A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.

Limonoids from the roots of Melia azedarach and their anti-inflammatory activity.

Twelve undescribed limonoids, meliazedarines J-U (1-12), along with a known one, were isolated from the roots of Melia azedarach. Their structures were elucidated by extensive spectroscopic investigations, X-ray diffraction analyses, and ECD calculations. Compounds 1-8 were identified as ring intact limonoids, while compounds 9-12 were established as ring C-seco ones. The anti-inflammatory potential of compounds 1-4, 6, 8, 9, and 11-13 was evaluated on macrophages. Compounds 1, 3, 4, 6, and 9 significantly suppressed nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, among them compound 3 showed the best inhibitory effect with an IC50 value of 7.07 ± 0.48 µΜ. Furthermore, compound 3 effectively reduced interleukin-1ß secretion in LPS plus nigericin-induced THP-1 macrophages by inhibiting NLRP3 inflammasome activation. The results strongly suggested that limonoids from the roots of M. azedarach might be candidates for treating inflammation-related diseases.

Germacrane-type sesquiterpenoids from the flowers of Chrysanthemum indicum with hepatoprotective activity.

Two new germacrane-type sesquiterpenoids, chrysanthemolides A (1) and B (2), and four known germacrane-type sesquiterpenoids, hanphyllin (3), 3ß-hydroxy-11α,13-dihydro-costunolide (4), costunolide (5), and 6,7-dimethylmethylene-4-aldehyde-1ß-hydroxy-10(15)-ene-(4Z)-dicyclodecylene (6), were isolated and identified from the flowers of Chrysanthemum indicum. The structures of the new compounds were elucidated via high resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR) spectra and electronic circular dichroism (ECD). Meanwhile, all the isolates were tested for their hepatoprotective activity in tert-butyl hydroperoxide (t-BHP) injured AML12 cells. Compounds 1, 2, and 4 showed significant protective effects at 40 µM, comparable with the positive control resveratrol at 10 µM. As the most potent one, compound 1 was chosen for further studies. Compound 1 dose-dependently increased the viability of t-BHP-injured AML12 cells. Furthermore, compound 1 decreased reactive oxygen species accumulation, while increased glutathione level, heme oxygenase-1 level and superoxide dismutase activity, through anchoring in the binding site of Kelch domain of the Kelch-like ECH-associated protein 1 (Keap1) to promote the dissociation of nuclear factor erythroid 2-related factor 2 from Keap1 and translocation to nuclei. In summary, germacrane-type sesquiterpenoids from C. indicum might be further developed to protect liver against oxidative damage.

Combining frog-leg lateral view may serve as a more sensitive X-ray position in monitoring collapse in osteonecrosis of the femoral head.

Load-bearing capacity of the bone structures of anterolateral weight-bearing area plays an important role in the progressive collapse in osteonecrosis of the femoral head (ONFH). The purpose of this study is to assess the efficacy of combined evaluation of anteroposterior (AP) and frog-leg lateral (FLL) view in diagnosing collapse. Between December 2016 and August 2018, a total of 478 hips from 372 patients with ONFH (268 male, 104 female; mean age 37.9 ± 11.4 years) were retrospectively evaluated. All patients received standard AP and FLL views of hip joints. Japanese Investigation Committee (JIC) classification system was used to classify necrotic lesion in AP view. Anterior necrotic lesion was evaluated by FLL view. All patients with pre-collapse ONFH underwent non-operative hip-preserving therapy. The collapse rates were calculated and compared with Kaplan-Meier survival analysis with radiological collapse as endpoints. Forty-four (44/478, 9.2%) hips were classified as type A, 65 (65/478, 13.6%) as type B, 232 (232/478, 48.5%) as type C1 and 137 (137/478, 28.7%) as type C2. Three hundred cases (300/478, 62.5%) were collapsed at the initial time point. Two hundred and twenty six (226/300, 75.3%) hips and 298 (298/300, 99.3%) hips collapse were identified with AP view and FLL view, respectively. An average follow-up of 37.0 ± 32.0 months was conducted to evaluate the occurrence of collapse in 178 pre-collapse hips. Collapses occurred in 89 hips (50.0%). Seventy-seven (77/89, 86.5%) hips were determined with AP view alone and 85 (85/89, 95.5%) hips were determined with the combination of AP and FLL views. The collapse rates at five years were reported as 0% and 0%, 16.2% and 24.3%, 58.3% and 68.1% and 100% and 100% according to AP view alone or combination of AP and FLL views for types A, B, C1 and C2, respectively. The collapse can be diagnosed more accurately by combination of AP and FLL views. Besides, JIC type A and type B ONFH can be treated with conservative hip preservation, but pre-collapse type C2 ONFH should be treated with joint-preserving surgery. Type C1 needs further study to determine which subtype has potential risk of collapse.

Triterpenoids from the fruits of Melia azedarach L. and their cytotoxic activities.

Eleven undescribed tetracyclic triterpenoids, meliazedarachins A-K, along with twenty-six known compounds were isolated from the fruits of Melia azedarach L.. Their structures were determined by HRESIMS, UV, IR, NMR, X-ray diffraction, electronic circular dichroism (ECD) spectra, and the modified Mosher's method. The cytotoxic activities of all the isolates were measured. Meliazedarachin K and mesendanin N showed cytotoxicity against five human cancer cell lines with IC50 values ranging from 9.02 to 31.31 µM. Meliazedarachin K showed significant cytotoxicity against HCT116 cell line with IC50 value of 9.02 ± 0.84 µM. 21α-methylmelianodiol showed significant cytotoxicity against HCT116 and RKO cell lines with IC50 values of 10.16 ± 1.22 and 8.57 ± 0.80 µM, respectively.

Honokiol: A naturally occurring lignan with pleiotropic bioactivities.

Honokiol is the dominant biphenolic compound isolated from the Magnolia tree, and has long been considered as the active constituent of the traditional Chinese herb, 'Houpo', which is widely used to treat symptoms due to 'stagnation of qi'. Pharmacological studies have shown that honokiol possesses a wide range of bioactivities without obvious toxicity. Honokiol protects the liver, kidneys, nervous system, and cardiovascular system through reducing oxidative stress and relieving inflammation. Moreover, honokiol shows anti-diabetic property through enhancing insulin sensitivity, and anti-obese property through promoting browning of adipocytes. In vivo and in vitro studies indicated that honokiol functions as an anti-cancer agent through multiple mechanisms: inhibiting angiogenesis, promoting cell apoptosis, and regulating cell cycle. A variety of therapeutic effects of honokiol may be associated with its physiochemical properties, which make honokiol readily cross the blood brain barrier and the blood-cerebrospinal fluid barrier, with high bioavailability. In the future, more clinical researches on honokiol are needed to fully authenticate its therapeutic values.

Synthesis of an AIEgen functionalized cucurbit[7]uril for subcellular bioimaging and synergistic photodynamic therapy and supramolecular chemotherapy.

Aggregation-induced emission (AIE) based fluorophores (AIEgens) have attracted increasing attention for biomedical applications due to their unique optical properties. Here we report an AIE photosensitizer functionalized CB[7], namely AIECB[7], which could spontaneously self-assemble into nanoaggregates in aqueous solutions. Interestingly, the carbonyl-lace of CB[7] may potentially act as a proton acceptor in an acidic environment to fine-tune the fluorescence and singlet oxygen generation of AIECB[7] nanoaggregates by regulating the inner stacking of AIEgens. Additionally, benefiting from the guest-binding properties of CB[7], oxaliplatin was included into AIECB[7] nanoaggregates for combined photodynamic therapy and supramolecular chemotherapy. To show the modular versatility of this supramolecular system, a hypoxia-activatable prodrug banoxantrone (AQ4N) was loaded into AIECB[7] nanoaggregates, which exhibited synergistic antitumor effects on a multicellular tumor spheroid model (MCTS). This work not only provides AIECB[7] for versatile theranostic applications, but also offers important new insights into the design and development of macrocycle-conjugated AIE materials for diverse biomedical applications.

Supramolecular nanomedicine for selective cancer therapy via sequential responsiveness to reactive oxygen species and glutathione.

Cancer cells are generally immersed in an oxidative stress environment with a high intracellular reduction level. Thus, nanocarriers with sequential responsiveness to oxidative and reductive species, matching the traits of high oxidation in the tumor tissue microenvironment and high reduction potential inside cancer cells, are highly desired for specific cancer therapy. Herein, we report a supramolecular nanomedicine comprised of a reduction-responsive nanoparticle (NP) core whose surface was modified by an oxidation-responsive polyethylene glycol (PEG) derivative via strong host-guest interactions. In this delicate design, the PEGylation of NPs not only reduced their immunogenicity and extended systemic circulation, but also enabled oxidation-responsive de-PEGylation in the tumor tissues and subsequent intracellular payload release in response to glutathione (GSH) inside tumor cells. As a proof of concept, this supramolecular nanomedicine exhibited specific chemotherapeutic effects against cancer in vitro and in vivo with a decent safety profile.

Bioactive Limonoids and Triterpenoids from the Fruits of Melia azedarach.

Nine new limonoids, meliazedarines A-I (1-9), seven known analogues (10-16), and five known triterpenoids (17-21) were isolated from the fruits of Melia azedarach. Their structures were determined by analysis of 1D and 2D NMR, HRESIMS, X-ray diffraction, and electronic circular dichroism (ECD) data. Compound 7 showed significant cytotoxicity against the HCT116 cell line with IC50 values of 0.3 ± 0.1 µM.

Finite element modeling of proximal femur with quantifiable weight-bearing area in standing position.

BACKGROUND: The positional distribution and size of the weight-bearing area of the femoral head in the standing position as well as the direct active surface of joint force can directly affect the result of finite element (FE) stress analysis. However, the division of this area was vague, imprecise, and un-individualized in most studies related to separate FE models of the femur. The purpose of this study was to quantify the positional distribution and size of the weight-bearing area of the femoral head in standing position by a set of simple methods, to realize individualized reconstruction of the proximal femur FE model. METHODS: Five adult volunteers were recruited for an X-ray and CT examination in the same simulated bipedal standing position with a specialized patented device. We extracted these image data, calculated the 2D weight-bearing area on the X-ray image, reconstructed the 3D model of the proximal femur based on CT data, and registered them to realize the 2D weight-bearing area to 3D transformation as the quantified weight-bearing surface. One of the 3D models of the proximal femur was randomly selected for finite element analysis (FEA), and we defined three different loading surfaces and compared their FEA results. RESULTS: A total of 10 weight-bearing surfaces in 5 volunteers were constructed, and they were mainly distributed on the dome and anterolateral of the femoral head with a crescent shape, in the range of 1218.63-1,871.06 mm2. The results of FEA showed that stress magnitude and distribution in proximal femur FE models among three different loading conditions had significant differences, and the loading case with the quantized weight-bearing area was more in accordance with the physical phenomenon of the hip. CONCLUSION: This study confirmed an effective FE modeling method of the proximal femur, which can quantify the weight-bearing area to define a more reasonable load surface setting without increasing the actual modeling difficulty.

Ethanol extract of Ophiorrhiza pumila suppresses liver cancer cell proliferation and migration.

BACKGROUND: Ophiorrhiza pumila, belonging to the genus Ophiorrhiza (Rubiaceae), is distributed throughout tropical and subtropical Asia. In this study, we evaluated for the first time the anti-proliferation and anti-migration effects of ethanol extract of O. pumila (OPE) on HepG2 and SMMC-7721 cells, and explored the related mechanism. METHODS: OPE was prepared by percolation with 95% ethanol and its main compounds were analyzed by HPLC-MS2. The anti-proliferation effect of OPE was evaluated by the CCK-8 assay and colony formation assay. Cell cycle distribution, apoptosis, and reactive oxygen species (ROS) level were detected by flow cytometry. Migration and invasion abilities were detected by Transwell migration/invasion assays. The expression of correlated proteins was determined using western blotting. RESULTS: A total of 5 tentative compounds were identified from OPE, including pumiloside, deoxypumiloside, camptothecin, aknadinine, and ß-stigmasterol. OPE displayed strong cytostatic effects on HepG2 and SMMC-7721 cells. OPE induced G2/M phase cell cycle arrest, increased apoptosis, and augmented ROS production in these cell lines. In addition, OPE possessed a significant inhibition on cell migration and invasion by reduction of MMP-9 and MMP-2 expression. Moreover, OPE significantly suppressed the phosphorylation of p65. CONCLUSIONS: Our data showed that OPE suppresses liver cancer cell proliferation and migration, which is possibly involved with the inhibition of the NF-κB pathway.

Leocarpinolide B attenuates LPS-induced inflammation on RAW264.7 macrophages by mediating NF-κB and Nrf2 pathways.

Macrophages-mediated inflammation is involved in the regulation of rheumatoid arthritis (RA). Sigesbeckiae Herba (SH) has been traditionally used for rheumatism. However, the bioactive ingredients of SH are still unclear. Recently, we isolated a compound (Leocarpinolide B, LB) from SH and identified its potent anti-inflammatory and antioxidant effects on RAW264.7 macrophages for the first time. LB effectively inhibited excessive production of nitric oxide (NO), prostaglandin E2 (PGE2), cytokines (IL-6, TNF-α and MCP-1), and the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthases (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 cells. LB blocked the degradation of inhibitor of kappa B (IκBα) and translocation of nuclear factor kappa B (NF-κB) p65. Additionally, LB reduced the intracellular reactive oxygen species, and increased the expression of heme oxygenase-1 (HO-1) and the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in the presence or absence of LPS. The results suggested that LB might be one of the bioactive components of SH, and be potential for the treatment of RA and valuable to be further investigated.

Eleven New Triterpenoid Glycosides from the Roots of Ilex asprella.

Asprellosides A-K, nine new ursane-type triterpenoid glycosides (1-9), and two new oleanane-type triterpenoid glycosides (10 and 11), including six rare sulfated triterpenoid glycosides, were isolated from the roots of Ilex asprella. Their structures were determined on the basis of comprehensive spectroscopic analysis and chemical methods. Among these compounds, asprelloside B (2) and asprelloside C (3) are the first examples of triterpenoid glycosides bearing a rare 3,4-O-disulfo-xylopyranosyl residue. All the saponins isolated showed no significant effects against respiratory syncytial virus (RSV) and lipopolysaccharide-induced nitric oxide production in Raw264.7 macrophages.

[Effect of electroacupunture on supplementary analgesia and the levels of serum ß-endorphin and prostaglandin E2 in patients with total knee arthroplasty].

OBJECTIVE: To observe the effect on supplementary analgesia after total knee arthroplasty (TKA) treated with electroacupunture, and explore it's mechanism. METHODS: A total of 40 patients with severe knee osteoarthritis were randomized into an observation group and a control group, 20 cases in each one. During the operation, patients were given epidural anesthesia in the two groups, conventional patient controlled epidural analgesia and oral celecoxib were applied after the operation. In the observation group, electroacupunture was used at Liangqiu (ST 34), Xuehai (SP 10), Yinlingquan (SP 9), Zusanli (ST 36), Fenglong (ST 40) and Qiuxu (GB 40) on the operation side from the 1st to 7th day after the operation to support analgesia, 30 min for each time, once a day. The visual analogue scale (VAS) was used to record postoperative pain of resting state and active state. The levels of serum prostaglandin E2 and ß-endorphin were measured on the 1st and 7th day after surgery in the two groups. RESULTS: In the observation group, the VAS scores of resting state and active state were superior to the control group on the 3rd, 5th and 7th day after the operaton (all P<0.05); after the treatment, the level of serum ß-endorphin was increased and the level of serum prostaglandin E2 was reduced in the two groups (all P<0.05), and the change of the observation group was larger than that of the control group (both P<0.05). CONCLUSION: Electroacupunture has the effect of supplementary analgesia for patients after TKA, the mechanism may be related to promote the synthesis of ß-endorphin and inhibit the synthesis of prostaglandin E2.

Cablinosides A and B, Two Glycosidic Phenylacetic Acid Derivatives from the Leaves of Pogostemon cablin.

A pair of new glycosidic epimers, cablinosides A (1a) and B (1b) were isolated from the leaves of Pogostemon cablin. The structures with absolute configurations of 1a and 1b were elucidated by extensive NMR investigation, and quantum chemical CD calculations. The epimer mixture 1 showed moderate α-glucosidase inhibitory activity and no significant cytotoxic activity against HepG2 cells.

Synthesis of novel 6,7-dimethoxy-4-anilinoquinolines as potent c-Met inhibitors.

HGF/c-Met signalling pathway plays an important role in the development of cancers. A series of 6,7-dimethoxy-4-anilinoquinolines possessing benzimidazole moiety were synthesised and identified as potent inhibitors of the tyrosine kinase c-Met. Their in vitro biological activities against three cancer cell lines (A549, MCF-7, and MKN-45) were also evaluated. Most of these compounds exhibited moderate to remarkable potency. Among them, compound 12n showed the most potent inhibitory activity against c-Met with IC50 value of 0.030 ± 0.008 µM and it also showed excellent anticancer activity against the tested cancer cell lines at low micromolar concentration. Molecular docking verified the results and revealed the possible binding mode of the most promising compound 12n into the ATP-binding site of c-Met kinase.

c-Met kinase inhibitors: an update patent review (2014-2017).

INTRODUCTION: The receptor tyrosine kinase c-Met is involved in the formation, metastasis and invasion of various malignant tumors thus it has been an attractive target for anti-tumor drug designing. Many compositions targeting c-Met have been developed in pharmaceutical industry for cancer therapy and some of them are in clinical study now. Among them, Crizotinib was the first small molecular inhibitor approved by FDA in 2011. AREAS COVERED: This review briefly summarizes the signal transduction pathway about c-Met, its role in oncogenesis, most recent patents of small-molecule inhibitors and antibodies of c-Met from 2014 to 2017. EXPERT OPINION: To date, some c-Met inhibitors have been launched in the market. In addition, their clinical performances have shown encouraging value in cancer therapy. Many potential agents are still in preclinical or clinical study now and achieve some promising progressions. Some patients have developed resistance to c-Met inhibitors which results in the need to develop inhibitors with novel structures. Development of several potent drugs also tends to be pharmacodynamically active against multiple targets.

[Electroacupuncture Intervention Reduces Post-surgical Pain of Patients Undergoing Total Knee Arthroplasty].

OBJECTIVE: To observe the analgesic effect and safety of electroacupuncture (EA) intervention for patients undergoing total knee arthroplasty (TKA). METHODS: A total of 40 patients undergoing TKA were randomly assigned to control group (simple multi-mode analgesia, n＝20) and EA group (EA combined with multi-mode analgesia, n＝20). Both groups were treated with epidural anesthesia during surgical operation, and conventional epidural automatic analgesia and oral Celecoxib after surgery. Following surgery, EA was applied to Liangqiu (ST 34)-Xuehai (SP 10), Yinlingquan (SP 9)-Zusanli (ST 36), Fenglong (ST 40)-Qiuxu(GB 40) on the operation side for 30 min, once daily for 7 consecutive days. The patients' pain state during rest and motion was assessed by using visual analogue scale (VAS). The active and passive knee flexion range of motion (ROM), use of painkillers including the number of patient's controlled epidural analgesia (PCEA) during 48 h after surgery, and other complications were recorded. RESULTS: After the treatment, the VAS scores under rest and motion state were both significantly lower in the EA group than in the control group on day 3, 5 and 7 after surgery (P<0.05). During 48 h after surgery, the number of PECA was significantly lower in the EA group than in the control group (P<0.05). Of the two 20 cases in the control and EA groups, 3 and 1 asked to receive muscular injection of Tramadol Hydrochloride for pain relief, 3 and 2 experienced nausea-vomiting, 2 and 1 had dizziness and headache, and 2 and 1 had a chest distress feeling, respectively, which had no significant differences between the two groups (P>0.05). The white blood cell (WBC) count in both groups were decreased gradually from day 1 to 7 after surgery, and plasma C-reactive protein content on day 5 and 7 were also lowered in both groups, without statistical differences between the two groups in the post-operative complications, dosages of additional postoperative analgesic drugs, and levels of plasma WBC and C-reactive protein (P>0.05). CONCLUSION: EA can effectively improve the early postoperative pain of TKA, reduce the incidence of postoperative complications and the use of analgesic drugs in TKA patients.

Ervadivamines A and B, Two Unusual Trimeric Monoterpenoid Indole Alkaloids from Ervatamia divaricata.

Ervadivamines A (1) and B (2), two unprecedented trimeric monoterpenoid indole alkaloids, were isolated from Ervatamia divaricata. They are the first examples of vobasine-iboga-vobasine-type alkaloid with both C-C and C-N linkage patterns. Their structures including absolute configurations were fully accomplished by extensive spectroscopic analysis, single-crystal X-ray diffraction, and electric circular dichroism methods. The plausible biogenetic pathways of these trimeric alkaloids were also proposed. In addition, compound 1 exhibited significant cytotoxicity against four cancer cells.

Coptidis rhizoma and its main bioactive components: recent advances in chemical investigation, quality evaluation and pharmacological activity.

BACKGROUND: Coptidis rhizoma (CR) is the dried rhizome of Coptis chinensis Franch., C. deltoidea C. Y. Cheng et Hsiao or C. teeta Wall. (Ranunculaceae) and is commonly used in Traditional Chinese Medicine for the treatment of various diseases including bacillary dysentery, typhoid, tuberculosis, epidemic cerebrospinal meningitis, empyrosis, pertussis, and other illnesses. METHODS: A literature survey was conducted via SciFinder, ScieneDirect, PubMed, Springer, and Wiley databases. A total of 139 selected references were classified on the basis of their research scopes, including chemical investigation, quality evaluation and pharmacological studies. RESULTS: Many types of secondary metabolites including alkaloids, lignans, phenylpropanoids, flavonoids, phenolic compounds, saccharides, and steroids have been isolated from CR. Among them, protoberberine-type alkaloids, such as berberine, palmatine, coptisine, epiberberine, jatrorrhizine, columamine, are the main components of CR. Quantitative determination of these alkaloids is a very important aspect in the quality evaluation of CR. In recent years, with the advances in isolation and detection technologies, many new instruments and methods have been developed for the quantitative and qualitative analysis of the main alkaloids from CR. The quality control of CR has provided safety for pharmacological applications. These quality evaluation methods are also frequently employed to screen the active components from CR. Various investigations have shown that CR and its main alkaloids exhibited many powerful pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetic, neuroprotective, cardioprotective, hypoglycemic, anti-Alzheimer and hepatoprotective activities. CONCLUSION: This review summarizes the recent phytochemical investigations, quality evaluation methods, the biological studies focusing on CR as well as its main alkaloids.