Therapeutic Mode Research Articles

GSH-Responsive Drug Delivery System for Active Therapy and Reducing the Side Effects of Bleomycin.

The application of drug delivery system (DDS) has achieved breakthroughs in many aspects, especially in the field of tumor treatment. In this work, polyethylene glycol (PEG)-modified hollow mesoporous manganese dioxide (HMnO2@PEG) nanoparticles were used to load the anti-tumor drug bleomycin (BLM). When the DDS reached the tumor site, HMnO2@PEG was degraded and reduced to Mn2+ by the overexpression of glutathione in the tumor microenvironment, and the drug was released simultaneously. BLM coordinated with Mn2+ in situ, thereby greatly improving the therapeutic activity of BLM. The results of in vivo and in vitro treatment experiments showed that the DDS had excellent responsive therapeutic activation ability. In addition, Mn2+ exhibited strong paramagnetism and was used for T1-weighted magnetic resonance imaging in vivo. Furthermore, this therapeutic mode of responsively releasing drugs and activating in situ effectively attenuated pulmonary fibrosis initiated by BLM. In short, this DDS could help in avoiding the side effects of drugs.

Intelligent Nanomedicine Approaches Using Medical Gas-Mediated Multi-Therapeutic Modalities Against Cancer

The emerging area of gas-mediated cancer treatment has received widespread attention in the medical community. Featuring unique physical, chemical, and biological properties, nanomaterials can facilitate the delivery and controllable release of medicinal gases at tumor sites, and also serve as ideal platforms for the integration of other therapeutic modalities with gas therapy to augment cancer therapeutic efficacy. This review presents an overview of anti-cancer mechanisms of several therapeutic gases: nitric oxide (NO), hydrogen sulfide (H₂S), carbon monoxide (CO), oxygen (O₂), and hydrogen (H₂). Controlled release behaviors of gases under different endogenous and exogenous stimuli are also briefly discussed, followed by their synergistic effects with different therapeutic modes. Moreover, the potential challenges and future prospects regarding gas therapy based on nanomaterials are also described, aiming to facilitate the advancement of gas therapeutic nanomedicine in new frontiers for highly efficient cancer treatment.

The roles of long non-coding RNAs in lung cancer.

Lung cancer is the most common malignancy, being a serious threat of human lives. The incidence and mortality of lung cancer has been increasing rapidly in the past decades. Although the development of new therapeutic modes, such as target therapy, the overall survival rate of lung cancer remains low. It is urgent to advance the understanding of molecular oncology and find novel biomarkers and targets for the early diagnosis, treatment, and prognostic prediction of lung cancer. Long non-coding RNAs (lncRNAs) are non-protein coding RNA transcripts that are more than 200 nucleotides in length. LncRNAs exert diverse biological functions by regulating gene expressions at transcriptional, translational, and post-translational levels. In the past decade, it has been shown that lncRNAs are extensively involved in the pathogenesis of various diseases, including lung cancer. In this review, we highlighted the lncRNAs characterized in lung cancer and discussed their translational potential in lung cancer clinics.

A study on alpha-terpineol in Alzheimer’s disease with the use of rodent in vivo model, restraint stress effect and in vitro Amyloid beta fibrils

Alzheimer’s disease (AD) is a neurological disorder in which the neuronal degeneration is associated with inflammatory processes and oxidative stress. Since alpha-terpineol was shown to possess antioxidant and anti-inflammatory effects, the administration of this compound was studied on a rat model of AD. To create this model, Aβ1-42 was injected into the hippocampus of male Wistar rats. Generated AD models were divided into simple AD models and AD models in which short-term immobilization stress was added. Preventive and therapeutic (post-AD induction) effects of alpha-terpineol consumption (100 mg/Kg) were subsequently investigated in AD models, which were compared with control groups. Biochemical factors (superoxide dismutase and malondialdehyde), histological manifestations (amyloid plaques and neuron counts) and possible memory impairment (shuttle-box experiment) were investigated in all groups. For the in vitro experiment, alpha-terpineol effect was checked on Aβ1-42 fibril formation. In preventive and therapeutic modes, alpha-terpineol consumption could improve neurogenesis and long-term memory while reducing amyloid plaque counts and ameliorating biochemical factors (higher levels of superoxide dismutase and malondialdehyde and reduced levels of MDA). In vitro, shorter fibrillar structures were formed in the presence of alpha-terpineol, which indicates an anti-amyloid effect for this compound. In conclusion, alpha-terpineol significantly counteracted AD consequences.

The importance of terminal complement inhibition in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic hematologic disorder associated with inappropriate terminal complement activity on blood cells that can result in intravascular hemolysis (IVH), thromboembolic events (TEs), and organ damage. Untreated individuals with PNH have an increased risk of morbidity and mortality. Patients with PNH experiencing IVH often present with an elevated lactate dehydrogenase (LDH; ⩾ 1.5 × the upper limit of normal) level which is associated with a significantly higher risk of TEs, one of the leading causes of death in PNH. LDH is therefore used as a biomarker for IVH in PNH. The main objective of PNH treatment should therefore be prevention of morbidity and mortality due to terminal complement activation, with the aim of improving patient outcomes. Approval of the first terminal complement inhibitor, eculizumab, greatly changed the treatment landscape of PNH by giving patients an effective therapy and demonstrated the critical role of terminal complement and the possibility of modulating it therapeutically. The current mainstays of treatment for PNH are the terminal complement component 5 (C5) inhibitors, eculizumab and ravulizumab, which have shown efficacy in controlling terminal complement-mediated IVH, reducing TEs and organ damage, and improving health-related quality of life in patients with PNH since their approval by the United States Food and Drug Administration in 2007 and 2018, respectively. Moreover, the use of eculizumab has been shown to reduce mortality due to PNH. More recently, interest has arisen in developing additional complement inhibitors with different modes of administration and therapeutics targeting other components of the complement cascade. This review focuses on the pathophysiology of clinical complications in PNH and explores why sustained inhibition of terminal complement activity through the use of complement inhibitors is essential for the management of patients with this chronic and debilitating disease.

Tumor-specific activatable biopolymer nanoparticles stabilized by hydroxyethyl starch prodrug for self-amplified cooperative cancer therapy.

Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required.Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu2+ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer.Results: Interestingly, the pre-doped Cu2+ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu2+ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively.Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.

Clinical efficacy of different therapeutic modes of CO2 fractional laser for treatment of static periocular wrinkles in Asian skin.

Periocular fine lines and wrinkles usually appear as a first visible sign of facial aging. Fractional ablative laser has been used to treat periorbital wrinkles. To compare the efficacy on treatment of static periorbital wrinkles using different emission modes of CO2 fractional laser. A total of 30 patients with static periorbital wrinkles were enrolled. The subjects were randomly assigned into two split-face groups: One side was treated with a deep (n=15) or mid-mode of CO2 superficial laser (n=15), and the other side of periocular region was treated by a fusion mode in combination of both modes (n=30). The patients in three groups showed significant improvements on indexes of periocular wrinkles, skin textures, and elasticity at three-month follow-up as compared with baseline (p<0.05). Fusion mode resulted in a significantly progressive improvement on periocular wrinkles at three-month follow-up as compared with one-month follow-up (p<0.05), which were not observed in other modes. Fusion mode delivered better improvements of periocular wrinkles and skin textures as compared to deep and mid-modes at three-month follow-up (p<0.05). Fusion mode also resulted in better scores of global esthetic improvement scale and patient satisfaction as compared to other modes at both follow-ups. The fusion mode has a synergistic effect in periorbital static wrinkle treatment, which is worthy of further evaluation and investigation.

Prospects of Inhaled Phage Therapy for Combatting Pulmonary Infections.

With respiratory infections accounting for significant morbidity and mortality, the issue of antibiotic resistance has added to the gravity of the situation. Treatment of pulmonary infections (bacterial pneumonia, cystic fibrosis-associated bacterial infections, tuberculosis) is more challenging with the involvement of multi-drug resistant bacterial strains, which act as etiological agents. Furthermore, with the dearth of new antibiotics available and old antibiotics losing efficacy, it is prudent to switch to non-antibiotic approaches to fight this battle. Phage therapy represents one such approach that has proven effective against a range of bacterial pathogens including drug resistant strains. Inhaled phage therapy encompasses the use of stable phage preparations given via aerosol delivery. This therapy can be used as an adjunct treatment option in both prophylactic and therapeutic modes. In the present review, we first highlight the role and action of phages against pulmonary pathogens, followed by delineating the different methods of delivery of inhaled phage therapy with evidence of success. The review aims to focus on recent advances and developments in improving the final success and outcome of pulmonary phage therapy. It details the use of electrospray for targeted delivery, advances in nebulization techniques, individualized controlled inhalation with software control, and liposome-encapsulated nebulized phages to take pulmonary phage delivery to the next level. The review expands knowledge on the pulmonary delivery of phages and the advances that have been made for improved outcomes in the treatment of respiratory infections.

RADT-16. CLINICAL CHARACTERISTICS AND PROGNOSIS OF ADULT BRAIN STEM GLIOMA: A SINGLE-CENTER 10-YEAR RETROSPECTIVE STUDY OF 81 PATIENTS

Abstract OBJECTIVE Adult brain stem glioma (ABSG) is a subset of brain tumor with a low incidence rate. This study reviewed the clinical characteristics and the risk factors affecting the prognosis of ABSG in a single center and explored the proper therapeutic mode for ABSG. METHODS The clinical data of adult patients (age over 18 years old) with brain stem gliomas from January 2010 to January 2021 of Guangdong Sanjiu brain hospital were retrospectively analyzed. Overall survival (OS) were determined by the Kaplan-Meier method, and Log-rank test was used for univariate analysis, COX proportion hazards regression was used for multivariate analysis. P &amp;lt; 0.05 was considered to be statistically significant. RESULTS Eighty-one ABSGs, including 46 males and 35 females, were analyzed. The median age of patients was 37 years (range, 19 to 67), and the median follow-up time was 17 months (range, 3 to 108) . The median OS of 81 patients was 18 months, and the OS for 1, 2, 3, and 5 years was 87.4%, 75.8%, 61.0%, and 36.5%, respectively. Univariate analysis demonstrated that the lesions enhancement on MRI, the WHO classifications, the expression status of H3K27M, radiotherapy status, and the status of adjuvant chemotherapy were related to prognosis. Multivariate Cox regression analysis revealed that age, the WHO classifications, radiotherapy status, and the maintenance chemotherapy followed radiotherapy were independent predictors for OS. CONCLUSIONS Radiotherapy is still the main treatment of ABSGs, and patients can be benefit from maintenance chemotherapy followed radiotherapy. The age &amp;gt; 40 years and WHO IV grade were two independent unfavorable prognostic factors. Research with expanded patient volume would help to further explore the influence of H3K27M expression on ABSG prognosis.

A review on the medicinal potential, toxicology, and phytochemistry of litchi fruit peel and seed.

The perception that many fruit wastes, particularly the peel, contain more phytochemicals than the edible portions has been largely supported by scientific evidence, making them potential sources of bioactive and therapeutic phytochemicals. The peel and seed of Litchi (Litchi chinensis Sonn.) contain bioactive principles and have been shown to exhibit antioxidative, antidiabetic, cancer preventive, anti-obesogenic, and anti-inflammatory properties. This review presents a critical analysis of previous and current perspectives on the medicinal, toxicological, and phytochemical profiles of litchi fruit peel and seed, thus providing an evidence-based platform to explore their medicinal potential. A literature search was done on "PubMed," "Google Scholar," and "ScienceDirect." Peer-reviewed published data on the medicinal profiles of litchi fruit peel and seed were identified and critically analyzed. The fruit peel and seed improved glycemic control and insulin signaling and downregulated lipogenic and cholesterogenic processes. Their neuroprotective, hepatoprotective, and renal protective potentials were influenced by antioxidative and anti-inflammatory actions. The anticancer effect was mediated by upregulated proapoptotic, proinflammatory, antiproliferative, and anti-metastatic processes in cancer cells. Simple flavonols, sesquiterpenes, phenolic acids, jasmonates, and proathocyanidins are the possible bioactive principles influencing the medicinal effects. Appropriate toxicity studies are, however, still lacking. Litchi fruit wastes may be further studied as useful sources of therapeutic agents that may have medicinal relevance in oxidative, metabolic, vascular, and carcinogenic ailments. PRACTICAL APPLICATIONS: Underutilized fruit wastes contribute to environmental pollution. Interestingly, these wastes contain phytochemicals that could be of medicinal relevance if their medicinal potentials are maximized. Litchi fruit is a widely consumed fruit with commercial value. Its peel and seeds contribute to fruit wastes. The review exposes the medicinal potential and bioactive principles and/or nutrients of the fruit's peel and seed while elucidating the underlying therapeutic mechanisms or modes of actions through which litchi peel and seed potentiate medicinal effects. Thus, the review provides an evidence-based platform to explore the medicinal potential of underutilized wastes from litchi fruit. Additionally, the fruit peel and seed could be low-cost residues that could afford ecofriendly opportunity if their medicinal potentials are properly maximized.

POEMS Syndrome: Real World Experience in Diagnosis and Systemic Therapy - 108 Patients Multicenter Analysis

POEMS syndrome, a rare plasma cell disorder, is challenging both in the diagnostic and therapeutic management. We present real word retrospective analysis of 108 cases analyzing clinical features and therapeutic modes. We compare our results with the available literature. This is the first description with such wide use of proteasome inhibitors in first line treatment.POEMS (Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome is a rare and challenging plasma cell disorder, both in the diagnostic and therapeutic management of the disease. Currently, the literature on POEMS is sparse with most evidence being case reports and small case studies.We present a retrospective real world experience of 108 patients with POEMS. We analyzed the clinical features and therapeutic interventions. Regarding clinical features, our findings demonstrated that skin lesions, thrombocythemia and polycythemia were present less frequently than reported previously. Regarding clinical interventions, this is one of the largest analyses of front line treatment in POEMS and the first one to include frequent utilization of proteasome inhibitors (37%). Bortezomib monotherapy was the most effective therapy achieving complete remission/very good partial remissions (CR/VGPR) in 69% of patients. Thirty percent of patients proceeded to planned autologous stem cell transplant (ASCT) as part of the front-line treatment resulting in statistically superior progression-free (PFS) and overall survival (OS) compared to non-ASCT treated patients (P= .003). In multivariate analysis, anemia, thrombocytopenia, and as age over 60 were associated with a negative impact on patient outcomes.

A benzophenoxazine-dyad as cancer indicator using for fluorescence-guided phototherapy

Clinically, phototherapy is adapted to tumors in semi-enclosed location, such as cervical, head & neck and gastric cancer, using optical fibers to introduce light. Different with general photodynamic therapy, it has special demands of tumor recognition and lower light dose. However, a merge of primary photosensitizer (ALA et.al) and magnetic resonance (or ultrasound) imaging is commonly used in the therapeutic mode, having low efficacy and complicated operation. To realize a fluorescence-guided phototherapy, here we designed a benzophenoxazine-dyad photosensitizer, namely NBS-NBSe, firstly realize a dyad-caused quenching (DCQ) method to regulate the fluorescence of benzophenoxazine as cancer indicator. The DCQ of NBS-NBSe drastically decrease the fluorescence of benzophenothiazine (NBS), while glutathione in cancer can efficiently release the fluorescence (9.3-fold) to guide the optical source in phototherapy. Meanwhile, the high singlet oxygen generation of benzophenoselenzinium (NBSe) provide an efficient photo ablation ability, and the NBS of anti-hypoxia can assist the therapy of hypoxia deep-seated tumors to reduce tumor recurrence. Under the low light dose of 2.4 J/cm2, NBS-NBSe showed excellent therapeutic efficacy toward tumor cells (24-fold than chlorins e6). The fluorescence recognition ability between tumor/normal cells and the powerful phototoxicity ensure the fluorescence-guided therapeutic mode using for these tumors.

Usage of Natural Volatile Organic Compounds as Biological Modulators of Disease.

Plants produce a wide variety of natural volatile organic compounds (NVOCs), many of which are unique to each species. These compounds serve many purposes, such as fending off herbivores and adapting to changes in temperature and water supply. Interestingly, although NVOCs are synthesized to deter herbivores, many of these compounds have been found to possess several therapeutic qualities, such as promoting nerve stability, enhancing sleep, and suppressing hyperresponsiveness, in addition to acting as antioxidants and anti-inflammatory agents. Therefore, many NVOCs are promising drug candidates for disease treatment and prevention. Given their volatile nature, these compounds can be administered to patients through inhalation, which is often more comfortable and convenient than other administration routes. However, the development of NVOC-based drug candidates requires a careful evaluation of the molecular mechanisms that drive their therapeutic properties to avoid potential adverse effects. Furthermore, even compounds that appear generally safe might have toxic effects depending on their dose, and therefore their toxicological assessment is also critical. In order to enhance the usage of NVOCs this short review focuses not only on the biological activities and therapeutic mode of action of representative NVOCs but also their toxic effects.

Chrysin modulates protein kinase IKKε/TBK1, insulin sensitivity and hepatic fatty infiltration in diet-induced obese mice.

Nuclear factor kappa B cells (NF-κB) activation causes induction of the noncanonical IκB kinases (I-kappa-B kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) in liver and fat after high fat diet which followed activating of cascade of counter-inflammation that conserves energy storage. Chrysin (5,7-dihydroxyflavone), a natural flavonoid, present in many plants, honey and propolis, used conventionally to treat numerous ailments. The present study was aimed to identify the protective role of chrysin on the glucose lowering and insulin sensitivity in diet induced obese (DIO) mice by regulating IKKε/TBK1. Chrysin administered therapeutically (60, 100, 200 mg/kg body weight) and preventive mode (200 mg/kg body weight) for 4 and 10 weeks respectively to DIO mice. At last fasting blood glucose, oral glucose tolerance test, serum lipid profile, as well as the expression level of IKKε/TBK1 and triglyceride in the liver tissue were assessed. DIO mice showed impaired glucose tolerance, reduced weight gain, elevated hepatic IKKε/TBK1 expression, fatty acid infiltration triglyceride and increased in plasma insulin and glucose. Chrysin in both therapeutic and preventive mode normalized the altered levels of the same. Overall chrysin improves glycemic control and insulin sensitivity through regulating expression of IKKε/TBK1 in liver of DIO mice.

“Why do They Want Others to Suffer the Same Pain They Have Endured?” Weibo Debates about Pain Relief during Childbirth in Neo/Non-Liberal China

In this article, we examine the cultural and gendered understandings of labor pain and the underlying obstacles that prevent Chinese women from seeking pain relief during labor and exercising their own autonomy. We conducted a critical discourse analysis of 178 posts containing the phrase wutong fenmian (literally “painless labor”) on Weibo, a popular Chinese microblogging platform. By situating our analysis in the contemporary context we call “neo/non-liberal China,” where traditional Chinese thought, market socialism, and a therapeutic mode of governance intertwine, we identify four major themes: traditional thinking rooted in Confucianism; health concerns for mother and child; women’s empowerment and control of reproduction; and structural issues within China’s healthcare system. We argue that Weibo discourses reflect young women’s resistance to Chinese traditional gender ideologies and reveal their strong yearning for self-determination and self-care even as their reproductive “choice” is limited by numerous relational and institutional constraints.

The self-efficacy for therapeutic use of self-questionnaire (SETUS): psychometric properties of the English version

Purpose The purpose of this paper is to investigate psychometric properties of the Self-Efficacy for Therapeutic Use of Self (SETUS) scales, a questionnaire based on the Intentional Relationship model, and to investigate the factor structure and internal consistency of the English version of three-part SETUS questionnaire in occupational therapy students. Design/methodology/approach The sample of this cross-sectional study included 155 students with age range 18–30 years, of which 95% were women. Principal Components Analysis (PCA) was performed on the questionnaire scales, including the Self-Efficacy for Therapeutic Mode Use (SETMU), Self-Efficacy for Recognizing Interpersonal Characteristics (SERIC) and Self-Efficacy for Managing Interpersonal Events (SEMIE). The internal consistencies were calculated. Pearson correlation analysis was used to evaluate the strength of correlation among the scales. Findings The PCA confirmed that the items of each of the three proposed scales loaded strongly on one factor (self-efficacy for three factors of therapeutic mode use, recognizing interpersonal characteristics and managing interpersonal events). The Cronbach’s alpha for the SETMU, SERIC and SEMIE was 0.85, 0.95 and 0.96, respectively. The three scales significantly inter-correlated strongly (r ranging 0.74–0.83, all p &lt; 0.001). Originality/value The SETUS questionnaire comprises three valid and reliable scales. It can be used by occupational therapy supervisors as a means to reflect on students’ self-efficacy in components of therapeutic use of self.

A bit thick: Hidden risks in thickening products’ labelling for dysphagia treatment

Thickening products (TPs) are a valid therapeutic strategy in patients with oropharyngeal dysphagia, their effect is mainly related to the bolus viscosity achieved. The aim of the study was to compare the information on the labels of 10 TPs of different thickening agents (hydrocolloids): modified starch-based, gum-based and mixtures. Viscosity was measured in SI units (mPa·s), using a rotational viscometer at 50 s−1 and 300 s−1, and the effect of oral amylase (α-SA) and shear thinning on the viscosity levels recommended by each manufacturer were assessed. Results were classified according to 3 textural classifications: National Dysphagia Diet (NDD), International Dysphagia Diet System (IDDSI) and Japanese Dysphagia Diet (JDD2013). Results are also presented in SI units (mPa·s) following a new proposed scientific labelling system developed in our laboratory at Hospital de Mataró and endorsed by eleven medical and scientific societies. The effect of α-SA was assessed after 30 s oral incubation of the thickened bolus.All TPs fulfil Food for Special Medical Purposes labelling regulations, use 3 thickness levels, and 70% use the NDD descriptors. Viscosities at 50 s−1 ranged between 75 and 350 mPa s for level 1, 256–1280 for level 2 and 377–6205 for level 3. α-SA caused 98–99% decrease in viscosity for modified starch-based TPs (MS) and 16% or even an increment for gum-based TPs. Shear thinning decreased viscosity from 40 to 60% for MS-based TPs and 70–75% for gum-based TPs. This study showed that TPs are commercialised using the same descriptors for very different viscosities when measured in mPa·s. Shear rate and α-SA strongly affect viscosity but this is not described on the labels. We claim labels should include viscosity in SI Units (mPa·s at 50 s−1) and the effect of α-SA and shear thinning as main factors affecting the therapeutic effect and mode of action of thickening agents.

P029 Activation of FXR restores expression of genes dysregulated in human IBD and suppresses TNFa and IL-6 signaling pathways in adoptive transfer colitis model

Abstract Background Farnesoid X receptor (FXR) is a ligand-activated nuclear hormone receptor highly expressed in the gastrointestinal tract. We have shown that FXR agonists improve disease in multiple chronic IBD models (Adoptive transfer (AT) colitis, Mdr1a-/- colitis, and SAMP1/YitFc ileitis) with efficacy similar to anti-IL-12/23. To explore the mechanisms by which FXR agonists reduce colitis in these models and the relevance to human IBD, we identified the genes and pathways regulated by FXR in the AT colitis mice, and compared them with the gene expression profile in human IBD patients. Methods Colitis was induced by transplanting CD4+CD45RBhi T-cells to C.B-17 SCID mice. Mice were treated with vehicle (n=10), an FXR agonist (p.o. daily, n=10) or anti-IL-12p40 (i.p., weekly, n=5) in therapeutic mode (started 21 days post AT) for 4 weeks. Efficacy was assessed by colon histopathology of inflammation, erosion, gland loss and hyperplasia (0–5 each). RNAseq was performed on colon RNAs (n=5–7 samples/group). Genes differentially regulated by the FXR agonist were compared with published FXR ChIPSeq data (Thomas et al 2010 Hepatology) and a IBD patients’ gene expression dataset (GSE73661) to identify FXR target genes associated with human IBD. Gene set enrichment analysis (GSEA) was performed to identify enriched pathways. Results Direct FXR target genes were identified by comparing genes upregulated by the FXR agonist in the AT mice with FXR ChIPSeq data. Further comparison with GSE73661 identified FXR target genes relevant to human IBD. The majority of these genes are down-regulated in diseased mice and IBD patients compared to healthy controls. Importantly, in GSE73661 dataset, those genes were upregulated in patients that responded to therapy, while remained down-regulated in refractory patients. The function of those genes includes reducing inflammation, improving gut healing and transporter activities. Further pathway analysis by GSEA identified a number of inflammatory pathways significantly upregulated in AT mice and IBD patients, many of which show reduction with the FXR agonist treatment. Of note, TNFα/NF-κB and IL-6/STAT3 pathways, targeted by approved IBD therapies, were significantly elevated in AT mice but reduced by the FXR agonist or anti-IL-12/23. Conclusion Activation of FXR directly induces IBD-dysregulated genes that can suppress inflammation, promote gut healing and transporter functions. In addition, FXR activation reduced TNFα/NF-κB and IL-6/STAT3 pathways in AT colitis model. These findings support further development of novel FXR agonists as a potential oral therapy for IBD.

A Traceable, Sequential Multistage‐Targeting Nanoparticles Combining Chemo/Chemodynamic Therapy for Enhancing Antitumor Efficacy

AbstractAlthough chemodynamic therapy (CDT) can effectively inhibit tumor growth and metastasis, it is challenging to eliminate tumors. Generally, CDT needs to combine with extra therapeutic modes for enhancing antitumor efficacy. Here, novel nanoparticles (BDTLAG NPs) are constructed via self‐assembly of cancer cell targeting prodrug (Bio‐PEG2K‐S‐S‐CPT), organic CDT agents (TPP‐PEG2K‐LND, TPP‐PEG2K‐TOS), pH‐responsive prodrug (PEG2K‐NH‐N‐DOX), T1‐enhanced magnetic resonance imaging contrast agents (Gd‐DTPA‐N16‐16), and anti‐angiogenic drug combrestatinA4 (CA4), realizing chemo(CT)‐chemodynamic combination therapy. The mechanism of BDTLAG NPs for enhancing antitumor efficacy involves: (i) BDTLAG NPs is accumulated in the tumor tissue by passive targeting; (ii) CA4 is released and specifically destroys angiogenesis, and the remaining BDTLG NPs enter the tumor cell via active targeting; (iii) the acid/glutathione (GSH)‐responsive prodrug release and GSH depletion; (iv) TPP‐PEG2K‐LND and TPP‐PEG2K‐TOS are accumulated in the tumor cell mitochondria due to mitochondria‐targeting, and is accompanied by endogenous reactive oxygen species bursts. This current strategy of single NPs that integrates spatiotemporally CT, CDT, GSH depletion, and MR imaging functions reflects the “all in one” concept, which provides a new opportunity for enhancing antitumor efficacy.

Lianhuaqingwen capsule inhibits influenza-induced bacterial adhesion to respiratory epithelial cells through down-regulation of cell adhesion molecules

Ethnopharmacological relevanceInfluenza virus infection is widely believed to cause mild symptoms, but can lead to high mortality and severe disease complicated by secondary bacterial pneumonia. Traditional Chinese medicine (TCM) has been proposed as a promising agent to treat respiratory viral infections. A herbal formula Lianhuaqingwen capsule (LHQW) comprising two prescriptions: Maxing Shigan decoction and Yinqiao San, has been used clinically to treat respiratory infection with immune regulatory effects. However, little is known about the capacity of LHQW against influenza-induced secondary bacterial pneumonia. Aim of studyThis study aimed to evaluate the efficacy and underlying mechanism of LHQW on influenza A virus A/PR/8/34 (PR8) secondary methicillin-resistant Staphy-lococcus aureus (MRSA) infection. MethodsThe anti-adhesion activity of LHQW against PR8-induced MRSA infection was assessed in human lung epithelial (A549) cells and the effect of LHQW on the expression of intracellular adhesion molecule 1 (ICAM-1) was detected. Also, the mRNA expression levels of inflammatory cytokines upon lipopolysaccharide (LPS) stimulation in PR8-infected A549 cells were determined. The body weight change, survivals, viral titers, colonies and the pathological parameters after LHQW treatment in severe pneumonia model have all been systematically determined. ResultsLHQW significantly reduced the adhesion of MRSA to PR8-infected A549 cells in a dose-dependent manner by suppressing the up-regulation of bacterial receptors. LHQW also markedly declined the overexpression of IL-6, IL-8, and TNF-α induced by LPS stimulated-A549 cells following influenza virus infection. Furthermore, the abnormal changes of lung index in dual-infection mice were relieved after administered with LHQW in preventive and therapeutic mode, but with no significantly difference (P > 0.05). LHQW could not effectively improve survival rate or prolong the survival time of mice (P > 0.05). LHQW (1000 mg/kg/d) administered prophylactically significantly decreased the lung viral titers (P < 0.05), slightly downregulated IL-6 but TNF-α, IL-1β levels and improved lung pathological inflammation including neutrophil infiltration, necrosis, which is consistent with the expression of inflammatory factors. ConclusionsLHQW inhibited influenza-induced bacterial adhesion by down-regulating the adhesion molecules with the improvement trend on severe pneumonia, indicating that it can be used as an adjuvant medication in severe viral-bacterial pneumonia therapy rather than as a single medication.