[Efficacy of a Daltuzumab-containing Regimen in Patients with mSMART High-Risk Multiple Myeloma].

OBJECTIVE: To investigate the efficacy and safety of a treatment regimen based on daratumumab in patients with high-risk relapsed refractory multiple myeloma(MM) with mSMART 3.0 score. METHODS: Clinical data were collected from 16 patients with mSMART3.0 score high-risk relapsed refractory MM treated at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from May 2020 to May 2023, all of whom received daltezumab-based regimen (regimen drugs including dexamethasone, isazomib, bortezomib, lenalidomide). The efficacy and safety of the treatment were retrospectively analyzed. RESULTS: The median age of 16 patients was 63.5 (47-70) years old, including 10 cases of IgG type, 2 cases of IgA type, and 4 cases of light chain type. The curative efficacy was judged in all 16 patients, with an overall response rate of 93.75% (15/16), including 4 cases of strict complete remission (sCR), 1 case of complete remission (CR), 2 case of very good partial remission (VGPR), partial remission (PR) in 5 cases, and minor remission (MR) in 3 cases. The median follow-up time was 11(2-30) months, and the median progression-free survival and median overall survival were not achieved in 16 patients at the median follow-up period. The hematologic adverse effects of the treatment regimen using daratumumab-based were mainly neutropenia, and the non-hematologic adverse effects were mainly infusion-related adverse reactions and infections. CONCLUSION: Daratumumab-based regimen for the treatment of relapsed refractory MM patients with high risk of mSMART3.0 score has better efficacy and safety.

Epimedin B exerts an anti-inflammatory effect by regulating the MAPK/NF-κB/NOD-like receptor signalling pathways.

Epimedin B (EB), a predominant compound found in Herba Epimedii, has been shown to be effective in the treatment of osteoporosis and peripheral neuropathy. However, the anti-inflammatory effect of EB has not yet been reported. The anti-inflammatory activity of EB was evaluated in a zebrafish inflammation model induced by copper sulfate (CuSO4) and tail cutting. Our findings demonstrated that EB effectively inhibited acute inflammation, mitigated the accumulation of reactive oxygen species (ROS), and ameliorated the neuroinflammation-associated impairment of locomotion in zebrafish. Moreover, EB regulates several genes related to the mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB)/Nod-like receptor signalling pathways (mapk8b, src, mmp9, akt1, mapk14a, mapk14b, mapk1, egfra, map3k4, nfκb2, iκbαa, pycard, nlrp3 and caspase1) and inflammatory cytokine (stat6, arg1, irfɑ, stat1ɑ, il-1ß, il-4, il-6, il-8, cox-2, ptges, tnf-α and tgf-ß). Therefore, our findings indicate that EB could serve as a promising therapeutic candidate for treating inflammation.

Three-Component Synthesis of Multiple Functionalized Allenes via Copper/Photoredox Dual Catalyzed 1,4-Alkylcyanation of 1,3-Enynes.

Efficient access to multiple functionalized allenes via a three component 1,4-alkylcyanation of enynes with cyclic alcohol derivatives in the presence of trimethylsilyl cyanide (TMSCN) under copper/photoredox dual catalysis has been developed. Both easily transformable aldehyde and cyano groups were introduced to tetra-substituted allenes through light-induced C-C bond cleavage of cyclic butanol and pentanol derivatives. The reactions proceeded smoothly under mild conditions with broad functional groups tolerance.

Electrophile-Controlled Regiodivergent Palladium-Catalyzed Imidoylative Spirocyclization of Cyclic Alkenes.

An intermolecular controllable Pd-catalyzed spirocyclization of isocyano cycloalkenes has been developed, offering efficient and selective approaches toward spirocyclic hydropyrrole scaffolds. 2-Azaspiro-1,7-dienes could be obtained through a "chain-walking" process with aryl/vinyl iodides as electrophiles, while the normal Heck product 2-azaspiro-1,6-dienes were selectively generated when aryl triflates were used as the coupling partner of isocyanides. Mechanistic studies suggested that the counteranion of the Pd(II) intermediate played a crucial role in the regioselectivity control. Dihydropyrrole-fused 5,6,7-membered spirocycles were switchably accessed under mild conditions with wide functional group tolerance.

Zinc Oxide Nanoparticles Trigger Autophagy in the Human Multiple Myeloma Cell Line RPMI8226: an In Vitro Study.

Multiple myeloma (MM) is a malignant clonal proliferative plasma cell tumor. Zinc oxide nanoparticles (ZnO NPs) are used for antibacterial and antitumor applications in the biomedical field. This study investigated the autophagy-induced effects of ZnO NPs on the MM cell line RPMI8226 and the underlying mechanism. After RPMI8226 cells were exposed to various concentrations of ZnO NPs, the cell survival rate, morphological changes, lactate dehydrogenase (LDH) levels, cell cycle arrest, and autophagic vacuoles were monitored. Moreover, we investigated the expression of Beclin 1 (Becn1), autophagy-related gene 5 (Atg5), and Atg12 at the mRNA and protein levels, as well as the level of light chain 3 (LC3). The results showed that ZnO NPs could effectively inhibit the proliferation and promote the death of RPMI8226 cells in vitro in a dose- and time-dependent manner. ZnO NPs increased LDH levels, enhanced monodansylcadaverine (MDC) fluorescence intensity, and induced cell cycle arrest at the G2/M phases in RPMI8226 cells. Moreover, ZnO NPs significantly increased the expression of Becn1, Atg5, and Atg12 at the mRNA and protein levels and stimulated the production of LC3. We further validated the results using the autophagy inhibitor 3-methyladenine (3­MA). Overall, we observed that ZnO NPs can trigger autophagy signaling in RPMI8226 cells, which may be a potential therapeutic approach for MM.

Stereoselective Construction of Unsymmetrically Linked Heterocycles via Palladium-Catalyzed Alkyne Insertion/Cycloimidoylation Cascade.

A novel strategy to access unsymmetrically linked heterocycles via palladium-catalyzed acylcycloimidoylation of alkyne-tethered carbamoyl chlorides with isocyanides has been developed. Functionalized isocyanides were successfully applied as imine-containing heterocycle precursors to capture the vinyl-PdII intermediate, which was generated from a syn-carbopalladation of alkyne, followed by subsequent intramolecular C-H bond activation/imidoylative Heck reactions. Methylene oxindoles within Z-tetrasubstituted olefins were obtained in high yields with excellent stereoselectivities. Broad functional groups were well tolerated under mild reaction conditions.

Distribution Characteristics of Nutritional Elements and Combined Health Risk of Heavy Metals in Medicinal Tea from Genuine Producing Area of China.

The development of the medicinal tea (MT) system has promoted the health awareness in the whole world, and the nutritional elements are also an important resource of health care delivery except for the medicinal components. Among various medicinal teas, Astragalus membranaceus (AM), Zingiberaceae rhizome (ZR), and Lonicera japonica (LJ) were the most popular ingredients in China. However, except for the nutrition value, MT was inevitably contaminated with heavy metals due to the special planting environment and processing system. This study was aimed to investigate the distribution characteristics of nutrition elements and combined health risk of heavy metals in MT sample, referring to the maximum residue limit (MRL), estimated daily intake (EDI), total target hazard quotients (TTHQs), and lifetime cancer risk (LCR). Furthermore, the bioaccessibility of gastrointestinal phase and bioavailability of human colon adeno carcinoma cell line were selected for elaborating the exact damage degree to human digestive system. The results showed that, the nutritional elements of Na, Se, K, Ca, and Mn were very rich in MT, but a total of 50% of MT were contaminated by Cr, Hg, and Cd in raw material. Although the cumulative lifetime cancer risk can be accepted under the bioaccessibility (26.62-99.27%), the heavy metals of Cr, As, Hg, and Fe in AM and LJ posed a slight threaten of non-carcinogenic risk to consumers. This study will give an exactly assessment of multiple elements in digestive system, thus further to predict the potential health risk under the consumption of MT products.

Induced effect of zinc oxide nanoparticles on human acute myeloid leukemia cell apoptosis by regulating mitochondrial division.

Zinc oxide nanoparticles (ZnO NPs) have exhibited excellent anti-tumor properties; the present study aimed to elucidate the underlying mechanism of ZnO NPs induced apoptosis in acute myeloid leukemia (AML) cells by regulating mitochondrial division. THP-1 cells, an AML cell line, were first incubated with different concentrations of ZnO NPs for 24 hr. Next, the expression of Drp-1, Bcl-2, Bax mRNA, and protein was detected, and the effects of ZnO NPs on the levels of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), apoptosis, and ATP generation in THP-1 cells were measured. Moreover, the effect of Drp-1 inhibitor Mdivi-1 and ZnO NPs on THP-1 cells was also detected. The results showed that the THP-1 cells survival rate decreased with the increment of ZnO NPs concentration and incubation time in a dose- and time-dependent manner. ZnO NPs can reduce the cell Δψm and ATP levels, induce ROS production, and increase the levels of mitochondrial division and apoptosis. In contrast, the apoptotic level was significantly reduced after intervention of Drp-1 inhibitor, suggesting that ZnO NPs can induce the apoptosis of THP-1 cells by regulating mitochondrial division. Overall, ZnO NPs may provide a new basis and idea for treating human acute myeloid leukemia in clinical practice.

Silver-promoted dearomative [3+4] cycloaddition of anthranils with α-isocyanoacetates: access to benzodiazepines.

The first example of silver-promoted [3+4] cycloaddition of α-isocyanoacetates with anthranils as aromatic Michael accepters, offering access to benzo[d][1,3]diazepinones, has been developed. Mechanistic studies revealed that an "oxygen migration" rearrangement process was involved in this dearomative cycloaddition reaction. Additionally, benzo[d][1,3]diazepinones were obtained efficiently as well under catalytic conditions. Broad functional groups were well tolerated under mild reaction conditions.

[Health risk assessment of exogenous harmful pollutants in Chinese medicine: a review].

In recent years, the quality and safety problems have been limiting the internationalization of Chinese medicine. The pollutants in Chinese medicine, particularly the exogenous harmful pollutants mainly including mycotoxins, pesticide residues, heavy metals, harmful elements, and sulfur dioxide, are of high risks for people. Therefore, the World Health Organization(WHO) and relevant national organizations have clearly defined the maximum residue limits(MRLs) of such pollutants. Chinese Pharmacopoeia(2020 edition, volume Ⅳ) also demonstrates the detection methods, MRLs and preliminary risk assessment methods for four typical exogenous harmful pollutants in Chinese medicine. Therefore, continuous optimization of the health risk assessment system can further help further raise the quality and safety of Chinese medicine. This paper reviews the research on the health risk assessment of four typical exogenous harmful pollutants in Chinese medicine and discusses the problems of and challenges for the assessment system, which is expected to lay a scientific basis for the establishment of the risk warning mode and response measures suitable for specific types of Chinese medicine.

Palladium-catalysed imidoylative spirocyclization of 3-(2-isocyanoethyl)indoles.

A palladium-catalysed construction of spiroindolines through dearomative spirocyclization of 3-(2-isocyanoethyl)indoles has been developed. 2'-Aryl-, vinyl-, and alkyl-substituted spiroindolines could be accessed under mild conditions with excellent functional group tolerance. C1-tethered oxindole- and indole-spiroindoline bisheterocycles were generated in high yields via alkene/allene insertion and an imidoylative spirocyclization cascade. Additionally, a tandem dearomatization of two different indoles was realized with N-(2-bromobenzoyl)indoles as the electrophilic coupling partner of 3-(2-isocyanoethyl)indoles, affording polyindoline - spiroindoline bisheterocyclic scaffolds conveniently. Under the catalysis of Pd(OAc)2 and a spinol-derived phosphoramidite ligand, chiral spiroindolines were successfully accessed with up to 95% yield and 85% ee.

Efficacy and safety of chemotherapy combined with different doses of IL-2 maintenance therapies for acute myeloid leukemia: A protocol for a Bayesian network meta-analysis.

BACKGROUND: Acute myeloid leukemia (AML) is the most common malignant tumor of the hematopoietic system, which seriously threatens the lives of patients. Most AML patients have acute onset, severe condition, and poor prognosis. The present study aimed to comprehensively evaluate the effectiveness and safety of chemotherapy combined with different doses of interleukin-2 (IL-2) maintenance treatments in AML by Bayesian network meta-analysis (NMA). METHODS: From its inception until October 2021, we will search PubMed, Cochrane Library, CNKI, Embase, and other databases to comprehensively collect randomized controlled trials (RCTs) of chemotherapy combined with different doses of IL-2 maintenance therapies for AML. Two independent researchers will complete the literature screening and data extraction according to the inclusion and exclusion criteria, and then independently conduct a bias risk assessment of all the evidence. Bayesian NMA was used to evaluate all the evidence comprehensively. Use STATA16.0 and WinBUGS1.4.3 software to process and analyze all data, and classify the quality of evidence in NMA according to grading of recommendations assessment, development, and evaluation . RESULTS: The study will evaluate the efficacy and safety of chemotherapy combined with different doses of IL-2 maintenance therapies for AML. CONCLUSION: The study will provide a basis for the efficacy and safety of chemotherapy combined with different doses of IL-2 maintenance therapies for AML. We hope that this study can provide meaningful support for clinicians and patients. PROTOCOL REGISTRATION NUMBER: INPLASY202140106. ETHICAL APPROVAL: Since the study is based on published or registered RCTs, ethical approval and patient informed consent are abandoned.

Palladium-Catalyzed Divergent Imidoylative Cyclization of Multifunctionalized Isocyanides: Tunable Access to Oxazol-5(4H)-ones and Cyclic Ketoimines.

A palladium-catalyzed tunable imidoylative cyclization of multifunctionalized isocyanides to construct diverse imine-containing heterocycles has been developed. Oxazol-5(4H)-one derivatives were obtained exclusively when allyl-2-benzyl(or allyl)-2-isocyanoacetates were used in the reaction with aryl triflates as electrophiles, whereas cyclic ketoimines were generated in the presence of aryl iodides with the allyl ester group remaining unreacted. The reactions proceeded smoothly under mild conditions with a wide functional group tolerance.

Palladium-catalysed dearomative aryl/cycloimidoylation of indoles.

The first example of a dearomative palladium-catalysed isocyanide insertion reaction has been developed using functionalized isocyanides as the reaction partner of N-(2-bromobenzoyl)indoles. The imidoyl-palladium intermediate generated by tandem indole double bond/isocyanide insertion reactions could be trapped by intramolecular functional groups such as the C(sp2)-H bond and alkenes, affording diversified indoline derivatives bearing C3 imine-containing heterocycles. The dearomative aryl/cycloimidoylation of indoles proceeded smoothly in good to excellent yields with a wide functional group tolerance.

Zinc oxide nanoparticles induce human multiple myeloma cell death via reactive oxygen species and Cyt-C/Apaf-1/Caspase-9/Caspase-3 signaling pathway in vitro.

BACKGROUND: Human multiple myeloma (MM) is a malignant and incurable B cell tumor. Zinc oxide nanoparticles (ZnO NPs) have been widely used in biomedical fields including anti-bacterial and anti-tumor. However, the influence of ZnO NPs on MM cells is still unclear. The present study aimed to investigate the effect of ZnO NPs on MM cell (a human myeloma-derived RPMI8226 cell line) death in vitro and the underlying mechanism. METHODS: The morphology of ZnO NPs was characterized by transmission electron microscopy (TEM), and the inhibitory and apoptotic effect of ZnO NPs on human MM cells was monitored by a CCK-8 method and an Annexin V-FITC/PI assay. Meanwhile, the morphological change in the cells after exposure to ZnO NPs was observed by a light field microscope. Moreover, the effects of ZnO NPs on the ATP level, reactive oxygen species (ROS) generation, and apoptosis were separately explored by the DCFH-DA fluorescent probe, flow cytometry, and ATP bioluminescence assay. Moreover, the expression of cytochrome C (Cyt-C), Apaf-1, Caspase-9 and Caspase-3 at mRNA and protein levels was further determined by using quantitative PCR (Q-PCR) and western blotting. In the present study, the human peripheral blood mononuclear cells (PBMCs) were used as normal control samples for the relevant experiment. RESULTS: The results indicated that ZnO NPs could significantly inhibit human MM cell proliferation and cell death in a time- and dose-dependent manner in vitro, and this outcome can be confirmed by cell morphology and apoptosis assay. Meanwhile, the results also showed that ZnO NPs could effectively increase ROS production and decrease ATP levels in human MM cells. ZnO NPs could also significantly elevate the expression of Cyt-C, Apaf-1, Caspase-9 and Caspase-3 at mRNA and protein levels, leading to cell death. By contrast, ZnO NPs showed little cytotoxic influence on PBMCs. CONCLUSION: ZnO NPs can significantly induce human MM cell death in a time- and dose-dependent manner in vitro, decrease the ATP production and enhance the ROS generation. ZnO NPs can also increase Cyt-C, Apaf-1, Caspase-9 and Caspase-3 expression at mRNA and protein levels in human MM cells, and initiate MM cell apoptosis, indicating that Cyt-C, Apaf-1, Caspase-9 and Caspase-3 play crucial roles in ZnO NPs-induced, mitochondria-mediated apoptosis in human MM cells. Overall, ZnO NPs may be a potential agent in treating human multiple myeloma in clinical practice.

Wedelolactone-Loaded Micelles Ameliorate Doxorubicin-Induced Oxidative Injury in Podocytes by Improving Permeability and Bioavailability.

Wedelolactone (WED) is commonly used for the treatment of doxorubicin (DOX)-induced kidney damage, but its efficacy is limited by its poor solubility and bioavailability. In this study, we developed a novel delivery system of WED-loaded micelles (WED-M) with Solutol® HS15 and lecithin at an optimized ratio of 7:3 to improve the poor permeability and bioavailability of WED and to enhance its efficacy. The spherically shaped WED-M (particle size: 160.5 ± 3.4 nm; zeta potential: -30.1 ± 0.9 mV; entrapment efficiency: 94.41 ± 1.64%; drug loading: 8.58 ± 0.25%; solubility: 1.89 ± 0.06 mg/ml) has continuous stability over 14 days and a sustained release profile. The permeability of WED-M in Caco-2 cells indicated a significant 1.61-fold higher Papp AP to BL ratio than WED alone. Additionally, pharmacokinetic evaluation of WED-M demonstrated that the bioavailability of WED was increased 2.78-fold. Both HE staining and transmission electron microscopy showed an obvious improvement of pathological damage in WED-M treatment. Moreover, WED-M significantly enhanced the ROS level in mice and MPC5 podocytes. We concluded that using this micelle delivery system for WED could improve its permeability and bioavailability to attenuate DOX-induced oxidative injury in podocytes. This study provided important information on the fact that the micelle delivery system, WED-M, showed a significant improvement of renal damage.

Phosphodiesterase 5 inhibitors as novel agents for the treatment of Alzheimer's disease.

Alzheimer's disease (AD), characterized by a progressive impairment of memory and cognition, is a major health problem in both developing and developed countries. Currently, no drugs can reverse the progression of AD. Phosphodiesterase 5 (PDE5) is a critical component of the cyclic guanosine monophosphate/protein kinase G (cGMP/PKG) signaling pathway in neurons, the inhibition of which has produced neuroprotective effects, and PDE5 inhibitors have recently been thought to be potential therapeutic agents for AD. In this paper, we summarized the outstanding progress that has been made in PDE5 inhibitors as anti-AD agents with encouraging results in animal studies, clinical trials and the investigations on the underlying mechanisms. The novel PDE5 inhibitors reported recently in the treatment of AD were also reviewed and discussed.

Migration of titanium dioxide from PET/TiO2 composite film for polymer-laminated steel.

PET/TiO2 composite film is the most widely used film for polymer-laminated steel, and the migration of TiO2 is very important for the safety evaluation of its packaged food. Microwave digestion, wet digestion and dry ashing were used for pretreatment of composite film to determine the content of TiO2 in composite film. Migration tests were carried out at 40°C, 60°C and 80°C 4% using acetic acid and 50% ethanol as the acid and ester food simulants. The migration amount of TiO2 was determined by inductively coupled plasma optical emission spectrometry (ICP-OES). With increasing temperature and time, the migration of TiO2 increased. In 4% acetic acid, the migration amount of TiO2 at 40°C for 10 days was 1.88 mg kg-1 and the migration amount at 80°C for 8 h was 3.32 mg kg-1, indicating that the effect of temperature on migration was more obvious. Under the same conditions, the migration amount of TiO2 in 4% acetic acid was greater than in 50% ethanol. X-ray diffraction (XRD), scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimeter (DSC) were used to analyse the crystal structure, morphology, chemical groups and thermal properties of the film before and after the migration tests. The results showed that filmTiO2 had a stable rutile type crystal structure and it was almost uniformly distributed. PET and TiO2 were combined with strong chemical bonds. After TiO2 migration, the crystallinity and the glass transition temperature (Tg) of the film decreased, but the change of melting temperature (Tm) was not obvious.

[Effects of Arsenic Trioxide on Cdc20 and Mad2 in Acute Myeloid Leukemia HL-60 Cell Line].

OBJECTIVE: To investigate the effects of arsenic trioxide (As2O3) on Cdc20 and Mad2 in process of AML HL-60 cell proliferation. METHODS: The proliferation of HL-60 cells was detected by CCK-8 method at different concentrations of arsenic trioxide for 24, 48 and 72 hours. The cell morphological changes were observed by inverted microscopy. The expressions of Mad2 and Cdc20 mRNA and protein in HL-60 cells treated with As2O3 for 48 h were detected by real-time PCR and Western blot respectively. RESULTS: Arsenic trioxide significantly inhibited the HL-60 cell proliferation and displayed a good time-dose correlation. RT-PCR and Western blot showed that the expression of Mad2 was up-regulated and the expression of Cdc20 was down-regulated in HL-60 cells treated with arsenic trioxide of different concentration (4,8,10 µmol/L). CONCLUSION: Arsenic trioxide can inhibit the human acute myeloid leukemia HL-60 cell proliferation, and its mechanism may be related with up-regulation of Mad2 expression and down-regulation of Cdc20 expression.

Regulation of Eclipta prostrata L. components on cigarette smoking-induced autophagy of bronchial epithelial cells via keap1-Nrf2 pathway.

Cigarette smoking extract (CSE)-induced autophagic injury has been regarded as an important contributor to the pathogenesis of lung cancer. We previously found that Eclipta prostrata L. component (CCE) reduced CSE-induced bronchial epithelial cells damage. However, the mechanism remains unknown. Human normal bronchial epithelial cells (NHBE) were exposed to CSE to establish stress model. Nrf2-siRNA and Keap1-siRNA transfection were performed. mRFP-GFP-LC3 dual fluorescence and transmission electron microscopy were used to observe the autophagic characteristics. CCE prevented CSE-induced Nrf2 transfer into cytoplasm and up-regulated Keap1 level of NHBE cells. Furthermore, CCE significantly increased p-p16, p-p21 and p-p53 phosphorylation levels in Nrf2-siRNA- or Keap1-siRNA-transfected cells. As demonstrated by transmission electron microscopy and mRFP-GFP-LC3 dual fluorescence assays, CCE mitigated autophagic injury, and also down-regulated autophagy-related Beclin-1, LC3II/LC3I ratio, Atg5 and ATF4 levels. Our findings showed the attenuation of CCE on CSE-induced NHBE cells injury was associated with Nrf-2-mediated oxidative signaling pathway.