TRIM38 Induced in Respiratory Syncytial Virus-infected Cells Downregulates Type I Interferon Expression by Competing with TRIM25 to Bind RIG-I.

Innate immune response is the first line of defense for the host against virus invasion. One important response is the synthesis and secretion of type I interferon (IFN-I) in the virus-infected host cells. Here, we found that respiratory syncytial virus (RSV) infection induced high expression of TRIM25, which belongs to the tripartite motif-containing (TRIM) family of proteins. TRIM25 bound and activated retinoic acid-inducible gene I (RIG-I) by K63-linked ubiquitination. Accordingly, RIG-I mediated the production of IFN-I mainly through the nuclear factor kappa-B (NF-κB) pathway in respiratory epithelial cells. Interestingly, IFN-I, in turn, promoted a high expression of TRIM38 which downregulated the expression of IFN-I by reducing the protein level of RIG-I by K48-linked ubiquitination. More importantly, the binding site of TRIM25 to RIG-I was found in the narrow 25th-43rd amino acid (aa) region of RIG-I N-terminus. In contrast, the binding sites of TRIM38 to RIG-I were found in a much wider amino acid region, which included the binding site of TRIM25 on RIG-I. As a result, TRIM38 inhibits the production of IFN-I by competing with TRIM25 for RIG-I binding. Thus, TRIM38 negatively regulates RIG-I activation to, in turn, downregulate IFN-I expression, thus interfering with host immune response. A negative feedback loop effectively "puts the brakes" on the reaction once host immune response is overactivated and homeostasis is unbalanced. We also discovered that TRIM25 bound RIG-I by a new K63-linked ubiquitination located at K-45 of the first caspase recruitment domain (CARD). Collectively, these results confirm an antagonism between TRIM38 and TRIM25 in regulating IFN-I production by affecting RIG-I activity following RNA virus infection.

Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.

Targeting nutrient metabolism has been proposed as an effective therapeutic strategy to combat breast cancer because of its high nutrient requirements. However, metabolic plasticity enables breast cancer cells to survive under unfavorable starvation conditions. The key mammalian target regulators rapamycin (mTOR) and hypoxia-inducible-factor-1 (HIF-1) tightly link the dynamic metabolism of glutamine and glucose to maintain nutrient flux. Blocking nutrient flow also induces autophagy to recycle nutrients in the autophagosome, which exacerbates metastasis and tumor progression. Compared to other common cancers, breast cancer is even more dependent on mTOR and HIF-1 to orchestrate the metabolic network. Therefore, we develop a cascade-boosting integrated nanomedicine to reprogram complementary metabolism coupled with regulators in breast cancer. Glucose oxidase efficiently consumes glucose, while the delivery of rapamycin inside limits the metabolic flux of glutamine and uncouples the feedback regulation of mTOR and HIF-1. The hydroxyl radical generated in a cascade blocks the later phase of autophagy without nutrient recycling. This nanomedicine targeting orchestrated metabolism can disrupt the coordination of glucose, amino acids, nucleotides, lipids, and other metabolic pathways in breast cancer tissues, effectively improving the durable antitumor effect and prognosis of breast cancer. Overall, the cascade-boosting integrated system provides a viable strategy to address cellular plasticity and efficient enzyme delivery.

Fabrication of hyaluronic acid-inulin coated Enterococcus faecium for colon-targeted delivery to fight Fusobacterium nucleatum.

The abundance of Fusobacterium nucleatum (F. nucleatum) is highly associated with the development and poor prognosis of colorectal cancer (CRC), which is regarded as a promising target for CRC. However, until now, the novel strategy to clear F. nucleatum in the colon and CRC has not been well proposed. Herein, a probiotic strain Enterococcus faecium (E. faecium, EF47) is verified to secrete various organic acids and bacteriocins to exert superior antimicrobial activity towards F. nucleatum. However, the oral delivery of EF47 is affected by the complex digestive tract environment, so we design the hyaluronic acid-inulin (HA-IN) coated EF47 for colon-targeted delivery to fight F. nucleatum. IN can protect EF47 from the harsh gastrointestinal tract environment and is degraded specifically in the colon, acting as prebiotics to further promote the proliferation of EF47. The exposed HA can also enhance the targeting effect to the tumor area via the interaction with the CD44 receptor on the tumor cells, which is confirmed to increase the adhesive ability in tumor tissues and inhibit the growth of F. nucleatum. Therefore, this colon-targeted delivery system provides a novel platform to realize high-activity and adhesive delivery of probiotics to assist the therapeutic efficiency of CRC.

Deep learning for sub-Nyquist sampling scanning white light interferometry.

This Letter introduces sub-Nyquist sampling vertical scanning white light interferometry (SWLI) using deep learning. The method designs Envelope-Deep Residual Shrinkage Networks with channel-wise thresholds (E-DRSN-cw), a network model extracting oversampling envelopes from undersampled signals. The model improves the training efficiency, accuracy, and robustness by following the soft thresholding nonlinear layer approach, pre-padding undersampled interference signals with zeros, using LayerNorm for augmenting inputs and labels, and predicting regression envelopes. Simulation data train the network, and experiments demonstrate its superior performance over classical methods in the accuracy and the robustness. The E-DRSN-cw provides a swift measurement solution for SWLI, removing the need for prior knowledge.

Combination of Bifidobacterium breve and antibiotics against Clostridioides difficile: effect of the time interval of combination on antagonistic activity / Combinación de Bifidobacterium breve y antibióticos contra Clostridioides difficile: efecto del intervalo de tiempo de la combinación sobre la actividad antagonista

Co-administration of probiotics and antibiotics has been used to prevent or treat primary Clostridioides difficile (pCDI), and the closer the interval between the combination, the more effective it is, but the reason behind this is unknown. In this study, the cell-free culture supernatant (CFCS) of Bifidobacterium breve YH68 was used in combination with vancomycin (VAN) and metronidazole (MTR) to treat C. difficile cells. The growth and biofilm production of C. difficile under different co-administration time interval treatments were determined by optical density and crystalline violet staining, respectively. The toxin production of C. difficile was determined by enzyme immunoassay, and the relative expressions of C. difficile virulence genes tcdA and tcdB were determined by real-time qPCR method. Meanwhile, the types and contents of organic acids in YH68-CFCS were investigated by LC-MS/MS. The results showed that YH68-CFCS in combination with VAN or MTR significantly inhibited the growth, biofilm production, and toxin production of C. difficile in the effective time interval range (0–12 h) but did not affect the expression level of C. difficile virulence genes. In addition, the effective antibacterial component of YH68-CFCS is lactic acid (LA).(AU)

Strategies for applying probiotics in the antibiotic management of Clostridioides difficile infection.

The vital role of probiotics in the food field has been widely recognized, and at the same time, probiotics are gradually exhibiting surprising effects in the field of nutraceuticals, especially in regulating gut inflammation and the nutritional environment. As a dietary supplement in clinical nutrition, the coadministration of probiotics with antibiotics model has been applied to prevent intestinal infections caused by Clostridioides difficile. However, the mechanism behind this "bacteria-drug combination" model remains unclear. In particular, the selection of specific probiotic strains, the order of probiotics or antibiotics, and the time interval of coadministration are key issues that need to be further explored and clarified. Here, we focus on the issues mentioned above and give reasonable opinions, mainly including: (1) probiotics are safer and more effective when they intervene after antibiotics have been used; (2) the choice of the time interval between coadministration should be based on the metabolism of antibiotics in the host, differences in probiotic strains, the baseline ecological environment of the host's intestine, and the host immune level; in addition, the selection of the coadministration regime should also take into account factors such as the antibiotic sensitivity of probiotics and dosage of probiotics; and (3) by encapsulating probiotics, combining probiotics with prebiotics, and developing next-generation probiotics (NGPs) and postbiotic formulations, we can provide a more reasonable reference for this type of "bacteria-drug combination" model, and also provide targeted guidance for the application of probiotic dietary supplements in the antibiotic management of C. difficile infection.

Use of machine learning-based integration to develop an immune-related signature for improving prognosis in patients with gastric cancer.

Gastric cancer is one of the most common malignancies. Although some patients benefit from immunotherapy, the majority of patients have unsatisfactory immunotherapy outcomes, and the clinical significance of immune-related genes in gastric cancer remains unknown. We used the single-sample gene set enrichment analysis (ssGSEA) method to evaluate the immune cell content of gastric cancer patients from TCGA and clustered patients based on immune cell scores. The Weighted Correlation Network Analysis (WGCNA) algorithm was used to identify immune subtype-related genes. The patients in TCGA were randomly divided into test 1 and test 2 in a 1:1 ratio, and a machine learning integration process was used to determine the best prognostic signatures in the total cohort. The signatures were then validated in the test 1 and the test 2 cohort. Based on a literature search, we selected 93 previously published prognostic signatures for gastric cancer and compared them with our prognostic signatures. At the single-cell level, the algorithms "Seurat," "SCEVAN", "scissor", and "Cellchat" were used to demonstrate the cell communication disturbance of high-risk cells. WGCNA and univariate Cox regression analysis identified 52 prognosis-related genes, which were subjected to 98 machine-learning integration processes. A prognostic signature consisting of 24 genes was identified using the StepCox[backward] and Enet[alpha = 0.7] machine learning algorithms. This signature demonstrated the best prognostic performance in the overall, test1 and test2 cohort, and outperformed 93 previously published prognostic signatures. Interaction perturbations in cellular communication of high-risk T cells were identified at the single-cell level, which may promote disease progression in patients with gastric cancer. We developed an immune-related prognostic signature with reliable validity and high accuracy for clinical use for predicting the prognosis of patients with gastric cancer.

Combination of Bifidobacterium breve and antibiotics against Clostridioides difficile: effect of the time interval of combination on antagonistic activity.

Co-administration of probiotics and antibiotics has been used to prevent or treat primary Clostridioides difficile (pCDI), and the closer the interval between the combination, the more effective it is, but the reason behind this is unknown. In this study, the cell-free culture supernatant (CFCS) of Bifidobacterium breve YH68 was used in combination with vancomycin (VAN) and metronidazole (MTR) to treat C. difficile cells. The growth and biofilm production of C. difficile under different co-administration time interval treatments were determined by optical density and crystalline violet staining, respectively. The toxin production of C. difficile was determined by enzyme immunoassay, and the relative expressions of C. difficile virulence genes tcdA and tcdB were determined by real-time qPCR method. Meanwhile, the types and contents of organic acids in YH68-CFCS were investigated by LC-MS/MS. The results showed that YH68-CFCS in combination with VAN or MTR significantly inhibited the growth, biofilm production, and toxin production of C. difficile in the effective time interval range (0-12 h) but did not affect the expression level of C. difficile virulence genes. In addition, the effective antibacterial component of YH68-CFCS is lactic acid (LA).

High levels of Myc expression are required for the robust proliferation of hepatocytes, but not for the sustained weak proliferation.

In contrast to the robust proliferation exhibited following acute liver injury, hepatocytes exhibit long-lasting proliferative activity in chronic liver injury. The mechanistic differences between these distinct modes of proliferation are unclear. Hepatocytes exhibited robust proliferation that peaked at 2 days following partial hepatectomy in mice, but this proliferation was completely inhibited by hepatocyte-specific expression of MadMyc, a Myc-suppressing chimeric protein. However, Myc suppression induced weak but continuous hepatocyte proliferation, thereby resulting in full restoration of liver mass despite an initial delay. Late-occurring proliferation was accompanied by prolonged suppression of proline dehydrogenase (PRODH) expression, and forced PRODH overexpression inhibited hepatocyte proliferation. In hepatocytes in chronic liver injury, Myc was not activated but PRODH expression was suppressed in regenerating hepatocytes. In liver tumors, PRODH expression was often suppressed, especially in the highly proliferative tumors with distinct Myc expression. Our results indicate that the robust proliferation of hepatocytes following acute liver injury requires high levels Myc expression and that there is a compensatory Myc-independent mode of hepatocyte proliferation with the regulation of proline metabolism, which might be relevant to liver regeneration in chronic injury.

Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies.

Respiratory syncytial virus (RSV) is a major pathogen that can cause acute respiratory infectious diseases of the upper and lower respiratory tract, especially in children, elderly individuals, and immunocompromised people. Generally, following viral infection, respiratory epithelial cells secrete cytokines and chemokines to recruit immune cells and initiate innate and/or adaptive immune responses. However, whether chemokines affect viral replication in nonimmune cells is rarely clear. In this study, we detected that chemokine CCL5 was highly expressed, while expression of its receptor, CCR1, was downregulated in respiratory epithelial cells after RSV infection. When we overexpressed CCR1 on respiratory epithelial cells in vivo or in vitro, viral load was significantly suppressed, which can be restored by the neutralizing antibody for CCR1. Interestingly, the antiviral effect of CCR1 was not related to type I interferon (IFN-I), apoptosis induction, or viral adhesion or entry inhibition. In contrast, it was related to the preferential recruitment and activation of the adaptor Gαi, which promoted inositol 1,4,5-triphosphate receptor type 3 (ITPR3) expression, leading to inhibited STAT3 phosphorylation; explicitly, phosphorylated STAT3 (p-STAT3) was verified to be among the important factors regulating the activity of HSP90, which has been previously reported to be a chaperone of RSV RNA polymerase. In summary, we are the first to reveal that CCR1 on the surface of nonimmune cells regulates RSV replication through a previously unknown mechanism that does not involve IFN-I induction. IMPORTANCE Our results revealed a novel mechanism by which RSV escapes innate immunity. That is, although it induces high CCL5 expression, RSV might attenuate the binding of CCL5 by downregulating the expression of CCR1 in respiratory epithelial cells to weaken the inhibitory effect of CCR1 on HSP90 activity and thereby facilitate RSV replication in nonimmune cells. This study provides a new target for the development of co-antiviral inhibitors against other components of the host and co-molecular chaperone/HSP90 and provides a scientific basis for the search for effective broad-spectrum antiviral drugs.

Suppressing the polarization aberrations by combining reflection and refraction optical groups.

Polarization remote sensing technology expands the dimensions of the target and enriches its basic information over traditional remote sensing methods. During the imaging process, polarization imaging changes the polarization information of the target by the modulation of the optical system, affecting the detection accuracy. We term the modulation of the polarization state of light by an optical system as polarization aberration, and we found that a lens group combined with mirrors is beneficial in suppressing polarization aberrations. This study analyzed the principles of suppression and the polarization aberration of the optical system before and after suppression. Simulation results show that the diattenuation's average value is reduced by 51.1% and the retardance's average value is reduced by 26.3% after suppression. The corrected polarization cross-coupled energy is reduced by 73.18% in the central field of view and by 69.80% in the fringe field of view. Adding a lens group also effectively suppresses traditional aberrations and expands the field of view.

Design of Compact Mid-Infrared Cooled Echelle Spectrometer Based on Toroidal Uniform-Line-Spaced (TULS) Grating.

A traditional flat-panel spectrometer does not allow high-resolution observation and miniaturization simultaneously. In this study, a compact, high-resolution cross-dispersion spectrometer was designed based on the theoretical basis of echelle grating for recording an infrared spectrum. To meet the high-resolution observation and miniaturization design requirements, a reflective immersion grating was used as the primary spectroscopic device. To compress the beam aperture of the imaging system, the order-separation device of the spectrometer adopted toroidal uniform line grating, which had both imaging and dispersion functions in the spectrometer. The aberration balance condition of the toroidal uniform line grating was analyzed based on the optical path difference function of the concave grating, and dispersion characteristics of the immersed grating and thermal design of the infrared lens were discussed based on the echelle grating. An immersion echelle spectrometer optical system consisting of a culmination system, an immersed echelle grating, and a converged system was used. The spectrometer was based on the asymmetrical Czerny-Turner and Littrow mount designs, and it was equipped with a 320 × 256 pixel detector array. The designed wavelength range was 3.7-4.8 µm, the F-number was 4, and the central wavelength resolution was approximately 30,000. An infrared cooling detector was used. The design results showed that, in the operating band range, the root implied that the square diameter of the spectrometer spot diagram was less than 30 µm, the energy was concentrated in a pixel size range, and the spectrometer system design met the requirements.

Therapeutic Effects of Bifidobacterium breve YH68 in Combination with Vancomycin and Metronidazole in a Primary Clostridioides difficile-Infected Mouse Model.

Probiotics have been widely used to prevent primary Clostridioides difficile infection (pCDI); however, there are fewer studies on their therapeutic aspects for pCDI. In this study, high doses of Bifidobacterium breve YH68 were used alone or in combination with vancomycin (VAN) and metronidazole (MTR) to treat pCDI mice. Mouse feces were collected from preinfection, postinfection, and posttreatment stages. Subsequently, the C. difficile number and toxin level in feces were detected by plate count method and C. difficile toxin enzyme-linked immunosorbent assay (ELISA). Simultaneously, 16S rRNA amplicon sequencing and untargeted metabolomics were employed to explore the changing patterns and characteristic markers of fecal microbiota and metabolome. The results indicated that high doses of YH68 used alone or in combination with VAN and MTR were more effective than the combination of VAN and MTR for pCDI mice and improved their final survival rate. This probiotic strain and its combination with antibiotics reduced C. difficile numbers and toxin levels in the feces, downregulated proinflammatory cytokine levels in colon tissue, and alleviated cecum tissue hyperplasia. Meanwhile, the level of fecal microbiota diversity increased significantly in pCDI mice after treatment, with an increase in the relative abundance of Bifidobacterium, Akkermansia, Oscillospira, unidentified_S24-7, and Ruminococcus, and this process was accompanied by elevated levels of secondary bile acid, butyric acid, and gentamicin C1a and reduced levels of primary bile acid and indoles. Most notably, the combination of YH68 with VAN and MTR diminished the damaging effect of antibiotic treatment alone on the microbiota. Our findings suggested that high doses of YH68 used in combination with VAN and MTR have a better therapeutic effect on pCDI mice than the combination of VAN and MTR alone. IMPORTANCE Many studies have focused on the preventive effects of probiotics against pCDI, but few studies have investigated in depth the therapeutic effects of probiotics, especially at the postinfection stage. We demonstrated that high doses of Bifidobacterium breve YH68 used alone or in combination with vancomycin (VAN) and metronidazole (MTR) exerted outstanding efficacy in the treatment of pCDI mice. This probiotic-antibiotic combination regimen has the potential to be a new option for the clinical treatment of pCDI.

Oscillospira - a candidate for the next-generation probiotics.

Oscillospira is a class of organism that often appears in high-throughput sequencing data but has not been purely cultured and is widely present in the animal and human intestines. There is a strong association between variation in Oscillospira abundance and obesity, leanness, and human health. In addition, a growing body of studies has shown that Oscillospira is also implicated in other diseases, such as gallstones and chronic constipation, and has shown some correlation with the positive or negative changes in its course. Sequencing data combined with metabolic profiling indicate that Oscillospira is likely to be a genus capable of producing short-chain fatty acids (SCFAs) such as butyrate, which is an important reference indicator for screening "next-generation probiotics ". Considering the positive effects of Oscillospira in some specific diseases, such as obesity-related metabolic diseases, it has already been characterized as one of the next-generation probiotic candidates and therefore has great potential for development and application in the future food, health care, and biopharmaceutical products.

Decreased Portal Circulation Augments Fibrosis and Ductular Reaction in Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease often progresses to cirrhosis and causes liver cancer, but mechanisms of its progression are yet to be elucidated. Although nonalcoholic fatty liver disease is often associated with abnormal portal circulation, there have not been any experimental studies to test its pathogenic role. Here, whether decreased portal circulation affected the pathology of nonalcoholic steatohepatitis (NASH) was examined using congenital portosystemic shunt (PSS) in C57BL/6J mice. Whereas PSS significantly attenuated free radical-mediated carbon tetrachloride injury, it augmented pericellular fibrosis in the centrilobular area induced by a 0.1% methionine choline-deficient l-amino acid-defined high-fat diet (CDAHFD). PSS aggravated ductular reaction and increased the expression of connective tissue growth factor. Pimonidazole immunohistochemistry of the liver revealed that the centrilobular area of PSS-harboring mice was more hypoxic than that of control mice. Although tissue hypoxia was observed in the fibrotic area in CDAHFD-induced NASH in both control and PSS-harboring mice, it was more profound in the latter, which was associated with higher carbonic anhydrase 9 and vascular endothelial growth factor expression and neovascularization in the fibrotic area. Furthermore, partial ligation of the portal vein also augmented pericellular fibrosis and ductular reaction induced by a CDAHFD. These results demonstrate that decreased portal circulation, which induces hypoxia due to disrupted intralobular perfusion, is an important aggravating factor of liver fibrosis in NASH.

New application of an old drug proparacaine in treating epilepsy via liposomal hydrogel formulation.

Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPC-HCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic.

Generation of combined hepatocellular-cholangiocarcinoma through transdifferentiation and dedifferentiation in p53-knockout mice.

The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC-CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS- or HRAS/Myc-induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte-derived liver tumors were induced in heterozygous and homozygous p53-knockout (KO) mice by hydrodynamic tail vein injection of HRAS- or Myc-containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase-expressing plasmid. The HRAS-induced and HRAS/Myc-induced tumors in the wild-type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53-KO mice was consistent with cHCC-CCA. The expression of fetal/neonatal liver proteins, including delta-like 1, was detected in the HRAS/Myc-induced but not in the HRAS-induced cHCC-CCA tissues. The dedifferentiation in the HRAS/Myc-induced tumors was more marked in the homozygous p53-KO mice than in the heterozygous p53-KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte-derived tumor cells through either transdifferentiation or Myc-mediated dedifferentiation.

Targeted Regulation of Blood-Brain Barrier for Enhanced Therapeutic Efficiency of Hypoxia-Modifier Nanoparticles and Immune Checkpoint Blockade Antibodies for Glioblastoma.

Glioblastoma is the most destructive type of brain cancer. The blood-brain barrier (BBB) is a tremendous obstacle that hinders therapeutic agents, such as chemical drugs and antibodies, from reaching glioblastoma tissues. Meanwhile, the abnormal microenvironment of glioblastoma extremely restricts the expected therapeutic effects of accumulated drugs. Therefore, in the present study, BBB-regulating nanovesicles (BRN) are developed to achieve targeted and controlled BBB regulation, carrying adenosine 2A receptor (A2AR) agonists and perfluorocarbon (PF). The red-blood-cell membrane (RBCM) is included on the outside to avoid the premature release of therapeutic agents. In the presence of ultrasonication (US), A2AR agonists are released and induce effects on both F-actin and tight junctions of endothelial cells. Subsequently, BBB permeability is temporarily increased and enables small molecules and nanoparticles to enter brain parenchymal tissues. The high affinity between manganese dioxide and temozolomide (TMZ) is utilized to form multifunctional nanoparticles to ameliorate the hypoxic microenvironment, which yields improved glioblastoma inhibition combined with radiotherapy. Moreover, with the aid of targeted BBB regulation, programmed death ligand-1 (PD-L1) antibody induces a tumor-specific immune response. Taken together, the findings suggest that synergistic combination may have the potential in amplifying the therapeutic efficacies of clinical drugs and immune checkpoint blockade antibodies to overcome the therapeutic resistance of glioblastoma.

GRPr-mediated photothermal and thermodynamic dual-therapy for prostate cancer with synergistic anti-apoptosis mechanism.

Conventional prostate cancer treatment strategies, including chemotherapy and radiotherapy, cannot effectively eradicate prostate cancer, especially castration resistance prostate cancer. Herein, we developed a novel nanotherapy platform that consists of synergic photothermal and photodynamic therapy via the unique properties of photothermal conversion by gold nanorods and free radicals generation by encapsulated initiators (AIPH). Mesoporous silica was employed as a coating material, and the bombesin peptide was conjugated onto the mesoporous silica coating layer as the targeting moiety to prostate cancer via its overexpressed gastrin-releasing peptide receptors. An in vitro study with the castration resistance prostate cancer cell exhibited a significant photothermal therapeutic effect as well as enhanced thermodynamic therapy via generating free radicals. P-p38 and p-JNK proteins, as key proteins involved in the cells' stress responses, were found to be upregulated by the synergetic treatment. The in vivo study demonstrated that a significant eradication of prostate tumour could be achieved by the nanoparticle therapeutic platform with a good biocompatibility profile. This work pioneers a novel approach for high-efficient castration resistance prostate cancer treatment by combining photothermal, thermodynamic, and site-specific drug delivery directed by an integrated nanoparticle system.

The efficacy of gabapentin combined with opioids for neuropathic cancer pain: a meta-analysis.

BACKGROUND: More than 30% of cancer patients experience neuropathic pain. Opioids, as standard pain-relief agents, cannot achieve satisfactory outcomes to treat neuropathic cancer pain due to drug resistance and side effects. Meanwhile, gabapentin, a third-generation anticonvulsant drug, has great potential in providing relief for neuropathic cancer pain. However, there is currently no sufficient evidence to support the efficacy of a combination of gabapentin and opioids in ameliorating neuropathic cancer pain. Hence, the aim of the present study was to explore the analgesic efficacy of gabapentin combined with opioids in treating neuropathic cancer pain. METHODS: PubMed, EMBASE, and Web of Science (Web of Knowledge) were searched for randomized controlled trials and prospective studies via the following keywords: "gabapentin", "opioid", "cancer", and "neuropathic pain". We used a scale of 0-10 (0 denoting no pain and 10 denoting the worst pain imaginable) to estimate pain intensity and utilized Review Manager 5.3 and Stata12 to analyze data. RESULTS: Seven studies meeting our criterion were selected from 110 records that were primarily searched. The mean difference of pooled pain intensity and the 95% confidence interval (CI) was -1.75 (-2.44, -1.07) (P value <0.00001; treatment group versus control group or time to outcome assessment versus baseline). The pain intensity of cancer patients after a combined treatment of gabapentin and opioids was significantly lower than that of patients receiving opioids alone. CONCLUSIONS: Our meta-analysis showed that gabapentin combined with opioids effectively alleviated neuropathic cancer pain compared with that of opioids alone.