Psoriasis and gut microbiota: A Mendelian randomization study.

In recent years, an increasing number of observational studies have revealed an association between gut microbiota composition and psoriasis patients. However, whether this association reflects a causal relationship remains unclear. This study aimed to identify the causal relationship between gut microbiota and psoriasis through relevant research. In order to determine whether gut microbiota and psoriasis are causally related, we conducted a Mendelian randomization analysis using summary statistics from genome-wide association studies (GWAS). As the exposure factor, we used summary statistics data from a GWAS study conducted by the MiBioGen Consortium, including 18,340 individuals with whole-genome gut microbiota composition, and data from the FinnGen GWAS study on psoriasis, including 9267 patients and 364,071 controls as the disease outcome. Two-sample Mendelian randomization analysis was subsequently performed with inverse variance weighted, MR-Egger and weighted median, while sensitivity analyses were conducted to address heterogeneity and horizontal pleiotropy. The IVW results confirmed the causal relationship between certain gut microbiota groups and psoriasis. Specifically, family Veillonellaceae (OR = 1.162, 95% CI: 1.038-1.301, p = 0.009), genus Candidatus Soleaferrea (OR = 1.123, 95% CI: 1.011-1.247, p = 0.030) and genus Eubacterium fissicatena group (OR = 0.831, 95% CI: 0.755-0.915, p = 0.00016) showed significant associations. Sensitivity analysis did not reveal any abnormalities in SNPs. Currently, we have found some causal relationship between the gut microbiota and psoriasis. However, the study needs further RCTs for further validation.

Enantiomer-Specific Colorimetric Tandem Assays for Salivary d-Alanine Associated with Gastric Cancer.

Salivary d-alanine (d-Ala) and d-proline (d-Pro) are of concern for their potential in the noninvasive diagnosis of gastric cancer (GC). Most reports have succeeded in determining the total concentration of d-Ala and d-Pro. However, for personalized diagnosis and better elucidation of the underlying specific correlation of d-Ala (or d-Pro) with GC, it is desirable to determine the specific concentration of d-Ala or d-Pro. Herein, we propose an enantiomer-specific tandem assay of d-Ala based on the colorimetric reaction between 2,4-dinitrophenylhydrazine and pyruvic acid generated from the deamination of d-Ala catalyzed by d-amino acid oxidase, which is easily distinguished from l-form amino acids, d-Pro, and many other species. A linear concentration range is established from 20 to 400 µmol/L with a limit of detection of 1.01 µmol/L. Real saliva sample tests reveal that the levels of d-Ala in GC cases are remarkably higher than those in healthy individuals, which offers a simple and low-cost strategy for GC diagnosis. Simultaneously, the total concentrations of d-Ala and d-Pro in saliva are determined. Hence, the concentration of d-Pro and the proportion of d-Ala could be calculated, which further provides more molecule- and individual-specific information. This research may offer a convenient method for noninvasive diagnosis of GC and pave a new route to explore the potentials of rare d-form amino acids in disease diagnosis and treatment.

Internal standard optimization advances sensitivity and robustness of ratiometric detection method.

We design a p-aminothiophenol (pATP) modified Au/ITO chip to determine nitrite ions in lake water by a ratiometric surface-enhanced Raman scattering (SERS) method based on nitrite ions triggering the transformation of pATP to p,p'-dimercaptoazobenzene (DMAB). Intriguingly, by using the SERS peak (at 1008 cm-1) from benzoic ring deforming as an internal standard instead of the traditional peak at 1080 cm-1, the detection sensitivity of the method was improved 10 times.

Surface-Enhanced Raman Scattering Enantioselective Detection of Gastric Cancer-Related d-Amino Acids in Saliva Based on Enzyme-Mediated Cascade Reaction.

The unusual d-amino acids (d-AAs), as the counter enantiomer of usual l-amino acids (l-AAs), have evoked increasing attention because of their potential relevance with diseases. Accordingly, it is essential to establish sensitive and selective detection methods for d-AAs without the interferences from l-AAs. The surface-enhanced Raman scattering (SERS) technique is efficacious for the detection of molecules but routinely ineffective in enantiomeric differentiation. d-Proline (d-Pro) and d-alanine (d-Ala) are regarded as biomarkers of gastric cancer. Herein, Raman-active boronate modified SERS chips are constructed to develop a d-amino acid oxidase (DAAO)-mediated cascade reaction-based SERS enantioselective assay for d-Pro and d-Ala. The principle is that DAAO selectively catalyzes the deamination of d-Pro and d-Ala, and the produced H2O2 oxidizes boronate to present a new SERS peak at 883 cm-1 for quantitative analysis in a ratiometric way. A linear range from 20 to 400 µmol/L and a limit of detection down to 14.8 µmol/L are reached. In addition, interferences from l-AAs and many other possible species coexisting in biofluids with the detection of d-Pro and d-Ala are ignorable. Enzyme-mediated cascade reaction-based SERS chips are further utilized for saliva sample analysis, and the total levels of d-Pro and d-Ala in salivary samples from gastric cancer patients are much higher than those of healthy persons. This work provides a solution for SERS enantioselective analysis and noninvasive screening chiral biomolecules for disease diagnosis.

Hexagon AgNCs/PVP Crystallization Induced Cathode Electrochemiluminescence Enhancement for miRNA221 Biosensing.

Aggredation-induced electrochemiluminescence (AIECL) promises an efficient strategy for synthesize highly luminescent emitter and co-reactant for ECL analysis, however, rational control of electrogenerated emission intensity is still challenging. The low electroconductivity and amorphous molecular configuration are intrinsic bottleneck. This work reveals the impact of polyvinyl pyrrolidone backbone regulated silver nanocrystallines (AgNCs/PVP) on the cathode AIECL properties in near infrared region, by employing the Box-Behnken designed response surface computation model to modulate crystal aggregates. Electron paramagnetic resonance spectroscopy discovered hydrogen radical (HO• ) dominant reductive-oxidative (R-O) ECL mechanism with AgNCs acting as the co-reaction accelerator in graphene oxide/persulfate system (GO/S2 O8 2- ). Both theoretical calculation and experimental measurement testified that the ECL of AgNCs in GO/S2 O8 2- dependent on the concentration of in situ electrochemical oxidized Ag+ . The high efficiency of crystallization-induced enhanced ECL (CIECL) originates from 1) the effective electron transfer of Ag+ accelerated HO• produce to notable promote radioactive transition, and 2) twisted intramolecular charge transfer from the electron-rich donor of PVP to electron-deficient receptor of Ag0 to restrict nonradioactive transition. The AgNCs/PVP with CIECL effect are applied to construct an ultrasensitive platform for miR-221 assay with a lower detection limit of 7.47 × 103  copies mL-1 than typical qPCR method.

Optimal design of integrated visible light communication and positioning system with energy harvesting.

In this paper, an optimization scheme that can simultaneously transmit communication information, positioning the information and energy in a visible light communication and positioning (VLCP) system with energy harvesting is proposed. The time switching-power splitting (TS-PS) method is applied, where the power and time allocation factors are defined as optimization variables, so that the system can maximize the harvested energy under the constraints of the information rate and positioning error. The multi-verse optimization (MVO) algorithm is introduced to obtain the optimal power and time allocation. In addition, the performance of the integrated system using the TS-PS method is investigated and compared with that using other conventional methods. The results show that a maximized harvested energy solution using the TS-PS method can harvest the most energy. Moreover, the effects of main external environment conditions, namely, the room height and field of view (FoV) of a photo diode (PD) on the system performance are also analyzed. The increase of the room height and FoV of the PD reduces the harvested energy, but does not change the information rate and positioning accuracy in the optimized system adopted in this paper.

Effects of Remote Ischemic Preconditioning on Delirium and Neurological Function in Patients Undergoing Cardiac Surgery: A Multicenter Randomized Controlled Trial.

BACKGROUND: Postoperative delirium (POD) and neurological dysfunction are very common following cardiac surgery and deteriorate the patient's prognosis and the outcome of surgical procedures. A clinically effective management strategy or drug is not yet available for POD. Additionally, it is unknown whether remote ischemic preconditioning (RIPC) has neuroprotective and anti-delirium benefits in patients who undergo cardiac surgery. METHODS: This study examined whether RIPC can improve POD and neurological function in cardiac surgery patients. We screened 510 consecutive adult patients aged 18 and older who underwent cardiac surgery between January 2018 and December 2022. Then, 448 of these patients were recruited in the trial as the intention to treat (ITT) group, who were then randomly assigned to receive either a control (n = 223) or RIPC treatment (n = 225). The primary outcome measures were hospitalization postoperative delirium, six-month modified Rankins scale (mRS), hospital cerebral infarction, 30-day overall mortality, neuron-specific enolase (NSE) and S-100b levels, related adverse effects, hospital costs, and hospital stay. RESULTS: A statistically significant variation was not observed between the two groups in terms of the baseline clinical data. In contrast to the control group, the POD in the RIPC group was considerably alleviated. RIPC treatment also decreased the levels of NSE and S-100b, which alleviated nerve injury. The adverse impacts of RIPC-induced objective indicators of tissue or neurovascular damage were similar in both groups, showing no significant variations between the two. The hospital stays and hospitalization costs also decreased significantly in the RIPC-treated patients. CONCLUSION: The study findings suggested that RIPC may benefit cardiac surgery patients by reducing POD, alleviating injury, and lowering hospital expenditures and length of stay. Cardiac surgery patients can be treated with RIPC, which is an effective and safe technique.

Compounding warning letters to 503A facilities between 2017 and 2021.

BACKGROUND: The growing population demand and the epidemic lead of coronavirus disease 2019 have highlighted the critical importance of patient access to compounded formulations, including for special purposes such as pediatrics, geriatrics, and other uses. However, there are many potential risks, including quality issues and 503A facilities have not received valid prescriptions for individually-identified patients for a portion of the drug products they produce. OBJECTIVE: The aim is to analyze the (503A facilities) warning letters and identify the problem of compounding medicines not meeting the United States Pharmacopoeia specifications. METHODS: Content analysis and descriptive statistics methods were used to analyze the violations of compounding warning letters from 2017 to 2021. The content of warning letter violations was analyzed in terms of both the compounding environment and 503A facilities that did not received valid prescriptions for individually-identified patients for a portion of the drug products they produced. RESULTS: A total of 113 compounding warning letters (503A facilities, N = 112) from 2017 to 2021 were analyzed in this study. The percentage of 503A facilities involved in sterile compounding environmental issues was 79.46%, with facility design and environmental controls (73/89, 82.02%), cleaning and disinfecting the compounding area (59/89, 66.29%), and personnel cleansing and garbing (44/89, 49.44%) being the top 3 issues. Seventy-two (72/112, 64.29%) 503A facilities that did not received valid prescriptions for individually-identified patients for a portion of the drug products they produced. Fifty-one (51/72, 70.83%) of these warning letters were related to sterile environment issues, and 28 warning letters identified specific drugs that did not qualify for Section 503A exemptions. CONCLUSION: The warning letter of compounding drugs issued by Food and Drug Administration can be used as a learning tool for compounders. Compounders can learn from the experience and lessons, improve compounding operations and reduce mistakes.

Chiral Detection of Glucose: An Amino Acid-Assisted Surface-Enhanced Raman Scattering Strategy Showing Opposite Enantiomeric Effects on SERS Signals.

It is of considerable concern to establish chiral detection methods for revealing enantioselective interactions among chiral molecules. Surface-enhanced Raman scattering (SERS) spectroscopy is sensitive to molecular interaction due to bond variations. However, its application in chiral detection is underexplored. Inspired by the chiral selectivity toward glucose and amino acids in life, we herein propose a SERS strategy based on molecular interactions for the discrimination of d- and l-glucose (Glu) using chiral phenylalanine (Phe) decorated on gold nanoparticles as a chirality selector and Raman reporter. Interestingly, the SERS signal of l-Phe is enhanced by d-Glu but suppressed by l-Glu. In contrast, the SERS signal of d-Phe is increased by l-Glu but decreased by d-Glu. According to the above-observed intensity change (ΔI) of the SERS signal of Phe induced by Glu, it is easy to determine the chiral configurations (judged by the positive or negative sign of ΔI), enantiomeric excess (ee) values, and concentrations (estimated by the magnitude of ΔI) of Glu. Taking advantage of the high SERS enhancement and opposite enantiomeric effects on SERS signals, the proposed strategy enables enantiomeric discrimination at a low Glu concentration (10-6 mol/L) and is further exerted for the noninvasive detection of d-/l-Glu in saliva samples. In contrast, the common chiroptical analysis tool of circular dichroism (CD) spectroscopy failed to directly detect Glu enantiomers.

Improved discrimination of phenylalanine enantiomers by surface enhanced Raman scattering assay: molecular insight into chiral interaction.

SERS spectroscopy, a nontraditional chiral analysis tool, is used to discriminate between D- and L-phenylalanine (Phe), with the Raman scattering enhancement degree of D-Phe being 50-fold greater than that of L-Phe. Such discrimination is achieved by chiral interactions between Phe and the chiral drug molecule of sertraline on silver coated gold nanorods.

Comparative analysis of PIM criteria and drug labels in the elderly.

PURPOSE: By discussing the corresponding situation of PIM criteria and labels, it provides a reference for the formulation and update of the criteria and the content of the section of "medications for the elderly" in the labels, so as to realize rational drug use for the elderly. METHODS: Extract the four indicators of Beers criteria, STOPP criteria, and the EU(7)-PIM list that involve dosage, duration, age, and mortality, and compare them with the latest labels for drugs marketed in the USA and the EU. RESULTS: There are 148 drugs involving four indicators in the criteria, and 85.14% of the drugs are found in at least one region. In terms of dose, there are 28 drugs with inconsistent descriptions in the labels of the two regions, accounting for 47.46% of the 59 drugs found in both regions. A total of 42.37% of the drugs are consistent in both regions with the criteria (25/59), 28.81% of the drugs are inconsistent in both regions with the criteria (17/59), and 28.81% of the drugs are inconsistent in only one region with the criteria (17/59). The doses of 50 drugs found in F/D labels are consistent with the criteria, accounting for 54.35% of the 92 drugs found in F/D labels, and of 41 drugs found in E/H SmPC are consistent with the criteria, accounting for 60.29% of the 68 drugs found in E/H SmPC. Only the duration of omeprazole in the labels in both regions is consistent with the criteria, and only the age of prasugrel in both regions is consistent with the criteria. Five drugs whose labels mentioned increased mortality, accounting for 38.46% of the 13 drugs found in both regions. CONCLUSION: There are certain differences between PIM criteria and PIM criteria, labels and labels, and PIM criteria and labels, which will affect the use of drugs in the elderly. Therefore, the unity between the criteria and labels should be strengthened to provide more instructive guidance for the elderly, so as to jointly realize rational drug use in the elderly.

SERS determination of dopamine using metal-organic frameworks decorated with Ag/Au noble metal nanoparticle composite after azo derivatization with p-aminothiophenol.

A specific surface-enhanced Raman scattering (SERS) assay for dopamine (DA) based on an azo derivatization reaction is proposed for the first time by preparation of p-aminothiophenol (PATP)-modified composite SERS substrate, composed of metal-organic framework (MIL-101) decorated with Au and Ag nanoparticles. As the result, the SERS method for detection of the azo reaction between PATP and DA exhibits superior sensitivity, selectivity, and stability. A reasonable linearity in the range 10-6 to 10-10 mol∙L-1 is achieved, and the limit of detection is 1.2 × 10-12 mol∙L-1. The reactive SERS assay is free from interference in complex physiological fluid. The feasibility of the proposed SERS method for the detection of DA levels in fetal bovine serum (FBS) samples and human serum samples is validated by HPLC-MS methods, displaying promising application potential in early disease diagnosis.

Dynamic Changes in Ascorbic Acid Content during Fruit Development and Ripening of Actinidia latifolia (an Ascorbate-Rich Fruit Crop) and the Associated Molecular Mechanisms.

Actinidia latifolia is one of the very few kiwifruit genotypes with extremely high ascorbic acid (AsA) content. However, a transcriptome atlas of this species is lacking. The accumulation of AsA during fruit development and ripening and the associated molecular mechanisms are still poorly understood. Herein, dynamic changes in AsA content at six different stages of A. latifolia fruit development and ripening were determined. AsA content of A. latifolia fruit reached 1108.76 ± 35.26 mg 100 g-1 FW at full maturity. A high-quality, full-length (FL) transcriptome of A. latifolia was successfully constructed for the first time using third-generation sequencing technology. The transcriptome comprises 326,926 FL non-chimeric reads, 15,505 coding sequences, 2882 transcription factors, 18,797 simple sequence repeats, 3328 long noncoding RNAs, and 231 alternative splicing events. The genes involved in AsA biosynthesis and recycling pathways were identified and compared with those in different kiwifruit genotypes. The correlation between the AsA content and expression levels of key genes in AsA biosynthesis and recycling pathways was revealed. LncRNAs that participate in AsA-related gene expression regulation were also identified. Gene expression patterns in AsA biosynthesis and metabolism exhibited a trend similar to that of AsA accumulation. Overall, this study paves the way for genetic engineering to develop kiwifruits with super-high AsA content.

Genome-Wide Identification of MYB Transcription Factors and Screening of Members Involved in Stress Response in Actinidia.

MYB transcription factors (TFs) play an active role in plant responses to abiotic stresses, but they have not been systematically studied in kiwifruit (Actinidia chinensis). In this study, 181 AcMYB TFs were identified from the kiwifruit genome, unevenly distributed on 29 chromosomes. The high proportion (97.53%) of segmental duplication events (Ka/Ks values less than 1) indicated that AcMYB TFs underwent strong purification selection during evolution. According to the conservative structure, 91 AcR2R3-MYB TFs could be divided into 34 subgroups. A combination of transcriptomic data under drought and high temperature from four AcMYB TFs (AcMYB2, AcMYB60, AcMYB61 and AcMYB102) was screened out in response to stress and involvement in the phenylpropanoid pathway. They were highly correlated with the expression of genes related to lignin biosynthesis. qRT-PCR analysis showed that they were highly correlated with the expression of genes related to lignin biosynthesis in different tissues or under stress, which was consistent with the results of lignin fluorescence detection. The above results laid a foundation for further clarifying the role of MYB in stress.

Chirality Detection by Raman Spectroscopy: The Case of Enantioselective Interactions between Amino Acids and Polymer-Modified Chiral Silica.

In chirality research area, it is of interest to reveal the chiral feature of inorganic nanomaterials and their enantioselective interactions with biomolecules. Although common Raman spectroscopy is not regarded as a direct chirality analysis tool, it is in fact effective and sensitive to study the enantioselectivity phenomena, which is demonstrated by the enantio-discrimination of amino acid enantiomers using the polydopamine-modified intrinsically chiral SiO2 nanofibers in this work. The Raman scattering intensities of an enantiomer of cysteine are more than twice as high as those of the other enantiomer with opposite handedness. Similar results were also found in the cases of cystine, phenylalanine, and tryptophan enantiomers. In turn, these organic molecules could be used as chirality indicators for SiO2, which was clarified by the unique Raman spectra-derived mirror-image relationships. Thus, an indirect chirality detection method for inorganic nanomaterials was developed.

Chiral Plasmonic Nanoparticle Assisted Raman Enantioselective Recognition.

Au nanoparticles (NPs) labeled with the handedness tag of "d-" or "l-", which were detached from inorganic chiral silica, showed both intrinsic chirality and surface enhanced Raman scattering (SERS) activity. In the presence of these chiral Au substrates, it was found that the enantiomer of cystine with the same handedness tag of Au NPs would show stronger Raman scattering signal intensities than those of the enantiomer with the opposite tag, where the differences could be over three times. Consequently, this work afforded a novel enantioselective recognition method on ordinary Raman spectroscopy by using chiral plasmonic metallic nanomaterials.

Enzyme-Assist-Interference-Free Strategy for Raman Selective Determination of Sialic Acid.

Abnormal physiological levels of sialic acid (SA) could be used to diagnosis cancer progression stages. In this work, we describe an enzyme-assist-interference-free strategy for Raman selective determination of SA in serum. First, we assemble gold nanoparticles (Au NPs) onto the indium tin oxide glass (ITO) to construct an ITO/Au two-dimension substrate. Through modification of 4-mercaptoboric acid (4-MPBA) onto the surface of ITO/Au, the SA response plate is prepared due to the reversible esterification bond. In this strategy, a sandwich structure is rationally designed as ITO/Au/4-MPBA/SA/4-MPBA/Au to enhance the Raman scattering. The Raman detection linear concentration of SA ranged from 2.5 × 10-7 to 1.5 × 10-6 M, and a limit of detection about 1.2 × 10-7 M could be achieved. Considering the presence of glucose (Glu) in physiological fluid, we introduce glucose oxidase to remove the interference from Glu and realize the accurate determination of SA. The proposed novel Raman rapid method provides an ultrasensitive and interference-free protocol for the early diagnosis of cancer.

A meta-analysis of efficacy and safety of S-1 monotherapy or combination therapy as first-line treatment in metastatic colorectal cancer.

PURPOSE: To compare the efficacy and safety profile of S-1-based versus non-S-1-based chemotherapy as first-line treatment in mCRC. METHODS: Relevant randomized controlled trials (RCTs) were obtained from PubMed, Embase, and Ovid databases and the Cochrane library from database set up in May 2018. The RCTs of S-1-based monotherapy or combination therapy as first-line treatment were selected. The impact of S-1-based chemotherapy on progression-free survival (PFS) and overall survival (OS) was assessed by pooling data via RevMan 5.3. RESULTS: Meta-analysis of 10 RCTs showed that S-1-based chemotherapy significantly improved PFS (HR 0.90, 95% CI 0.84-0.97, P = 0.006). In subgroup analysis, there was a statistically significant increase in PFS when S-1-based chemotherapy was compared with 5-FU-based (HR 0.92, 95% CI 0.84-1.00, P = 0.04) or capecitabine-based chemotherapy (HR 0.85, 95% CI 0.73-0.99, P = 0.04). The meta-analysis of OS (HR 0.95, 95% CI 0.86-1.05, P = 0.36), overall response rate (ORR) (HR 0.99, 95% CI 0.84-1.17, P = 0.90), and disease control rate (DCR) (HR 1.61, 95% CI 0.87-3.00, P = 0.13) showed no statistical significance between S-1-based and non-S-1-based chemotherapy. The statistically significant differences in the meta-analysis indicated less incidence of graded 3-4 leucopenia (OR = 0.30, 95% CI 0.13-0.71, P = 0.006) and hand-foot syndrome (HFS) (OR = 0.24, 95% CI 0.10-0.58, P = 0.001) in the S-1-based chemotherapy, and there was no statistically significant difference for other adverse events. CONCLUSIONS: S-1-based chemotherapy in mono or combined therapy was an attractive alternative to standard first-line regimen for patients of mCRC.

The synergistic effect of PFK15 with metformin exerts anti-myeloma activity via PFKFB3.

High glucose metabolism provides sufficient energy for cancer cells and is enabled by metabolic enzymes. PFKFB3 (6-phosphofructo-2-kinase) accelerates the synthesis of fructose 2,6-bisphosphate (F2,6P2), which is a powerful allosteric regulatory activator of 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme of glycolysis. The aim of this study was to investigate the anti-myeloma function and underlying mechanism of suppressing PFKFB3 via PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one). The role of PFK15 in killing multiple myeloma (MM) cells was evaluated by cytotoxicity and apoptosis assays, flow cytometry and Western blotting. The oral hypoglycemic drug metformin (Met) was found to inhibit PFKFB3 protein expression by gene chip and Western blotting techniques in our study. PFK15 also demonstrated a synergistic effect with metformin to eliminate MM cells. Taken together, our findings indicate that PFK15 inhibits MM cell proliferation through the PFKFB3/MAPKs/STAT signaling pathway. The combination therapy of PFK15 and metformin may be a promising anticancer drug regimen for the treatment of MM.

Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells.

BACKGROUND/AIMS: Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new therapeutic options that bypass these resistance mechanisms. Metformin is a widely prescribed antidiabetic drug with direct antitumor activity against various tumor cell lines. FTY720, also known as fingolimod, is an immune-modulating agent approved by the FDA as oral medication to treat the relapsing form of multiple sclerosis (MS). In recent years, FTY720 has attracted attention due to its anti-tumor activity. To explore an optimized combinational therapy, interactions between metformin and FTY720 were examined in MM cells. METHODS: MTT assays were employed to assess the viability of MM cells. An apoptotic nucleosome assay was employed to measure apoptosis. Loss of mitochondrial membrane potential (MMP, ΔΨm) and cellular levels of ROS were measured by flow cytometry. qRT-PCR was used to analyze the expression of mRNAs. Western blotting assays were applied to measure the levels of proteins involved in different signaling pathways. RESULTS: Coadministration of metformin and FTY720 synergistically inhibited the proliferation of MM cells. Increased levels of apoptosis, activation of caspase-3 and cleavage of PARP were detected after cotreatment with metformin and FTY720. These events were associated with modulation of Bcl-2 proteins, loss of MMP, ER stress induction, and inhibition of the PI3K/AKT/mTOR signaling pathway. The metformin/FTY720 regimen markedly induced ROS generation; moreover, apoptosis, ER stress and inhibition of PI3K/AKT/ mTOR were attenuated by the ROS scavenger NAC. CONCLUSIONS: Exposure to metformin in combination with FTY720 potently induces apoptosis in MM cells in a ROS-dependent manner, suggesting that a strategy combining these agents warrants further investigation in MM.