axons degenerated, and the expression of cyclins was up-regulated, showing the gene and protein characteristics of cellular hyperfunction. EGCG + L-theanine inhibited inflammation and aggregate formation pathways, significantly increased the percentage of G0/G1 in the cell cycle, downregulated the expression of proteins such as p-mTOR, Cyclin D1, and Cyclin B1, upregulated the expression of GAP43, Klotho, p-AMPK, and other proteins, promoted mitochondrial activity and energy metabolism, and had repair and regeneration effects on differentiated nerve cells. The synergistic mechanism study showed that under the premise that EGCG inhibits amyloid stress and inflammation and promotes metabolism, L-theanine could play a nourish nerve effect. EGCG + L-theanine keeps differentiated nerve cells in a quiescent state, which is beneficial to the repair and regeneration of nerve cells. In addition, EGCG + L-theanine maintains the high-fidelity structure of cellular proteins. This study revealed for the first time that the synergistic effect of EGCG with L-theanine may be an effective way to promote nerve cell repair and regeneration and slow down the progression of AD. Our findings provide a new scientific basis for the relationship between tea drinking and brain protection.

Inhibitory Effects of Six Types of Tea on Aging and High-Fat Diet-Related Amyloid Formation Activities.

Aging and lipid metabolism disorders promote the formation and accumulation of amyloid with ß-sheet structure, closely related to cardiovascular disease, senile dementia, type 2 diabetes, and other senile degenerative diseases. In this study, five representative teas were selected from each of the six types of tea, and a total of 30 teas were selected to evaluate the inhibitory activities on the formation of aging-related amyloid in vitro. The results showed that the 30 teas had a significant inhibitory effect on the formation activity on aging-related amyloid at the protein level in vitro. Although the content of catechins is relatively low, black tea and dark tea still have significant antioxidant activity and inhibit the formation of amyloid. A high-fat diet established the model of lipid metabolism disorder in premature aging SAMP8 mice, and these mice were gavaged different tea water extracts. The results showed that different tea types have a significant inhibitory effect on the formation of ß-amyloid and Aß42 mediated by age-related lipid metabolism disorders, and the in vivo activity of fully fermented teas was better than that of green tea. The action mechanism was related to antioxidation, anti-inflammatory, and improving lipid metabolism.

Anti-damage effect of theaflavin-3'-gallate from black tea on UVB-irradiated HaCaT cells by photoprotection and maintaining cell homeostasis.

Keratinocytes are rich in lipids and are the main sensitive cells to ultraviolet (UV) rays. Theaflavins are the core functional components of black tea and are known as the "soft gold" in tea. In this study, ultraviolet-B (UVB) irradiation caused apoptosis and necrosis of human epidermal keratinocytes (HaCaT). EGCG and the four theaflavins had anti-UVB damage activity, among which theaflavin-3'-gallate (TF3'G) had the best activity. The results of biophysical and molecular biology experiments showed that TF3'G has anti-damage effects on UVB-irradiated HaCaT cells through the dual effects of photoprotection and maintenance of cell homeostasis. That is, TF3'G preincubation could absorb UV rays, reduce the accumulation of aging-related heterochromatin (SAHF) formation, increase mitochondrial membrane potential, downregulate NF-κB inflammation pathways, inhibit the formation of cytotoxic aggregates, and protect biological macromolecules Structure, etc. The accumulation of conjugated π bonds and the balance benzoquinone are the core functional structure of TF3'G with high efficiency and low toxicity. The study indicates that TF3'G has the potential to inhibit the photoaging and intrinsic aging of skin cells.

Research progress of epigallocatechin-3-gallate (EGCG) on anti-pathogenic microbes and immune regulation activities.

At the end of 2019, the COVID-19 virus spread worldwide, infecting millions of people. Infectious diseases induced by pathogenic microorganisms such as the influenza virus, hepatitis virus, and Mycobacterium tuberculosis are also a major threat to public health. The high mortality caused by infectious pathogenic microorganisms is due to their strong virulence, which leads to the excessive counterattack by the host immune system and severe inflammatory damage of the immune system. This paper reviews the efficacy, mechanism and related immune regulation of epigallocatechin-3-gallate (EGCG) as an anti-pathogenic microorganism drug. EGCG mainly shows both direct and indirect anti-infection effects. EGCG directly inhibits early infection by interfering with the adsorption on host cells, inhibiting virus replication and reducing bacterial biofilm formation and toxin release; EGCG indirectly inhibits infection by regulating immune inflammation and antioxidation. At the same time, we reviewed the bioavailability and safety of EGCG in vivo. At present, the bioavailability of EGCG can be improved to some extent using nanostructured drug delivery systems and molecular modification technology in combination with other drugs. This study provides a theoretical basis for the development of EGCG as an adjuvant drug for anti-pathogenic microorganisms.

Research progress on the potential delaying skin aging effect and mechanism of tea for oral and external use.

Skin aging is characterized by the gradual loss of elasticity, the formation of wrinkles and various color spots, the degradation of extracellular matrix proteins, and the structural changes of the dermis. With the increasingly prominent problems of environmental pollution, social pressure, ozone layer thinning and food safety, skin problems have become more and more complex. The skin can reflect the overall health of the body. Skincare products for external use alone cannot fundamentally solve skin problems; it needs to improve the overall health of the body. Based on the literature review in recent 20 years, this paper systematically reviewed the potential delaying effect of tea and its active ingredients on skin aging by oral and external use. Tea is the second-largest health drink after water. It is rich in tea polyphenols, l-theanine, tea pigments, caffeine, tea saponins, tea polysaccharides and other secondary metabolites. Tea and its active substances have whitening, nourishing, anti-wrinkle, removing spots and other skincare effects. Its mechanism of action is ultraviolet absorption, antioxidant, anti-inflammatory, inhibition of extracellular matrix aging, inhibiting the accumulation of melanin and toxic oxidation products, balancing intestinal and skin microorganisms, and improving mood and sleep, among other effects. At present, tea elements skincare products are deeply loved by consumers. This paper provides a scientific theoretical basis for tea-assisted beauty and the high-end application of tea in skincare products.

Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced chemo-immunotherapy.

The binding between the immune checkpoints, programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1), compromises T-cell-mediated immune surveillance. Immune checkpoint therapy using immune checkpoint inhibitors (ICIs) to block PD-L1 on cancer cell membrane or PD-1 on activated T cell membrane can restore antitumor function of T cell. However, the intracellular expression of PD-L1 and its active redistribution to cancer cell membrane may impair the therapeutic benefits of ICIs. To address this issue, herein we develop a nanodrug (MS NPs) capable of reducing PD-L1 expression and enhancing antitumor effects. Methods: The nanodrug was self-assembled from immunoadjuvant metformin (Met, an old drug) and anticancer agent 7-ethyl-10-hydroxycamptothecin (SN38) via hydrogen bonds and electrostatic interactions. A series of experiments, including the characterization of MS NPs, the validation of MS NPs-mediated down-regulation of PD-L1 expression and in vitro therapeutic effect, the MS NPs-mediated in vivo chemo-immunotherapy and tumor metastasis inhibition were carried out. Results: Different from ICIs that conformationally block PD-L1 on cancer cell membrane, MS NPs directly reduced the PD-L1 level via metformin to achieve immunotherapy. Therefore, MS NPs showed enhanced chemo-immunotherapy effect than its counterparts. MS NPs were also effective in inhibiting tumor metastasis by remodeling the extracellular matrix and restoring immune surveillance. Additionally, no obvious toxicity was observed in major organs from MS NPs-treated mice and a high survival rate of mice was obtained after MS NPs treatment. Conclusion: We have designed nanodrug MS NPs by self-assembly of the immunoadjuvant Met and the anticancer agent SN38 for combined immunotherapy and chemotherapy. MS NPs might break the deadlock of antibody-based ICIs in immunotherapy, and repurposing old drug might provide a new perspective on the development of novel ICIs.

Photogenerated Holes Mediated Nitric Oxide Production for Hypoxic Tumor Treatment.

Nitric oxide (NO) is a gaseous signal molecule with multiple physiological functions, and it also plays a key role in cancer therapy. However, the production of NO which depends on O2 or H2 O2 is limited within the tumor microenvironment, leading to unsatisfactory anticancer effect. Herein, we report a NO-based phototherapeutic strategy mediated by photogenerated holes for hypoxic tumors, which is achieved by irradiation of the poly-L-arginine modified carbon-dots-doped graphitic carbon nitride nanomaterial (ArgCCN). Upon red light irradiation, the photogenerated holes on ArgCCN oxidized water into H2 O2 which subsequently oxidized the arginine residues to produce NO. In vitro and in vivo experiments showed that the high concentration of NO produced by ArgCCN could induce cancer cell apoptosis. The presented phototherapeutic strategy is based on microenvironment-independent photogenerated holes mediated oxidation reaction, paving the way for the development of NO therapeutic strategy.

Self-Assembled mRNA-Responsive DNA Nanosphere for Bioimaging and Cancer Therapy in Drug-Resistant Cells.

DNA assembly has provided new opportunities for the development of a novel drug delivery system (DDS) for real-time monitoring and precision treatment of cancer lesions. Herein, we propose mRNA-responsive DNA nanospheres (DNA-NS), whose self-assembly can be triggered by products of rolling circle amplification and functional hairpins and deliver anticancer drug doxorubicin (DOX) for bioimaging and cancer therapy. It has been demonstrated that DNA-NS exhibited good stability in biological environments. Hence, DNA-NS can serve as a universal platform of detections of mRNA related to various tumor cells. DNA-NS can also be applied in the mRNA-dependent DDS. For drug-resistant cells, which are widely present in actual cancer models, DNA-NS can effectively overcome the efflux action of drug-resistant cells to improve the therapeutic efficacy of DOX. In summary, this study provides a potential strategy for constructing the endogenous mRNA-responsive DDS for cancer diagnosis and chemotherapy in vivo.

Dark tea extracts: Chemical constituents and modulatory effect on gastrointestinal function.

Processing of dark tea varieties, such as Fu brick tea, Liupao tea, Qianliang tea, and Qing brick tea, includes solid-state fermentation involving microorganisms. In this study, we analyzed the major chemical constituents of dark tea extracts and evaluated their modulatory effect on the gastrointestinal function in normal mice, including the improvement of gastrointestinal transit and intestinal microbial, as well as the attenuation of intestinal microbial dysbiosis and intestinal pathological damage, and the adjustment of immune function in antibiotic-treated mice. Substantial differences in major chemical constituents, including total polyphenols, total organic acids, water extract content, 18 free amino acids, gallic acid, and six tea catechins, were observed among Fu brick tea, Qianliang tea, Qing brick tea, and Liupao tea extracts. Extracts from the four dark tea varieties significantly promoted gastrointestinal transit and colonization of beneficial Bifidobacterium and Lactobacillus, and inhibited the growth of harmful Escherichia coli and Enterococcus in normal mice. In addition, Qianliang tea, Qing brick tea, and Liupao tea extracts significantly accelerated the reversal of the ampicillin sodium-induced pathological damage in the ileum, intestinal bacterial dysbiosis (Bifidobacterium, Lactobacillus, E. coli, and Enterococcus), and low immunity.

Endurance exercise protects aging Drosophila from high-salt diet (HSD)-induced climbing capacity decline and lifespan decrease by enhancing antioxidant capacity.

A high-salt diet (HSD) is a major cause of many chronic and age-related defects such as myocardial hypertrophy, locomotor impairment and mortality. Exercise training can efficiently prevent and treat many chronic and age-related diseases. However, it remains unclear whether endurance exercise can resist HSD-induced impairment of climbing capacity and longevity in aging individuals. In our study, flies were given exercise training and fed a HSD from 1-week old to 5-weeks old. Overexpression or knockdown of salt and dFOXO were built by UAS/Gal4 system. The results showed that a HSD, salt gene overexpression and dFOXO knockdown significantly reduced climbing endurance, climbing index, survival, dFOXO expression and SOD activity level, and increased malondialdehyde level in aging flies. Inversely, in a HSD aging flies, endurance exercise and dFOXO overexpression significantly increased their climbing ability, lifespan and antioxidant capacity, but they did not significantly change the salt gene expression. Overall, current results indicated that a HSD accelerated the age-related decline of climbing capacity and mortality via upregulating salt expression and inhibiting the dFOXO/SOD pathway. Increased dFOXO/SOD pathway activity played a key role in mediating endurance exercise resistance to the low salt tolerance-induced impairment of climbing capacity and longevity in aging DrosophilaThis article has an associated First Person interview with the first author of the paper.

Tea consumption and colorectal cancer risk: a meta-analysis of prospective cohort studies.

PURPOSE: Data from in vitro and animal studies support the preventive effect of tea (Camellia sinensis) against colorectal cancer. Further, many epidemiologic studies evaluated the association between tea consumption and colorectal cancer risk, but the results were inconsistent. We conducted a meta-analysis of prospective cohort studies to systematically assess the association between tea consumption and colorectal cancer risk. METHODS: A comprehensive literature review was conducted to identify the related articles by searching PubMed and Embase up to June, 2019. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a fixed effect model. RESULTS: Twenty cohort articles were included in the present meta-analysis involving 2,068,137 participants and 21,437 cases. The combined RR of colorectal cancer for the highest vs. lowest tea consumption was determined to 0.97 (95% CI 0.94-1.01) with marginal heterogeneity (I2 = 24.0%, P = 0.093) among all studies. This indicated that tea consumption had no significant association with colorectal cancer risk. Stratified analysis showed that no significant differences were found in all subgroups. We further conducted the gender-specific meta-analysis for deriving a more precise estimation. No significant association was observed between tea consumption and colorectal cancer risk in male (combined RR = 0.97; 95% CI 0.90-1.04). However, tea consumption had a marginal significant inverse impact on colorectal cancer risk in female (combined RR = 0.93; 95% CI 0.86-1.00). Further, we found a stronger inverse association between tea consumption and risk of colorectal cancer among the female studies with no adjustment of coffee intake (RR: 0.90; 95% CI 0.82-1.00, P < 0.05) compared to the female studies that adjusted for coffee intake (RR = 0.97; 95% CI 0.87-1.09, P > 0.05). CONCLUSIONS: Our finding indicates that tea consumption has no significant impact on the colorectal cancer risk in both genders combined, but gender-specific meta-analysis shows that tea consumption has a marginal significant inverse impact on colorectal cancer risk in female.

Effects and Mechanisms of Tea for the Prevention and Management of Diabetes Mellitus and Diabetic Complications: An Updated Review.

Diabetes mellitus has become a serious and growing public health concern. It has high morbidity and mortality because of its complications, such as diabetic nephropathy, diabetic cardiovascular complication, diabetic neuropathy, diabetic retinopathy, and diabetic hepatopathy. Epidemiological studies revealed that the consumption of tea was inversely associated with the risk of diabetes mellitus and its complications. Experimental studies demonstrated that tea had protective effects against diabetes mellitus and its complications via several possible mechanisms, including enhancing insulin action, ameliorating insulin resistance, activating insulin signaling pathway, protecting islet ß-cells, scavenging free radicals, and decreasing inflammation. Moreover, clinical trials also confirmed that tea intervention is effective in patients with diabetes mellitus and its complications. Therefore, in order to highlight the importance of tea in the prevention and management of diabetes mellitus and its complications, this article summarizes and discusses the effects of tea against diabetes mellitus and its complications based on the findings from epidemiological, experimental, and clinical studies, with the special attention paid to the mechanisms of action.

Inhibition by microbial metabolites of Chinese dark tea of age-related neurodegenerative disorders in senescence-accelerated mouse prone 8 (SAMP8) mice.

Dark tea has a significant effect on the prevention and treatment of age-related degenerative diseases. At present, further exploration of its functional mechanisms is delayed because of the complexity of post-fermentation microbial metabolites during the production phase. In this study, new isolated microbial metabolites extracted from dark tea were used to explore the neuroprotective effects, and they also helped allow further exploration of the mechanism of dark tea. Taking senescence-accelerated mouse prone 8 (SAMP8) mice as a biological model, we examined the protective effect on brain neurons of post-fermentation microbial metabolites which were extracted from dark tea. The 4-month-old mice were given treatments of the same concentration (10 mg kg-1 d-1) which were l-theanine, 3,3'-azanediylbis(4-hydroxybenzoic acid) (CDT-1) and one of the 8-C N-ethyl-2-pyrrolidinone substituted flavan-3-ols (CDT-2) by gavage for 14 weeks. Relative measurements such as RT-PCR, ELISA, western blotting, and section staining (HE, Nissl and myelin) were carried out. The results showed that l-theanine, CDT-1 and CDT-2 could inhibit the decrease in body weight, and down-regulate the formation of 4-HNE and ubiquitinated protein aggregates and the Aß metabolic pathway. They could also increase endogenous antioxidant capacity, relieve cell hypoxia, and reduce the rate of neuronal apoptosis. This means that their protective activity regarding SAMP8 neurons was excellent and the activity of CDT-2 was the most significant.

DNA Octahedron-Based Fluorescence Nanoprobe for Dual Tumor-Related mRNAs Detection and Imaging.

With the development of biotechnology, the detection of cancer biomarkers has been a promising approach for cancer diagnosis and therapy. Herein, we reported a DNA octahedron-based fluorescence nanoprobe, which was capable of detecting and imaging of two kinds of tumor-related mRNAs in living cells simultaneously. The DNA nanoprobe was constructed of eight single-stranded DNAs, in which two oligonucleotides (recognition sequences) were modified with quenchers (BHQ2 and BHQ3) and the adjacent sequences were modified with fluorophores (Cy3 and Cy5), respectively. In the presence of targets, the recognition sequences could dissociate from the nanoprobe skeleton by strand displacement reaction and the fluorescence was recovered accordingly. With the modification of AS1411 aptamer, the nanoprobe could internalize cancer cells more efficiently and distinguish cancer cells from normal cells. In addition, the nanoprobe exhibited good stability, biocompatibility, selectivity, and responded quickly to the targets as well. The DNA nanoprobe was designed in the formation of octahedron and may provide an inspiration for multidetection of cancer biomarkers based on the DNA nanotechnology.

MiR-155 aggravated septic liver injury by oxidative stress-mediated ER stress and mitochondrial dysfunction via targeting Nrf-2.

OBJECTIVE: Liver is uniquely vulnerable during sepsis. MicroRNA-155 (miR-155) is confirmed to play crucial roles in septic liver injury. The present study aims to investigate the mechanisms of miR-155 in septic liver injury. METHODS: The sepsis model was established by intraperitoneal injection of lipopolysaccharide (LPS) in mice. Mice were divided into four groups: Vehicle, miR-155 antagomir, LPS, LPS+ miR-155 antagomir. The survival rate and body weight were monitored. Liver injury was assessed by H&E staining. The levels of serum ALT and inflammatory cytokines were determined by ELISA kits. Oxidative stress was detected by MDA and SOD detection kits. The miR-155, Nrf-2, and markers related to oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial injury and apoptosis were detected by western blotting and qPCR. Apoptosis in liver tissues was detected by TUNELstaining. RESULTS: MiR-155 antagomir alleviated liver injury as evidenced by enhancing survival rate and body weight, inhibiting inflammatory cell infiltration, liver cells necrosis and decreasing ALT level. The productions of TNF-α, IL-6 were suppressed, while anti-inflammatory cytokine IL-10 was promoted by miR-155 antagomir. Oxidative stress was inhibited by miR-155 antagomir via enhancing nuclear factor, erythroid 2-like 2 (Nrf-2) expression. ER stress and Cytochrome C (Cyto-C) release were restrained by miR-155 antagomir. Sepsis-induced apoptosis was repressed by miR-155 antagomir as manifested by the decreased levels of Bax, cleaved caspase-12, 9 and 3, and increased levels of Bcl-2 and uncleaved PARP. CONCLUSION: MiR-155 antagomir relieved septic liver injury through inhibiting oxidative stress-mediated ER stress, mitochondrial dysfunction and apoptosis via targeting Nrf-2, suggesting miR-155 as a therapeutic target for septic liver injury.

l-Theanine prevents ETEC-induced liver damage by reducing intrinsic apoptotic response and inhibiting ERK1/2 and JNK1/2 signaling pathways.

l-Theanine (LTA; γ-glutamylethylamide), a peculiar non-protein-derived amino acid isolated from tea, is widely used as a functional ingredient and dietary supplement. l-Theanine has been confirmed to have hepatoprotective effects, but the underlying mechanism remains unknown. This study investigated the protective effect of l-Theanine-in vivo, using an enterotoxigenic Escherichia coli (ETEC)-infected mouse model. l-Theanine significantly decreased the elevated serum activities of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT), two biomarkers of hepatic impairment. This was consistent with histopathological images from the microscopic observation of liver tissue. In addition, l-theanine significantly increased the mRNA and protein expression of Bcl-2 and decreased the expression of Bax, anti- and pro-apoptotic molecules, respectively, compared with levels in the ETEC control group. The expression of cleaved caspase-3 protein in the group pre-treated with l-theanine was significantly lower than that in the ETEC group. Additionally, decreases in extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase(JNK1/2) MAPK phosphorylation were observed in the l-theanine pre-treated group. Our study demonstrates that l-theanine possesses anti-apoptotic activity, which can be attributed to suppression of the intrinsic mitochondria-mediated apoptosis and MAPK phosphorylation signaling pathways.

Neuroprotective Effects of Theaflavins Against Oxidative Stress-Induced Apoptosis in PC12 Cells.

Oxidative stress can induce neuronal apoptosis via the production of superoxide and hydroxyl radicals. This process is as a major pathogenic mechanism in neurodegenerative disorders. In this study, we aimed to clarify whether theaflavins protect PC12 cells from oxidative stress damage induced by H2O2. A cell model of PC12 cells undergoing oxidative stress was created by exposing cells to 200 µM H2O2 in the presence or absence of varying concentrations of theaflavins (5, 10, and 20 µM). Cell viability was monitored using the MTT assay and Hoechst 33258 staining, showing that 10 µM theaflavins enhanced cell survival following 200 µM H2O2 induced toxicity and increased cell viability by approximately 40 %. Additionally, we measured levels of intracellular reactive oxygen species (ROS) and antioxidant enzyme activity. This suggested that the neuroprotective effect of theaflavins against oxidative stress in PC12 cells is derived from suppression of oxidant enzyme activity. Furthermore, Western blot analyses indicated that theaflavins downregulated the ratio of pro-apoptosis/anti-apoptosis proteins Bax/Bcl-2. Theaflavins also downregulated the expression of caspase-3 compared with a H2O2-treated group that had not been treated with theaflavins. Interestingly, this is the first study to report that the four main components of theaflavins found in black tea can protect neural cells (PC12) from apoptosis induced by H2O2. These findings provide the foundations for a new field of using theaflavins or its source, black tea, in the treatment of neurodegenerative diseases caused by oxidative stress.