Causal associations between the gut microbiota and multiple myeloma: a two-sample Mendelian randomization study.

Background: Previous observational studies have indicated a potential association between the gut microbiota and multiple myeloma (MM). However, the relationship between the gut microbiota and MM remains unclear. This study aimed to ascertain the existence of a causal link between the gut microbiota and MM. Methods: To investigate the potential causal relationship between gut microbiota and MM, a two-sample Mendelian randomization (MR) analysis was conducted. Exposure data was obtained from the MiBioGen consortium, which provided genetic variants associated with 211 bacterial traits. MM outcome data was obtained from the FinnGen consortium. The selection of Single nucleotide polymorphisms estimates was performed through meta-analysis using inverse-variance weighting, and sensitivity analyses were conducted using weighted median, MR Egger, Simple mode, and MR-PRESSO. Results: The results of the study demonstrated a significant positive correlation between the genus Eubacterium ruminantium group and the risk of MM (OR 1.71, 95% CI 1.21 to 2.39). Conversely, the genus: Dorea (OR 0.46, 95% CI 0.24 to 0.86), Coprococcus1 (OR 0.47, 95% CI 0.22 to 1.00), RuminococcaceaeUCG014 (OR 0.57, 95% CI 0.33 to 0.99), Eubacterium rectale group (OR 0.37, 95% CI 0.18 to 0.77), and order: Victivallales (OR 0.62, 95% CI 0.41-0.94), class: Lentisphaeria (OR 0.62, 95% CI 0.41 to 0.94), exhibited a negative association with MM. The inverse variance weighting analysis provided additional support for these findings. Conclusion: This study represents an inaugural exploration of MR to investigate the connections between gut microbiota and MM, thereby suggesting potential significance for the prevention and treatment of MM.

Comparison of Thoracoscopy-Guided Thoracic Paravertebral Block and Ultrasound-Guided Thoracic Paravertebral Block in Postoperative Analgesia of Thoracoscopic Lung Cancer Radical Surgery: A Randomized Controlled Trial.

INTRODUCTION: Ultrasound-guided thoracic paravertebral block (UTPB) is widely used for postoperative analgesia in thoracic surgery. However, it has many disadvantages. Thoracoscopy-guided thoracic paravertebral block (TTPB) is a new technique for thoracic paravertebral block (TPB). In this study, we compared the use of TTPB and UTPB for pain management after thoracoscopic radical surgery for lung cancer. METHODS: In total, 80 patients were randomly divided 1:1 into the UTPB group and the TTPB group. The surgical time of TPB, the success rate of the first puncture, block segment range, visual analog scale (VAS) scores at 2, 6, 12, 24, and 48 h post operation, and the incidence of postoperative adverse reactions were compared between the two groups. RESULTS: The surgical time of TPB was significantly shorter in the TTPB group than in the UTPB group (2.2 ± 0.3 vs. 5.7 ± 1.7 min, t = - 12.411, P < 0.001). The success rate of the first puncture and the sensory block segment were significantly higher in the TTPB group than in the UTPB group (100% vs. 76.9%, χ2 = 8.309, P < 0.001; 6.5 ± 1.2 vs. 5.1 ± 1.3 levels, t = - 5.306, P < 0.001, respectively). The VAS scores were significantly higher during rest and coughing at 48 h post operation than at 2, 6, 12, and 24 h post operation in the TTPB group. The VAS scores were significantly lower during rest and coughing at 12 and 24 h post operation in the TTPB group than in the UTPB group (rest: 2.5 ± 0.4 vs. 3.4 ± 0.6, t = 7.325, P < 0.001; 2.5 ± 0.5 vs. 3.5 ± 0.6, t = 7.885, P < 0.001; coughing: 3.4 ± 0.6 vs. 4.2 ± 0.7, t = 5.057, P < 0.001; 3.4 ± 0.6 vs. 4.2 ± 0.8, t = 4.625, P < 0.001, respectively). No significant difference was observed in terms of postoperative adverse reactions between the two groups. CONCLUSIONS: Compared with UTPB, TTPB shows advantages, such as simpler and more convenient surgery, shorter surgical time, a higher success rate of the first puncture, wider block segments, and superior analgesic effect. TTPB can effectively reduce postoperative pain due to thoracoscopic lung cancer radical surgery. TRIAL REGISTRATION: https://www.chictr.org.cn , identifier ChiCTR2300072005, prospectively registered on 31/05/2023.

[Structural Chinese medicine: new research field on pharmacodynamic substance basis of traditional Chinese medicine].

The research on the pharmacodynamic substance basis of traditional Chinese medicine(TCM) is a key scientific issue for the inheritance and development of TCM. At present, a large number of remarkable achievements have been made in the field of chemical components in Chinese medicine, however, another important aspect, namely the physical structure and mode of action of the multi-component assembly of TCM, has not been clearly understood and deeply studied. From the bottleneck of restricting material ba-sic research, we objectively analyzed the common cause of the existing problems. Based on the new discoveries and advances of active substances from TCM emerging in recent years, we extracted and summarized the concept of structural Chinese medicine, elaborated the basic ideas, main features and research modes, hoping to provide theoretical and practical references for the study on the pharmacodynamic substance basis and other research fields of TCM.

Eriodictyol attenuates TNBS-induced ulcerative colitis through repressing TLR4/NF-kB signaling pathway in rats.

Ulcerative colitis (UC) is a chronic disease characterized by mucosal and submucosal inflammation, which has a low cure rate and is prone to relapse, due to the immune imbalance of the body. Inhibition of inflammation-related pathways can delay the progression of UC. Toll-like receptor 4 (TLR4) pathway is considered to be one of the important signaling pathways involved in colon inflammation. Eriodictyol (EDT) is a natural flavonoid widely distributed in foodborne plants. EDT plays an important role in the regulation of inflammation and related signaling pathways. However, whether EDT plays a role in UC remains unknown. Herein, we established a TNBS induced animal model of enteritis in Wistar rats. Our data confirmed the establishment of TNBS induced animal model of enteritis and the administration Eriodictyol in Wistar rats. EDT treatment alleviated TNBS-induced intestinal tissue injury in rats. We further found that EDT reduced MPO expression and regulated the cytokine parameters in TNBS-induced intestinal tissues of rats. The levels of TNF-α, IL-1ß, IL-6, IL-10, IL-2, and IL-12 were also affected by the treatment of EDT. EDT also affected SOD, CAT, GSH-Px, and MDA level in rats with colitis. Moreover, EDT regulated TNBS-induced TLR4/NF-κB pathway activation, therefore inhibiting the progression of UC. Our results suggest that EDT could be a potential therapeutic agent for UC.

Xanthatin inhibits STAT3 and NF-κB signalling by covalently binding to JAK and IKK kinases.

Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor-κB (NF-κB) signalling pathways is associated with the development of cancer and inflammatory diseases. JAKs and IKKs are the key regulators in the STAT3 and NF-κB signalling respectively. Therefore, the two families of kinases have been the major targets for developing drugs to regulate the two signalling pathways. Here, we report a natural compound xanthatin from the traditional Chinese medicinal herb Xanthium L. as a potent inhibitor of both STAT3 and NF-κB signalling pathways. Our data demonstrated that xanthatin was a covalent inhibitor and its activities depended on its α-methylene-γ-butyrolactone group. It preferentially interacted with the Cys243 of JAK2 and the Cys412 and Cys464 of IKKß to inactivate their activities. In doing so, xanthatin preferentially inhibited the growth of cancer cell lines that have constitutively activated STAT3 and p65. These data suggest that xanthatin may be a promising anticancer and anti-inflammation drug candidate.

Small molecule IVQ, as a prodrug of gluconeogenesis inhibitor QVO, efficiently ameliorates glucose homeostasis in type 2 diabetic mice.

Gluconeogenesis is a major source of hyperglycemia in patients with type 2 diabetes mellitus (T2DM), thus targeting gluconeogenesis to suppress glucose production is a promising strategy for anti-T2DM drug discovery. In our preliminary in vitro studies, we found that a small-molecule (E)-3-(2-(quinoline-4-yl)vinyl)-1H-indol-6-ol (QVO) inhibited the hepatic glucose production (HGP) in primary hepatocytes. We further revealed that QVO suppressed hepatic gluconeogenesis involving calmodulin-dependent protein kinase kinase ß- and liver kinase B1-adenosine monophosphate-activated protein kinase (AMPK) pathways as well as AMPK-independent mitochondrial function-related signaling pathway. To evaluate QVO's anti-T2DM activity in vivo, which was impeded by the complicated synthesis route of QVO with a low yield, we designed and synthesized 4-[2-(1H-indol-3-yl)vinyl]quinoline (IVQ) as a prodrug with easier synthesis route and higher yield. IVQ did not inhibit the HGP in primary hepatocytes in vitro. Pharmacokinetic studies demonstrated that IVQ was quickly converted to QVO in mice and rats following administration. In both db/db and ob/ob mice, oral administration of IVQ hydrochloride (IVQ-HCl) (23 and 46 mg/kg every day, for 5 weeks) ameliorated hyperglycemia, and suppressed hepatic gluconeogenesis and activated AMPK signaling pathway in the liver tissues. Furthermore, IVQ caused neither cardiovascular system dysfunction nor genotoxicity. The good druggability of IVQ has highlighted its potential in the treatment of T2DM and the prodrug design for anti-T2DM drug development.

Elaboration in type, primary structure, and bioactivity of polysaccharides derived from mollusks.

Over the past decades, numerous Mollusca species have received more attention in development and utilization as valuable bio-resources. Many efforts have been focused on investigating mollusk polysaccharides because of their rich content, ease of extraction, diversified sorts, specific structure, various biofunctions and potent activities. To date, many mollusks, especially species of gastropods, bivalves, or cephalopods, have been reported containing polysaccharide compounds in tissues with abundant amount, and most of polysaccharides are obtainable through combining techniques of extraction, separation and purification. The polysaccharides isolated from mollusks appeared with various structural and physicochemical characteristics, ranged from neutral polysaccharides and sulfated polysaccharides, to GAGs series (including Hep/HS, CS/DS, HA and similarities), even to heterogeneous glycan with high molecular weight. This review article provides comprehensive knowledge of recent researches on type classification, tissue origins and possible biofunctions of various polysaccharides from mollusks. The highlights were placed in structure variation including molecular weight, sulfation pattern, linkages and monomer compositions for repeating unit, and primary molecular construction of the mollusks polysaccharides. In addition, this article covers general information on exhibition of mollusks polysaccharide extracts or preparations in the various bioactivities, such as anticoagulant, antiatherogenic, antioxidant, immunomodulatory, antivirus and antitumor activities, which would reveal their possible potentials in medical application. Furthermore, the article presents a brief overview on several challenges and future scope in this field.

BF211, a derivative of bufalin, enhances the cytocidal effects in multiple myeloma cells by inhibiting the IL-6/JAK2/STAT3 pathway.

Despite remarkable advances in multiple myeloma (MM) therapy, this condition remains incurable. BF211 is an active compound derived from bufalin, which is isolated from the Traditional Chinese Medicine, Chansu. In this study, we explored the cytotoxicity of BF211 in 20 tumor cell lines and discovered that the MM cell lines, ARP-1 and CAG, exhibited greater sensitivity to BF211. Compared with bufalin, BF211 induced a greater apoptotic effect and lower acute toxicity at nanomolar concentration. The IL-6/JAK2/STAT3 signaling pathway is essential to the progression and development of MM. We showed that exogenous IL-6 promoted MM cell proliferation in a dose-dependent manner and this effect was blocked by BF211. Furthermore, BF211 suppressed the phosphorylation of JAK2 and STAT3 both in vivo and in vitro. In a mouse MM xenograft model, BF211 significantly inhibited tumor growth and did not affect body weight. In conclusion, the anti-MM activity of BF211 is mediated mainly by suppressing the IL-6/JAK2/STAT3 signaling pathway. Thus, we suggest that BF211 warrants further investigation in clinical trials in MM.

Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-α.

BF211, a bufalin (BF) derivative, exhibits stronger anti-cancer activity than BF but with potential cardiotoxicity. Fibroblast activation protein-α (FAPα) is a membrane-bound protease specifically expressed by carcinoma-associated fibroblasts, thus has been used for the selective delivery of anticancer agents. In this study, we used a FAPα-based prodrug strategy to synthesize a dipeptide (Z-Gly-Pro)-conjugated BF211 prodrug named BF211-03. BF211-03 was hydrolyzed by recombinant human FAPα (rhFAPα) and cleaved by homogenates of human colon cancer HCT-116 or human gastric cancer MGC-803 xenografts. In contrast, BF211-03 showed good stability in plasma and in the homogenates of FAPα-negative normal tissues, such as heart and kidney. In HCT-116 and MGC-803 cells with low levels of FAPα expression, BF211-03 displayed a lower in vitro cytotoxicity than BF211 with approximately 30 to 40-fold larger IC50 values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPα expression, the IC50 value difference between BF211-03 and BF211 was small (approximately 4-fold). Although the cytotoxicity of BF211-03 against tumor cells was dramatically decreased by the chemical decoration, it was restored after cleavage of BF211-03 by rhFAPα or tumor homogenate. In HCT-116 tumor-bearing nude mice, doubling the dose of BF211-03, compared with BF211, caused less weight loss, but showing similar inhibitive effects on tumor growth. Our results suggest that BF211-03 is converted to active BF211 in tumor tissues and exhibits anti-tumor activities in tumor-bearing nude mice. FAPα-targeted BF211-03 displays tumor selectivity and may be useful as a targeting agent to improve the safety profile of cytotoxic natural products for use in cancer therapy.

Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury - Corrected and republished from: Biomedicine (Taipei). 2016 Jun; 6 (2): 9. doi: 10.7603/s40681-016-0009-1PMCID: PMC4864770.

Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP up-regulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepato-protective agent.

LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy.

Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities, and the vicious interplay between oxidative stress (OS) and tauopathy is believed to be one of the major players in AD development. Here, we demonstrated the capability of the small molecule N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) to ameliorate the cognitive dysfunction of AD model rats by inhibiting OS-induced neuronal apoptosis and tauopathy. Streptozotocin (STZ) was used to induce OS in neuronal cells in vitro and in AD model rats that were made by intracerebroventricular injection of STZ (3 mg/kg, bilaterally), and Morris water maze test was used to evaluate the cognitive dysfunction in ICV-STZ rats. Treatment with LX2343 (5-20 µmol/L) significantly attenuated STZ-induced apoptosis in SH-SY5Y cells and mouse primary cortical neurons by alleviating OS and inhibiting the JNK/p38 and pro-apoptotic pathways. LX2343 was able to restore the integrity of mitochondrial function and morphology, increase ATP biosynthesis, and reduce ROS accumulation in the neuronal cells. In addition, LX2343 was found to be a non-ATP competitive GSK-3ß inhibitor with IC50 of 1.84±0.07 µmol/L, and it potently inhibited tau hyperphosphorylation in the neuronal cells. In ICV-STZ rats, administration of LX2343 (7, 21 mg·kg-1·d-1, ip, for 5 weeks) efficiently improved their cognitive deficits. LX2343 ameliorates the cognitive dysfunction in the AD model rats by suppressing OS-induced neuronal apoptosis and tauopathy, thus highlighting the potential of LX2343 for the treatment of AD.

DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated pathogenesis and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. G protein-coupled receptors (GPCRs) are classified as distinct families by heterotrimeric G proteins, primarily including Gαs, Gαi and Gαq. Gαs-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Gαi-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Gαq-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7-(thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(1H)-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in db/db mice decreased fasting blood glucose and hemoglobin A1C (HbA1c) levels, while improved glucose tolerance and pyruvate tolerance. Mechanism study demonstrated that DMT-inhibited gluconeogenesis by regulating the Gαq/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca2+)/calmodulin (CaM)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling pathway. To our knowledge, DMT might be the first reported small molecule able to suppress hepatic gluconeogenesis by regulating Gαq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM.

Bortezomib protects against dextran sulfate sodium­induced ulcerative colitis in mice.

Bortezomib, a first­in­class proteasome inhibitor, is a standard method of treatment in multiple myeloma. In the present study, the therapeutic effect of bortezomib was evaluated in an ulcerative colitis model induced by dextran sulfate sodium (DSS) in mice, and the mechanism of action was also investigated. Mice were administered with 3% DSS drinking water for 7 consecutive days and then they were intraperitoneally treated with bortezomib (0.2, 0.6 or 1 mg/kg) for 1, 3 or 7 days. Mice in the control group and the DSS group were provided the same volume of PBS, respectively. Body weight, stool characteristics and hematochezia were observed. Serum levels of tumor necrosis factor­α (TNF­α), C­reactive protein (CRP), albumin (ALB) and colonic activity of superoxide dismutase (SOD) were evaluated using specific kits. The expression of the transcription factor nuclear factor­κB (NF­κB) p65 gene and the DNA­binding activity of NF­κB protein were also evaluated. Administration of bortezomib attenuates colonic inflammation in mice. After 3 or 7 days of treatment, Disease Activity Index (DAI) as well as histological scores and NF­κB p65 protein expression were significantly reduced in mice treated with bortezomib at a dose of 0.6 or 1 mg/kg/day. Furthermore, it was also revealed that bortezomib was able to reduce serum levels of CRP and TNF­α caused by DSS and increase the level of ALB in serum and the activity of SOD in colonic tissues. These results demonstrated that bortezomib exerts a protective effect on DSS­induced colitis, and its underlying mechanisms are associated with the NF­κB gene inhibition that mitigates colon inflammatory responses in intestinal epithelial cells.

Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aß and Tau pathologies.

Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both Aß level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both Aß levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APPswe, PS1dE9)] were administered THA (300 mg·kg-1·d-1, ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate Aß and sAPPß contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, THΑ (1, 10, 20 µg/mL) significantly stimulated PI3K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of Aß clearance as both a PI3K inhibitor and an AMPK indirect activator, and restrained Aß production as a suppressor against PERK/eIF2α-mediated BACE1 expression. Additionally, THA functioned as a GSK3ß inhibitor with an IC50 of 1.32±0.85 µg/mL, repressing Tau hyperphosphorylation. Similar effects on Aß accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA for the treatment of AD.

Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid ß production and clearance.

AIM: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aß pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. METHODS: Cell-based assays for screening anti-amyloid compounds were established by assessing Aß accumulation in HEK293-APPsw and CHO-APP cells, and Aß clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aß and sAPPß levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. RESULTS: LX2343 (5-20 µmol/L) dose-dependently decreased Aß accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aß clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 µmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aß clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aß pathology in their brains. CONCLUSION: LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aß production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.

A Novel Bufalin Derivative Exhibited Stronger Apoptosis-Inducing Effect than Bufalin in A549 Lung Cancer Cells and Lower Acute Toxicity in Mice.

BF211 is a synthetic molecule derived from bufalin (BF). The apoptosis-inducing effect of BF211 was stronger than that of BF while the acute toxicity of BF211 was much lower than that of BF. BF211 exhibited promising concentration-dependent anti-cancer effects in nude mice inoculated with A549 cells in vivo. The growth of A549 tumor xenografts was almost totally blocked by treatment with BF211 at 6 mg/kg. Notably, BF and BF211 exhibited differences in their binding affinity and kinetics to recombinant proteins of the α subunits of Na+/K+-ATPase. Furthermore, there was a difference in the effects of BF or BF211 on inhibiting the activity of porcine cortex Na+/K+-ATPase and in their time-dependent effects on intracellular Ca2+ levels in A549 cells. The time-dependent effects of BF or BF211 on the activation of Src, which was mediated by the Na+/K+-ATPase signalosome, in A549 cells were also different. Both BF and BF211 could induce apoptosis-related cascades, such as activation of caspase-3 and the cleavage of PARP (poly ADP-ribose polymerase) in A549 cells, in a concentration-dependent manner; however, the effects of BF211 on apoptosis-related cascades was stronger than that of BF. The results of the present study supported the importance of binding to the Na+/K+-ATPase α subunits in the mechanism of cardiac steroids and also suggested the possibility of developing new cardiac steroids with a stronger anti-cancer activity and lower toxicity as new anti-cancer agents.

Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury.

Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP upregulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepatoprotective agent.