Development of a novel colon adenocarcinoma m6A-related lncRNA pair prognostic model.

Background: Colon adenocarcinoma (COAD) is among the most prevalent malignancies. Changes to N6-methyladenosine (m6A), the most common RNA modification, can affect how COAD develops. Furthermore, the involvement of long noncoding RNA (lncRNA) in COAD is significant, and it exhibits a close association with m6A modification. Nevertheless, the prognostic significance of lncRNAs that are related to m6A modification in COAD remains unclear. This study aims to establish a m6A-related lncRNA pair signature and reveal its prognostic value in COAD. Methods: The current study utilized data from The Cancer Genome Atlas (TCGA) to investigate the predictive significance of m6A-related lncRNA pair signatures in COAD. The identification of m6A-related lncRNAs was conducted through co-expression analysis using the Pearson correlation coefficient. Then, the lncRNA pairs related to prognosis were identified using univariate Cox regression analysis. Receiver operating characteristic (ROC) curves were produced using the least absolute shrinkage and selection operator (LASSO) penalized with Cox analysis to predict overall survival (OS) in order to build a risk score prognostic model. The relationship among the risk scoring model and clinical characteristics, immune-related variables, and medication sensitivity was examined after identifying independent prognostic factors. Results: Thirty-five of the 319 lncRNA pairings associated with m6A were linked to a pattern that predicted risk ratings. It was verified that the risk score model was a reliable predictor that stood alone from clinicopathological features. Differences between high- and low-risk groups were found in clinicopathological traits, immune-related variables, and medication sensitivity analysis according to correlation analyses. Conclusions: Based on paired differentially expressed m6A-related lncRNAs, the proposed COAD prognostic model demonstrated potential clinical predictive value.

Multiple Treatment of Triple-Negative Breast Cancer Through Gambogic Acid-Loaded Mesoporous Polydopamine.

Triple-negative breast cancer (TNBC) is a highly heterogeneous subtype of breast cancer, characterized by aggressiveness and high recurrence rate. As monotherapy provides limited benefit to TNBC patients, combination therapy emerges as a promising treatment approach. Gambogic acid (GA) is an exceedingly promising anticancer agent. Nonetheless, its application potential is hampered by low drug loading efficiency and associated toxic side effects. To overcome these limitations, using mesoporous polydopamine (MPDA) endowed with photothermal conversion capabilities is considered as a delivery vehicle for GA. Meanwhile, GA can inhibit the activity of heat shock protein 90 (HSP90) to enhance the photothermal effect. Herein, GA-loaded MPDA nanoparticles (GA@MPDA NPs) are developed with a high drug loading rate of 75.96% and remarkable photothermal conversion performance. GA@MPDA NPs combined with photothermal treatment (PTT) significantly inhibit the tumor growth, and effectively trigger the immunogenic cell death (ICD), which thereby increase the number of activated effector T cells (CD8+ T cells and CD4+ T cells) in the tumor, and hoist the level of immune-inflammatory cytokines (IFN-γ, IL-6, and TNF-α). The above results suggest that the combination of GA@MPDA NPs with PTT expected to activate the antitumor immune response, thus potentially enhancing the clinical therapeutic effect on TNBC.

Biomimetic "Gemini nanoimmunoregulators" orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages.

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy. Here, a new type of spatiotemporal biomimetic "Gemini nanoimmunoregulators" was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death (ICD), tumor-associated macrophages (TAMs) phenotype reprogramming and programmed cell death ligand 1 (PD-L1) degradation. The "Gemini nanoimmunoregulators" PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine (mPDA) as nanovectors to deliver metformin (Met) and toll-like receptor 7/8 agonist resiquimod (R848) to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane (RM) inlaid with T7 or M2 peptides. mPDA/Met@RM-T7 (abbreviated as PM@RM-T7) was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity. Meanwhile, PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion. Subsequently, mPDA/R848@RM-M2 (abbreviated as PR@RM-M2) specifically recognized TAMs and reset the phenotype from M2 to M1 state, thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes. This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity, which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis. This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

Smart nanoparticles for cancer therapy.

Smart nanoparticles, which can respond to biological cues or be guided by them, are emerging as a promising drug delivery platform for precise cancer treatment. The field of oncology, nanotechnology, and biomedicine has witnessed rapid progress, leading to innovative developments in smart nanoparticles for safer and more effective cancer therapy. In this review, we will highlight recent advancements in smart nanoparticles, including polymeric nanoparticles, dendrimers, micelles, liposomes, protein nanoparticles, cell membrane nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, iron oxide nanoparticles, quantum dots, carbon nanotubes, black phosphorus, MOF nanoparticles, and others. We will focus on their classification, structures, synthesis, and intelligent features. These smart nanoparticles possess the ability to respond to various external and internal stimuli, such as enzymes, pH, temperature, optics, and magnetism, making them intelligent systems. Additionally, this review will explore the latest studies on tumor targeting by functionalizing the surfaces of smart nanoparticles with tumor-specific ligands like antibodies, peptides, transferrin, and folic acid. We will also summarize different types of drug delivery options, including small molecules, peptides, proteins, nucleic acids, and even living cells, for their potential use in cancer therapy. While the potential of smart nanoparticles is promising, we will also acknowledge the challenges and clinical prospects associated with their use. Finally, we will propose a blueprint that involves the use of artificial intelligence-powered nanoparticles in cancer treatment applications. By harnessing the potential of smart nanoparticles, this review aims to usher in a new era of precise and personalized cancer therapy, providing patients with individualized treatment options.

Remodeling the tumor immune microenvironment via siRNA therapy for precision cancer treatment.

How to effectively transform the pro-oncogenic tumor microenvironments (TME) surrounding a tumor into an anti-tumoral never fails to attract people to study. Small interfering RNA (siRNA) is considered one of the most noteworthy research directions that can regulate gene expression following a process known as RNA interference (RNAi). The research about siRNA delivery targeting tumor cells and TME has been on the rise in recent years. Using siRNA drugs to silence critical proteins in TME was one of the most efficient solutions. However, the manufacture of a siRNA delivery system faces three major obstacles, i.e., appropriate cargo protection, accurately targeted delivery, and site-specific cargo release. In the following review, we summarized the pharmacological actions of siRNA drugs in remolding TME. In addition, the delivery strategies of siRNA drugs and combination therapy with siRNA drugs to remodel TME are thoroughly discussed. In the meanwhile, the most recent advancements in the development of all clinically investigated and commercialized siRNA delivery technologies are also presented. Ultimately, we propose that nanoparticle drug delivery siRNA may be the future research focus of oncogene therapy. This summary offers a thorough analysis and roadmap for general readers working in the field.

Biomimetic Nano-Immunoactivator via Ionic Metabolic Modulation for Strengthened NIR-II Photothermal Immunotherapy.

Reprogramming the immunologically "cold" environment of solid tumors is currently becoming the mainstream strategy to elicit powerful and systemic anticancer immunity. Here, a facile and biomimetic nano-immunnoactivator (CuS/Z@M4T1 ) is detailed by engineering a Zn2+ -bonded zeolitic imidazolate framework-8 (ZIF-8) with CuS nanodots (NDs) and cancer cell membrane for amplified near-infrared-II (NIR-II) photothermal immunotherapy via Zn2+ metabolic modulation. Taking advantage of the NIR-II photothermal effect of CuS NDs and the acidic responsiveness of ZIF-8, CuS/Z@M4T1 rapidly causes intracellular Zn2+ pool overload and disturbs the metabolic flux of 4T1 cells, which effectively hamper the production of heat shock proteins and relieve the resistance of photothermal therapy (PTT). Thus, amplified immunogenic cell death is evoked and initiates the immune cascade both in vivo and in vitro as demonstrated by dendritic cells maturation and T-cell infiltration. Further combination with antiprogrammed death 1 (aPD-1) achieves escalated antitumor efficacy which eliminates the primary, distant tumor and avidly inhibits lung metastasis due to cooperation of enhanced photothermal stimulation and empowerment of cytotoxic T lymphocytes by aPD-1. Collectively, this work provides the first report of using the intrinsic modulation property of meta-organometallic ZIF-8 for enhanced cancer photoimmunotherapy together with aPD-1, thereby inspiring a novel combined paradigm of ion-rich nanomaterials for cancer treatment.

Mesoporous Silica Nanoparticles-Based Nanoplatforms: Basic Construction, Current State, and Emerging Applications in Anticancer Therapeutics.

In recent years, researchers are developing novel nanoparticles for diagnostic applications using imaging techniques and for therapeutic purposes through drug delivery techniques. The unique physical and chemical properties of mesoporous silica nanoparticles (MSNs) make it possible to integrate a variety of commonly used therapeutic and imaging agents to construct a multimodal synergistic anticancer drug delivery system. Herein, recent advances in MSNs synthesis for drug delivery and smart response applications are reviewed. First, synthetic strategies for the fabrication of ordered MSNs, hollow MSNs, core-shell structured MSNs, dendritic MSNs, and biodegradable MSNs are outlined. Then, the recent research progress in designing functional MSN materials with various controlled release mechanisms in anticancer therapy is discussed, and new properties are introduced to suggest the latest design requirements as drug delivery materials. The review also highlights significant achievements in bioimaging using MSNs and their multifunctional counterparts as delivery vehicles. Finally, personal views on key directions for future work in this area are presented.

Aquatic resistance training repercussions on the dynamic stability in volleyball athletes / Repercussões do treino de resistência aquático sobre a estabilidade dinâmica dos atletas de vôlei / Repercusiones del entrenamiento de resistencia acuática en la estabilidad dinámica de los atletas de voleibol

ABSTRACT Introduction Resistance training is considered a practical pathway for increasing strength and speed. Objective Explore the aquatic resistance training on the dynamic stability in volleyball athletes. Methods Using aquatic resistance training reinforcement, 20 first-level national male volleyball athletes were randomly divided into control and experimental groups. The time of the experiment was ten weeks. In the end, lower limb muscle strength, jumping ability, dynamic stability, and muscle pain were compared. Residual effects were also checked six weeks after the end of the experiment. Results The aquatic resistance training group stopped training for six weeks, peak torque at 60°/s, 180°s of relative knee extension, jump height, full arm swing, and all three phases of the high jump were significantly better than the preliminary test; water entry speed in the vertical direction was also significantly better one week after training. Conclusion Aquatic resistance training can significantly improve the dynamic stability of the lower limbs, and its effect can be maintained up to 6 weeks after completion. It is recommended to apply resistance enhancement training to maintain fitness, especially for long periods. Evidence Level II; Therapeutic Studies - Investigating the result.

RESUMO Introdução O treino de resistência é considerado um meio eficaz para aumento de força e a velocidade. Objetivo Explorar as repercussões do treino de resistência aquática sobre a estabilidade dinâmica dos atletas de vôlei. Métodos 20 atletas de primeiro nível nacionais de vôlei masculino, foram divididos aleatoriamente em um grupo de treinamento para controle e outro grupo experimental com reforço utilizando treino de resistência aquático. O tempo do experimento foi de 10 semanas. Ao final, foram comparadas força muscular do membro inferior, capacidade de salto, estabilidade dinâmica, dor muscular. Foram verificados também os efeitos residuais em seis semanas após o término do experimento. Resultados O grupo de treino de resistência aquática parou de treinar por 6 semanas, com pico de torque a 60°/s, 180°s de extensão relativa do joelho, a altura de salto, o balanço completo dos braços e as três fases do salto em altura foram significativamente melhores do que o teste primário; a velocidade de entrada na água na direção vertical também foi significativamente melhor uma semana após o treinamento. Conclusão O treino de resistência aquático pode melhorar significativamente a estabilidade dinâmica dos membros inferiores e seu efeito pode ser mantido até 6 semanas após o término. Recomenda-se aplicar o treino de aprimoramento da resistência para manter o condicionamento físico, especialmente por longos períodos. Nível de evidência II; Estudos Terapêuticos - Investigação de Resultados.

RESUMEN Introducción El entrenamiento de resistencia se considera una forma eficaz de aumentar la fuerza y la velocidad. Objetivo Explorar las repercusiones del entrenamiento de resistencia acuática en la estabilidad dinámica de los atletas de voleibol. Métodos 20 atletas masculinos de voleibol de primer nivel nacional, fueron divididos aleatoriamente en un grupo de entrenamiento de control y otro grupo experimental con refuerzo mediante entrenamiento de resistencia acuática. El tiempo del experimento fue de 10 semanas. Al final, se comparó la fuerza muscular de las extremidades inferiores, la capacidad de salto, la estabilidad dinámica y el dolor muscular. También se comprobaron los efectos residuales a las seis semanas de finalizar el experimento. Resultados El grupo de entrenamiento de resistencia acuática dejó de entrenar durante 6 semanas, el pico máximo de torque a 60°/s, la extensión relativa de la rodilla a 180°s, la altura del salto, el balanceo completo del brazo y las tres fases del salto de altura fueron significativamente mejores que en la prueba primaria; la velocidad de entrada al agua en la dirección vertical también fue significativamente mejor una semana después del entrenamiento. Conclusión El entrenamiento de resistencia acuática puede mejorar significativamente la estabilidad dinámica de los miembros inferiores y su efecto puede mantenerse hasta 6 semanas después de su realización. Se recomienda aplicar un entrenamiento de mejora de la resistencia para mantener la forma física, especialmente durante largos periodos. Nivel de evidencia II; Estudios terapéuticos - Investigación de resultados.

Caveolin-1 signaling-driven mitochondrial fission and cytoskeleton remodeling promotes breast cancer migration.

Mitochondria are highly dynamic organelles that constantly divide and fuse to maintain their proper structure and function. Cancer cells are often accompanied by an imbalance of mitochondrial fusion and fission, cancer progression is greatly affected by this imbalance. Here, we found that high-metastatic breast cancer MDA-MB-231 cells possess higher caveolin-1 (Cav-1) expression compared with low-metastatic breast cancer MCF-7 cells or normal breast epithelial MCF-10A cells. Downregulation of Cav-1 decreases the migratory and invasive abilities of MDA-MB-231 cells. Our results further demonstrated that downregulation of Cav-1 facilitated DRP1 and MFN2 to translocate to mitochondria, increasing the inhibitory phosphorylation level of DRP1 at Ser637 by protein kinase A (PKA), resulting in mitochondria elongation. We also showed that downregulation of Cav-1 significantly reduced the Rac1 activity by affecting intracellular reactive oxygen species (ROS) generation, which then inhibited F-actin formation. Based on these findings, we proposed that Cav-1 mediated mitochondrial fission-affected intracellular ROS generation and activated Rho GTPases, leading to F-actin-dependent formation of lamellipodia and promotion of breast cancer motility.

Local delivery of gambogic acid to improve anti-tumor immunity against oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral cavity malignancies. However, despite significant advances in the last four decades, little improvement has been achieved in the overall survival rates for OSCC patients. While gambogic acid (GA) is a potential candidate compound for treating a variety of malignancies, its anti-cancer impact on OSCC has not to be completely investigated. The tumor immune microenvironment (TIME) has been proven to play a crucial role in the prognosis of cancer patients. Although there are few reports on the T cell activation effect of GA, the regulation of GA on the TIME of OSCC has barely been studied yet. In this study, GA was applied to treat OSCC-bearing mice through in situ controlled release. First, GA-loaded mPEG2000-PCL micelles (GA-MIC) were prepared by the thin-film hydration method to improve the aqueous dispersibility of GA. Second, poly(D, l-lactide)-poly(ethylene glycol)-poly(D, l-lactide) (PLEL) was synthesized for thermosensitive hydrogel preparation. Third, GA-MIC was mixed with PLEL to form an injectable therapeutic hydrogel (GA-MIC-GEL). The anti-tumor and TIME regulation effects of GA-MIC-GEL on tumor-bearing mice were further examined. The results showed that the thermosensitive GA-MIC-GEL with sensitive sol-gel transition characteristics could form hydrogel at 37 °C within 24 s, facilitating the local delivery and sustained GA release. Biochemical, hematological, and pathological analysis proved that GA-MIC-GEL has good biological safety. Moreover, GA-MIC-GEL promoted an obvious regression of both primary and distant tumors on the OSCC mouse models. Mechanically, GA-MIC-GEL down-regulated the expression of PD-1, increased the frequency of cytotoxic T cells and reduced the immunosuppressive cellular components, which boosted the anti-tumor immunity of OSCC-bearing mice. The constructed thermosensitive hydrogel for local delivery of GA has provided a safe and effective strategy with great potential for OSCC therapy.

Xanthomonas oryzae Pv. oryzicola Response Regulator VemR Is Co-opted by the Sensor Kinase CheA for Phosphorylation of Multiple Pathogenicity-Related Targets.

Two-component systems (TCSs) (cognate sensor histidine kinase/response regulator pair, HK/RR) play a crucial role in bacterial adaptation, survival, and productive colonization. An atypical orphan single-domain RR VemR was characterized by the non-vascular pathogen Xanthomonas oryzae pv. oryzicola (Xoc) is known to cause bacterial leaf streak (BLS) disease in rice. Xoc growth and pathogenicity in rice, motility, biosynthesis of extracellular polysaccharide (EPS), and the ability to trigger HR in non-host tobacco were severely compromised in the deletion mutant strain RΔvemR as compared to the wild-type strain RS105. Site-directed mutagenesis and phosphotransfer experiments revealed that the conserved aspartate (D56) residue within the stand-alone phosphoacceptor receiver (REC) domain is essential for phosphorelay and the regulatory activity of Xoc VemR. Yeast two-hybrid (Y2H) and co-immunoprecipitation (co-IP) data identified CheA as the HK co-opting the RR VemR for phosphorylation. Affinity proteomics identified several downstream VemR-interacting proteins, such as 2-oxoglutarate dehydrogenase (OGDH), DNA-binding RR SirA, flagellar basal body P-ring formation protein FlgA, Type 4a pilus retraction ATPase PilT, stress-inducible sensor HK BaeS, septum site-determining protein MinD, cytoskeletal protein CcmA, and Type III and VI secretion system proteins HrpG and Hcp, respectively. Y2H and deletion mutant analyses corroborated that VemR interacted with OGDH, SirA, FlgA, and HrpG; thus, implicating multi-layered control of diverse cellular processes including carbon metabolism, motility, and pathogenicity in the rice. Physical interaction between VemR and HrpG suggested cross-talk interaction between CheA/VemR- and HpaS/HrpG-mediated signal transduction events orchestrating the hrp gene expression.

STAT3 pathway in cancers: Past, present, and future.

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed.

'Candidatus Liberibacter asiaticus'-Encoded BCP Peroxiredoxin Suppresses Lipopolysaccharide-Mediated Defense Signaling and Nitrosative Stress In Planta.

The lipopolysaccharides (LPS) of gram-negative bacteria trigger a nitrosative and oxidative burst in both animals and plants during pathogen invasion. Liberibacter crescens strain BT-1 is a surrogate for functional genomic studies of the uncultured pathogenic 'Candidatus Liberibacter' spp. that are associated with severe diseases such as citrus greening and potato zebra chip. Structural determination of L. crescens LPS revealed the presence of a very long chain fatty acid modification. L. crescens LPS pretreatment suppressed growth of Xanthomonas perforans on nonhost tobacco (Nicotiana benthamiana) and X. citri subsp. citri on host orange (Citrus sinensis), confirming bioactivity of L. crescens LPS in activation of systemic acquired resistance (SAR). L. crescens LPS elicited a rapid burst of nitric oxide (NO) in suspension cultured tobacco cells. Pharmacological inhibitor assays confirmed that arginine-utilizing NO synthase (NOS) activity was the primary source of NO generation elicited by L. crescens LPS. LPS treatment also resulted in biological markers of NO-mediated SAR activation, including an increase in the glutathione pool, callose deposition, and activation of the salicylic acid and azelaic acid (AzA) signaling networks. Transient expression of 'Ca. L. asiaticus' bacterioferritin comigratory protein (BCP) peroxiredoxin in tobacco compromised AzA signaling, a prerequisite for LPS-triggered SAR. Western blot analyses revealed that 'Ca. L. asiaticus' BCP peroxiredoxin prevented peroxynitrite-mediated tyrosine nitration in tobacco. 'Ca. L. asiaticus' BCP peroxiredoxin (i) attenuates NO-mediated SAR signaling and (ii) scavenges peroxynitrite radicals, which would facilitate repetitive cycles of 'Ca. L. asiaticus' acquisition and transmission by fecund psyllids throughout the limited flush period in citrus.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Tad pilus-mediated twitching motility is essential for DNA uptake and survival of Liberibacters.

Axenically cultured Liberibacter crescens (Lcr) is a closely related surrogate for uncultured plant pathogenic species of the genus Liberibacter, including 'Candidatus L. asiaticus' (CLas) and 'Ca. L. solanacearum' (CLso). All Liberibacters encode a completely conserved gene repertoire for both flagella and Tad (Tight Adherence) pili and all are missing genes critical for nucleotide biosynthesis. Both flagellar swimming and Tad pilus-mediated twitching motility in Lcr were demonstrated for the first time. A role for Tad pili in the uptake of extracellular dsDNA for food in Liberibacters was suspected because both twitching and DNA uptake are impossible without repetitive pilus extension and retraction, and no genes encoding other pilus assemblages or mechanisms for DNA uptake were predicted to be even partially present in any of the 35 fully sequenced Liberibacter genomes. Insertional mutations of the Lcr Tad pilus genes cpaA, cpaB, cpaE, cpaF and tadC all displayed such severely reduced growth and viability that none could be complemented. A mutation affecting cpaF (motor ATPase) was further characterized and the strain displayed concomitant loss of twitching, viability and reduced periplasmic uptake of extracellular dsDNA. Mutations of comEC, encoding the inner membrane competence channel, had no effect on either motility or growth but completely abolished natural transformation in Lcr. The comEC mutation was restored by complementation using comEC from Lcr but not from CLas strain psy62 or CLso strain RS100, indicating that unlike Lcr, these pathogens were not naturally competent for transformation. This report provides the first evidence that the Liberibacter Tad pili are dynamic and essential for both motility and DNA uptake, thus extending their role beyond surface adherence.

Microenvironment Activatable Nanoprodrug Based on Gripper-like Cyclic Phenylboronic Acid to Precisely and Effectively Alleviate Drug-induced Hepatitis.

Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance. Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application. Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects. Methods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE). The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated. The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated. Results: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core. In HepaRG cells, cPBA-BE showed stronger cellular uptake. Due to the H2O2- and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells. Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice. cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver. Conclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H2O2 and pH-responsive properties by coupling a wide range of drugs containing o-diol. In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.

Theranostic nanoplatform to target macrophages enables the inhibition of atherosclerosis progression and fluorescence imaging of plaque in ApoE(-/-) mice.

BACKGROUND: Rupture of atherosclerotic plaque can cause acute malignant heart and cerebrovascular events, such as acute coronary heart disease, stroke and so on, which seriously threaten the safety of human life and property. Therefore, the early diagnosis and inhibition of atherosclerotic plaque progress still be a vital task. RESULTS: In this study, we presented the development of composite mesoporous silica nanoparticle (Ru(bpy)3@SiO2-mSiO2, CMSN)-based nanomedicines (NMs) (Ru(bpy)3@SiO2-mSiO2@SRT1720@AntiCD36, CMSN@SRT@Anti) for accurate diagnosis and treatment of atherosclerosis (AS). In vitro cell experiments showed that both RAW264.7 and oxidized low density lipoprotein (ox-LDL)-stimulated RAW264.7 cells could significantly uptake CMSN@SRT@Anti. Conversely, little fluorescence signal could be observed in CMSN@SRT group, showing the excellent targeting ability of CMSN@SRT@Anti to Class II scavenger receptor, CD36 on macrophage. Additionally, such fluorescence signal was significantly stronger in ox-LDL-stimulated RAW264.7 cells, which might benefit from the upregulated expression of CD36 on macrophages after ox-LDL treatment. For another, compared with free SRT1720, CMSN@SRT@Anti had a better and more significant effect on the inhibition of macrophage foaming process, which indicated that drug-carrying mesoporous silicon with targeting ability could enhance the efficacy of SRT1720. Animal experimental results showed that after the abdominal injection of CMSN@SRT@Anti, the aortic lesions of ApoE-/-mice could be observed with obvious and persistent fluorescence signals. After 4 weeks post-treatment, the serum total cholesterol, aortic plaque status and area were significantly improved in the mouse, and the effect was better than that in the free SRT1720 group or the CMSN@SRT group. CONCLUSIONS: The designed CMSN@SRT@Anti with excellent biocompatibility, high-performance and superior atherosclerosis-targeting ability has great potential for accurate identification and targeted therapy of atherosclerotic diseases.

Polydopamine-Based Nanoparticles for Photothermal Therapy/Chemotherapy and their Synergistic Therapy with Autophagy Inhibitor to Promote Antitumor Treatment.

Polydopamine (PDA) has attracted much attention recently due to its strong adhesion capability to most substrates. After combining with organic (such as organic metal framework, micelles, hydrogel, polypeptide copolymer) or inorganic nanomaterials (such as gold, silicon, carbon), polydopamine-based nanoparticles (PDA NPs) exhibit the merging of characteristics. Until now, the preparation methods, polymerization mechanism, and photothermal therapy (PTT) or chemotherapy (CT) applications of PDA NPs have been reported detailly. Since the PTT or CT treatment process is often accompanied by exogenous stimuli, tumor cells usually induce pro-survival autophagy to protect the cells from further damage, which will weaken the therapeutic effect. Therefore, an in-depth understanding of PDA NPs modulated PTT, CT, and autophagy is required. However, this association is rarely reviewed. Herein, we briefly described the relationship between PTT/CT, autophagy, and tumor treatment. Then, the outstanding performances of PDA NPs in PTT/CT and their combination with autophagy inhibitors for tumor synergistic therapy have been summarized. This work is expected to shed light on the multi-strategy antitumor therapy applications of PDA NPs.

Regulation of tumor microenvironment for pancreatic cancer therapy.

Pancreatic cancer (PC) is one kind of the most lethal malignancies worldwide, owing to its insidious symptoms, early metastases, and negative responses to current therapies. With an increasing understanding of pathology, the tumor microenvironment (TME) plays a significant role in ineffective treatment and poor prognosis of PC. Thus, a growing number of studies have focused on whether components of the TME could be effective targets for PC therapy. Biomaterials have been widely applied in cancer therapy, and numerous organic or inorganic biomaterials for TME regulation have been developed to inhibit the growth and metastasis of PC, as well as reverse therapeutic resistance. In this review, we discuss various biomaterials utilized to treat PC based on different components of the TME, including, but not limited to, extracellular matrix (ECM), abnormal tumor vascularization, and tumor-associated immune cells, as well as other unconventional therapeutic strategies. Besides, the perspectives on the underlying future of theranostic nanomedicines for PC therapy are also presented.