Correction: PRH1 mediates ARF7-LBD dependent auxin signaling to regulate lateral root development in Arabidopsis thaliana.

[This corrects the article DOI: 10.1371/journal.pgen.1008044.].

Acidity-Triggered "Sticky Spotlight": CCK2R-Targeted TME-Sensitive NIR Fluorescent Probes for Tumor Imaging In Vivo.

Cancer which causes high mortality globally threatens public health seriously. There is an urgent need to develop tumor-specific near-infrared (NIR) imaging agents to achieve precise diagnosis and guide effective treatment. In recent years, imaging probes that respond to acidic environments such as endosomes, lysosomes, or acidic tumor microenvironments (TMEs) are being developed. However, because of their nonspecific internalization by both normal and tumor cells, resulting in a poor signal-to-noise ratio in diagnosis, these pH-sensitive probes fail to be applied to in vivo tumor imaging. To address this issue, a cholecystokinin-2 receptor (CCK2R)-targeted TME-sensitive NIR fluorescent probe R2SM was synthesized by coupling pH-sensitive heptamethine cyanine with a CCK2R ligand, minigastrin analogue 11 (MG11) for in vivo imaging, in which MG11 would target overexpressed CCK2Rs in gastrointestinal stromal tumors (GISTs). Cell uptake assay demonstrated that R2SM exhibited a high affinity for CCK2R, leading to receptor-mediated internalization and making probes finally accumulated in the lysosomes of tumor cells, which suggested in the tumor tissues, the probes were distributed in the extracellular acidic TME and intracellular lysosomes. With a pKa of 6.83, R2SM can be activated at the acidic TME (pH = 6.5-6.8) and lysosomes (pH = 4.5-5.0), exhibiting an apparent pH-dependent behavior and generating more intense fluorescence in these acidic environments. In vivo imaging showed that coupling of MG11 with a pH-sensitive NIR probe facilitated the accumulation of probe and enhanced the fluorescence in CCK2R-overexpressed HT-29 tumor cells. A high signal was observed in the tumor region within 0.5 h postinjection, indicating its potential application in intraoperative imaging. Fluorescence imaging of R2SM exhibited higher tumor-to-liver and tumor-to-kidney ratios (2.1:1 and 2.3:1, respectively), compared separately with the probes that are lipophilic, pH-insensitive, or MG11-free. In vitro and in vivo studies demonstrated that the synergistic effect of tumor targeting with pH sensitivity plays a vital role in the high signal-to-noise ratio of the NIR imaging probe. Moreover, different kinds of tumor-targeting vectors could be conjugated simultaneously with the NIR dye, which would further improve the receptor affinity and targeting efficiency.

Quadrivalent hemagglutinin and adhesion expressed on Saccharomyces cerevisiae induce protective immunity against Mycoplasma gallisepticum infection and improve gut microbiota.

Mycoplasma gallisepticum (MG) infection causes infectious respiratory diseases in poultry, causing economic losses to the poultry industry. Therefore, this study aims to develop a safe, convenient, and effective multivalent recombinant Saccharomyces cerevisiae vaccine candidate and to explore its potential for oral immunization as a subunit vaccine. Mycoplasma gallisepticum Cytadhesin (MGC) and variable lipoprotein and hemagglutinin (vlhA) are associated with the pathogenesis of MG. In this study, a quadrivalent recombinant Saccharomyces cerevisiae (ST1814G-MG) displaying on MGC2, MGC3, VLH5, and VLH3, proteins was innovatively constructed, and its protective efficiency was evaluated in birds. The results showed that oral immunization with ST1814G-MG stimulates specific antibodies in chickens, reshapes the composition of the gut microbiota, reduces the Mycoplasma loading and pulmonary disease injury in the lungs. In addition, we found that oral ST1814G-MG had better protection against MG infection than an inactivated vaccine, and co-administration with the inactivated vaccine was even more effective. The results suggest that ST1814G-MG is a potentially safer and effective agent for controlling MG infection.

Health-related quality of life in primary care patients: a comparison between EQ-5D-5L utility score and EQ-visual analogue scale.

OBJECTIVE: The EQ-VAS is an important component of the EQ-5D questionnaire. However, there is limited evidence comparing its performance to the EQ-5D utility score, which restricts its use in the population. This study aimed to EQ-5D-5L utility score and EQ-visual analogue scale (EQ-VAS) in primary care patients in Hong Kong (HK). METHODS: Secondary data analysis was performed on the data collected from a cross-sectional survey to investigate patient engagement in HK. Participants were recruited through random sampling from a single general outpatient clinic. Trained investigators conducted face-to-face interviews with all eligible patients attending the clinic. Patients who were: 1) ≥ 18 years old, 2) have visited the clinic at least once in the last 6 months, 3) no cognitive problems, and 4) can speak and understand the local language. Pearson correlation was used to explore the association between EQ-5D utility and EQ-VAS score. Ordinary least squares regression and heteroscedastic Tobit regression models were adopted to analyze the EQ-VAS and EQ-5D utility data, respectively. RESULTS: The analysis included data from 1,004 responses (response rate = 65%). Around 52.7% of participants were female, 25.9% completed tertiary or above education, and 75.1% living with chronic disease. The mean EQ-5D utility and EQ-VAS score were 0.92 (SD = 0.13) and 72.27 (SD = 14.69), respectively. A significant association was found between EQ-5D utility and EQ-VAS score, with coefficients ranging from 0.335 (participants who divorced) to 0.744 (participants living alone). Around 98.5% reported having no problems with 'Self-care', followed by 'Usual activities' (96.3%), 'Mobility' (91.5%) and 'Anxiety/depression' (79.9%). The correlation between EQ-VAS score and EQ-5D utility was positive for each dimension of the EQ-5D instrument (correlation coefficients ranged between 0.211 and 0.623). Age strongly influenced the magnitude and trajectory of EQ-VAS score and utility, as observed in the changes. The regression model showed that 'Mobility', 'Pain/discomfort', and 'Anxiety/depression' have considerable influence on EQ-VAS score. CONCLUSIONS: This study compared the EQ-5D utility score and EQ-VAS in HK primary care setting. Although heterogeneity existed, the EQ-VAS and utility score are significantly correlated and reliable for evaluating health-related quality of life in this population.

PRH1 mediates ARF7-LBD dependent auxin signaling to regulate lateral root development in Arabidopsis thaliana.

The development of lateral roots in Arabidopsis thaliana is strongly dependent on signaling directed by the AUXIN RESPONSE FACTOR7 (ARF7), which in turn activates LATERAL ORGAN BOUNDARIES DOMAIN (LBD) transcription factors (LBD16, LBD18 and LBD29). Here, the product of PRH1, a PR-1 homolog annotated previously as encoding a pathogen-responsive protein, was identified as a target of ARF7-mediated auxin signaling and also as participating in the development of lateral roots. PRH1 was shown to be strongly induced by auxin treatment, and plants lacking a functional copy of PRH1 formed fewer lateral roots. The transcription of PRH1 was controlled by the binding of both ARF7 and LBDs to its promoter region.

Liver transplantation for Hepatocellular Carcinoma: A prognostic model incorporating pretransplant inflammatory cytokines.

PURPOSE: Liver transplantation (LT) remains an optimal treatment for selected hepatocellular carcinoma (HCC). Cytokines can be obtained by minimally invasive techniques and are associated with the development of HCC. The purpose of our investigation was to explore the prognostic value of pretransplant serum inflammatory cytokine profiles in HCC patients for LT. METHODS: We detected forty inflammatory cytokines in pre-LT serum from 42 HCC patients by using an inflammation-related antibody array. A pretransplant serum inflammatory cytokine-associated risk assessment model (pre-SCRAM) was developed and was validated in an external cohort of 213 HCC patients who underwent LT and were then followed prospectively. RESULTS: The pre-LT factors independently associated with recurrence-free survival (RFS) were as follows: B-lymphocyte chemoattractant (BLC), interleukin (IL)-12p40 and maximum tumor diameter. High IL-12P40 level was associated with a significantly smaller maximum tumor diameter (p = 0.021), decreased proportion of nodules ≥ 3 (p = 0.001), lower platelet counts (p = 0.011) and lower portal vein tumor thrombus (p = 0.031). Conversely, recipients with poor BLC level had higher alpha-fetoprotein (AFP) levels (p = 0.016). Kaplan-Meier analyses revealed that high pre-LT BLC or IL-12p40 level was associated with superior RFS. The pre-SCRAM stratified recipients into three risk groups: high risk, intermediate risk and low risk. In the validation cohort, for patients in the high, intermediate, and low risk groups, the 3-year RFS rates were 29.3%, 58.7%, and 82.2%, respectively, the 3-year HCC-specific survival rates were 54.5%, 73.8%, and 86%, respectively, and the 3-year overall survival rates were 44.4%, 60.9%, and 79.9%, respectively. The pre-SCRAM model performed well and remained significant in optimizing the risk stratification of recurrence in patients beyond the Milan criteria or the AFP model. CONCLUSION: Pretransplant cytokine profiles can provide powerful prognostic information in the setting of LT for HCC. A pre-LT risk model incorporating cytokines showed excellent efficiency in recurrence prediction for HCC patients, which could ultimately stratify the prognosis in patients beyond the Milan criteria or the AFP model.

Methylation site APC112043544 as a potential biomarker for post-transplant hepatocellular carcinoma recurrence.

Objective: To investigate the prognostic value of DNA methylation of tumor suppressor genes for hepatocellular carcinoma (HCC) recurrence after liver transplantation. Methods: APC gene was selected according to The Cancer Genome Atlas dataset. Tumor tissues and clinical data of 85 HCC patients who received a liver transplantation were retrospectively enrolled and next-generation methylation sequencing was performed. Risk factors were determined using the Cox proportional-hazard-regression model. Results: The APC methylation site (chromosome 5, position 112043544) was an independent predictor of post-transplant HCC recurrence. Patients with hyper-methylated APC112043544 experienced superior recurrence-free survival (p = 0.021) and had a decreased proportion of microvascular invasion (p = 0.017). APC112043544 also predicted recurrence risk in patients beyond selection criteria. Conclusions: APC112043544 methylation may serve as a potential biomarker for post-transplant HCC recurrence.

Neutrophil membrane-coated nanoparticles for enhanced nanosecond pulsed electric field treatment of pancreatic cancer.

OBJECTIVE: Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Poor prognosis and low survival rates have driven the development of novel therapeutic strategies. Nanosecond pulsed electric field has emerged as a novel, minimal invasive and non-thermal treatment for solid tumors. It is of great significance to study the combination therapy of nsPEF and other treatment strategies for pancreatic cancer. METHODS: We developed neutrophil membrane-wrapped liposomal nanoparticles loaded with gemcitabine (NE/Lip-GEM) and investigated their use as a complementary agent for nsPEF treatment. RESULTS: Our results showed that neutrophil-mediated delivery of liposomal-gemcitabine (NE/Lip-GEM) efficiently inhibited the growth of pancreatic tumors in mice whose has been treated with incomplete nsPEF ablation. CONCLUSIONS: The combination of nsPEF and NE/Lip-GEM may be a promising synergistic strategy for pancreatic cancer therapy.

The glycosyltransferase ST3GAL2 modulates virus proliferation and the inflammation response in porcine reproductive and respiratory syndrome virus infection.

ß-galactoside α-2,3-sialyltransferase 2 (ST3GAL2) is a member of the sialyltransferase family that mediates terminal modification of glycoproteins and glycolipids. ST3GAL2 has been found to play a role in obesity, aging, and malignant diseases. In this study, we cloned porcine ST3GAL2 (pST3GAL2) from porcine alveolar macrophages (PAMs), and its role in porcine reproductive and respiratory syndrome virus (PRRSV) infection was investigated by transcriptome analysis. pST3GAL2 was found to be located in the Golgi apparatus, and it was expressed at high levels in PRRSV-infected PAMs. Overexpression of pST3GAL2 resulted in a slight increase in PRRSV proliferation, and the interaction between pST3GAL2 and GP2a of PRRSV was detected by coimmunoprecipitation and confocal microscopy. The expression of pro-inflammatory cytokines (IFN-ß, IL-2, IL-6, IL-18, IL-1ß and TNF-α) was significantly inhibited in pST3GAL2-overexpressing, PRRSV-infected cells and upregulated in PRRSV-infected pST3GAL2-knockout cells, while the pattern of expression of anti-inflammatory cytokines (IL-4 and IL-10) was diametrically opposite. Our results demonstrate that the regulation of pST3GAL2 plays an important role in PRRSV proliferation and functional alterations in virus-infected cells. These results contribute to our understanding of the role of ß-galactoside α-2,3-sialyltransferase 2 in antiviral immunity.

Self-compassion and life-satisfaction among Chinese self-quarantined residents during COVID-19 pandemic: A moderated mediation model of positive coping and gender.

Concern for the psychological health of people affected by the COVID-19 pandemic is necessary. Previous studies suggested that self-compassion contributes to life-satisfaction. However, little is known about the mechanism underlying this relation. This study investigated the relationship between self-compassion and life-satisfaction among Chinese self-quarantined residents during the COVID-19 pandemic. Furthermore, we examined the mediating effect of positive coping and the moderating role of gender in this relation. Participants consist of 337 self-quarantined residents (129 men, 208 women) from a community in China, who completed measures of demographic information, Self-Compassion Scale, Satisfaction with Life Scale, and Simplified Coping Style Questionnaire. The results revealed that self-compassion was positively linked with life-satisfaction. Moreover, positive coping partially mediated the relationship between self-compassion and life-satisfaction for males and not females. In the female group, self-compassion was positively linked with positive coping and life-satisfaction; however, positive coping and life-satisfaction were not significantly linked. These findings indicated that intervention focus on self-compassion could increase life-satisfaction in self-quarantined people during the COVID-19, and self-compassion may contribute to life-satisfaction via positive coping only in the male.

Genetic polymorphisms of human hepatic OATPs: functional consequences and effect on drug pharmacokinetics.

1. Organic anion transporting polypeptides (OATPs) belong to the superfamily of solute carriers (SLC), which are important membrane transporters in animals and humans. Liver is an important organ for drug disposition. In human liver, three OATPs, namely OATP1B1, 1B3 and 2B1, are expressed on the basolateral membrane of hepatocytes.2. OATPs have multiple substrate specificity, mediating transport of a wide range of endo- and exogenous substances such as bile salts, bilirubin, hormones and their conjugates, toxins and various drugs. Therefore, they are important for drug disposition in human body. In this review, we compiled a complete list of the substrates for human hepatic OATPs.3. OATP genes have single-nucleotide polymorphisms (SNPs), which could lead to the alteration of their function, and thus might result in the change of pharmacokinetic properties for their substrate drugs. In this review, we summarized the genetic polymorphisms of the three hepatic OATPs and their effect on in vitro transport function and in vivo pharmacokinetics of substrate drugs.4. Finally, some concerns and perspectives on OATP polymorphism research are discussed.

[Research advancement in mechanisms of processing and compatibility for detoxication of Aconitums].

Aconitums,represented by Aconite Radix,Aconiti Lateralis Radix Praeparata and Aconiti Kusnezoffh Folium,is a kind of traditional Chinese medicine with a long medicinal history in China. They possess the significant toxicity and therapeutic effects simultaneously. Their potent effects of rescuing from dying,curing rheumatism,anti-inflammation,and analgesia make Aconitums highly regarded by physicians and pharmacists of various dynasties. However,countless poisoning cases caused by an irrational use of Aconitums were reported. In case of improper application and exceeding the therapeutic window,the acute cardiotoxicity and neurotoxicity would be caused,seriously threatening health and even life of the users. Therefore,the clinical application of Aconitums is limited to some extent. To avoid its toxicity and ensure the safety of medicinal use,Aconitums is usually used in a form of its processed products instead of the crude herbs,or combined with some other traditional Chinese medicines in a normal prescription. A proper processing and compatibility method can detoxicate its severe toxicity,reduce the adverse reactions,and also significantly broaden the indications and application range of Aconitums. This provides a guarantee for the secondary exploitation and utilization of Aconitums. In this paper,the traditional processing methods of Aconitums,along with the modern advancement were reviewed,and the mechanisms of detoxification by processing and compatibility were also illuminated. The physical detoxification mode and chemical detoxification mode were found as two main detoxification ways for Aconitums. In particular,the detoxification by hydrolysis,ion-pair,and saponification were three main means. The mechanisms illustrated in this paper can be a reference to the development of modern processing method and a guidance for appropriate use of Aconitums in clinical application.

NMR-based metabolomic analysis of spatial variation in soft corals.

Soft corals are common marine organisms that inhabit tropical and subtropical oceans. They are shown to be rich source of secondary metabolites with biological activities. In this work, soft corals from two geographical locations were investigated using ¹H-NMR spectroscopy coupled with multivariate statistical analysis at the metabolic level. A partial least-squares discriminant analysis showed clear separation among extracts of soft corals grown in Sanya Bay and Weizhou Island. The specific markers that contributed to discrimination between soft corals in two origins belonged to terpenes, sterols and N-containing compounds. The satisfied precision of classification obtained indicates this approach using combined ¹H-NMR and chemometrics is effective to discriminate soft corals collected in different geographical locations. The results revealed that metabolites of soft corals evidently depended on living environmental condition, which would provide valuable information for further relevant coastal marine environment evaluation.

Out-of-Hospital Cardiac Arrest Before and During the COVID-19 Pandemic in Hong Kong: Registry-Based Study From 2017 to 2023.

BACKGROUND: The COVID-19 pandemic has exerted a significant toll on individual health and the efficacy of health care systems. However, the influence of COVID-19 on the frequency and outcomes of out-of-hospital cardiac arrest (OHCA) within the Chinese population, both before and throughout the entire pandemic period, remains to be clarified. OBJECTIVE: This study aimed to fill the gaps by investigating the prevalence and outcomes of OHCA in Hong Kong (HK) both before and during the whole pandemic period. METHODS: This is a retrospective regional registry study. The researchers matched OHCA data with COVID-19-confirmed case records between December 2017 and May 2023. The data included information on response times, location of OHCA, witness presence, initial rhythm, bystander cardiopulmonary resuscitation (CPR), use of public-access defibrillation, resuscitation in the accident and emergency department, and survival to admission. Descriptive analyses were conducted, and statistical tests such as analysis of variance and χ2 were used to examine differences between variables. The incidence of OHCA and survival rates were calculated, and logistic regression analysis was performed to assess associations. The prevalence of OHCA and COVID-19 during the peak of the pandemic was also described. RESULTS: A total of 43,882 cases of OHCA were reported in HK and included in our analysis. Around 13,946 cases were recorded during the prepandemic period (2017-2019), and the remaining 29,936 cases were reported during the pandemic period (2020-2023). During the pandemic period, the proportion of female patients increased to 44.1% (13,215/29,936), and the average age increased slightly to 76.5 (SD 18.5) years. The majority of OHCAs (n=18,143, 61.1% cases) occurred at home. A witness was present in 45.9% (n=10,723) of the cases, and bystander CPR was initiated in 44.6% (n=13,318) of the cases. There was a significant increase in OHCA incidence, with a corresponding decrease in survival rates compared to the prepandemic period. The location of OHCA shifted, with a decrease in incidents in public places and a potential increase in incidents at home. We found that CPR (odds ratio 1.48, 95% CI 1.17-1.86) and public-access defibrillation (odds ratio 1.16, 95% CI 1.05-1.28) were significantly associated with a high survival to admission rate during the pandemic period. There was a correlation between the development of OHCA and the prevalence of COVID-19 in HK. CONCLUSIONS: The COVID-19 pandemic has had a significant impact on OHCA in HK, resulting in increased incidence and decreased survival rates. The findings highlight the importance of addressing the indirect effects of the pandemic, such as increased stress levels and strain on health care systems, on OHCA outcomes. Strategies should be developed to improve OHCA prevention, emergency response systems, and health care services during public health emergencies to mitigate the impact on population health.

Catalytic Synthesis of (S)-CHBE by Directional Coupling and Immobilization of Carbonyl Reductase and Glucose Dehydrogenase.

Ethyl (S)-4-chloro-3-hydroxybutyrate ((S)-CHBE) is an important chiral intermediate in the synthesis of the cholesterol-lowering drug atorvastatin. Studying the use of SpyTag/SpyCatcher and SnoopTag/SnoopCatcher systems for the asymmetric reduction reaction and directed coupling coenzyme regeneration is practical for efficiently synthesizing (S)-CHBE. In this study, Spy and Snoop systems were used to construct a double-enzyme directed fixation system of carbonyl reductase (BsCR) and glucose dehydrogenase (BsGDH) for converting 4-chloroacetoacetate (COBE) to (S)-CHBE and achieving coenzyme regeneration. We discussed the enzymatic properties of the immobilized enzyme and the optimal catalytic conditions and reusability of the double-enzyme immobilization system. Compared to the free enzyme, the immobilized enzyme showed an improved optimal pH and temperature, maintaining higher relative activity across a wider range. The double-enzyme immobilization system was applied to catalyze the asymmetric reduction reaction of COBE, and the yield of (S)-CHBE reached 60.1% at 30 °C and pH 8.0. In addition, the double-enzyme immobilization system possessed better operational stability than the free enzyme, and maintained about 50% of the initial yield after six cycles. In summary, we show a simple and effective strategy for self-assembling SpyCatcher/SnoopCatcher and SpyTag/SnoopTag fusion proteins, which inspires building more cascade systems at the interface. It provides a new method for facilitating the rapid construction of in vitro immobilized multi-enzyme complexes from crude cell lysate.

Treatment of Rheumatoid Arthritis Based on the Inherent Bioactivity of Black Phosphorus Nanosheets.

Rheumatoid arthritis (RA) is an autoimmune disease that affects the living quality of patients, especially the elderly population. RA-related morbidity and mortality increase significantly with age, while current clinical drugs for RA are far from satisfactory and may have serious side effects. Therefore, the development of new drugs with higher biosafety and efficacy is demanding. Black phosphorus nanosheets (BPNSs) have been widely studied because of their excellent biocompatibility. Here, we focus on the inherent bioactivity of BPNSs, report the potential of BPNSs as a therapeutic drug for RA and elucidate the underlying therapeutic mechanism. We find that BPNSs inhibit autophagy at an early stage via the AMPK-mTOR pathway, switch the energy metabolic pathway to oxidative phosphorylation, increase intracellular ATP levels, suppress apoptosis, reduce inflammation and oxidative stress, and down-regulate senescence-associated secretory phenotype (SASP)-related genes in rheumatoid arthritis synovial fibroblasts (RA-SFs). Further, BPNSs induce the apoptosis of macrophages and promote their transition from the M1 to the M2 phenotype by regulating related cytokines. Significantly, the administration of BPNSs can alleviate key pathological features of RA in mice, revealing great therapeutic potential. This study provides a novel option for treating RA, with BPNSs emerging as a promising therapeutic candidate.

Engineering marine phospholipid nanoliposomes via glycerol-infused proliposomes: Mechanisms, strategies, and versatile applications in scalable food-grade nanoliposome production.

This study presents a novel approach using polyol-based proliposome to produce marine phospholipids nanoliposomes. Proliposomes were formulated by blending glycerol with phospholipids across varying mass ratios (2:1 to 1:10) at room temperature. Analysis employing polarized light microscopy, FTIR, and DSC revealed that glycerol disrupted the stacked acyl groups within phospholipids, lowering the phase transition temperature (Tm). Krill oil phospholipids (KOP) proliposomes exhibited superior performance in nanoliposomes formation, with a mean diameter of 125.60 ± 3.97 nm, attributed to the decreased Tm (-7.64 and 7.00 °C) compared to soybean phospholipids, along with a correspondingly higher absolute zeta potential (-39.77 ± 1.18 mV). The resulting KOP proliposomes demonstrated liposomes formation stability over six months and under various environmental stresses (dilution, thermal, ionic strength, pH), coupled with in vitro absorption exceeding 90 %. This investigation elucidates the mechanism behind glycerol-formulated proliposomes and proposes innovative strategies for scalable, solvent-free nanoliposome production with implications for functional foods and pharmaceutical applications.

PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically devastating pathogen that has evolved various strategies to evade innate immunity. Downregulation of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5 (MDA5), a receptor that senses viral RNA. In this study, the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed, and the detailed mechanisms were explored. We found that the interaction between P62 and MDA5 is enhanced due to two factors: the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2α and the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells. As a result of these modifications, the classic P62-mediated autophagy is triggered. Additionally, porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2 (CCT2), which is enhanced by PRRSV nsp3. This interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitination. In summary, enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways: the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2, leading to intense innate immune suppression. The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

MIIP downregulation drives colorectal cancer progression through inducing peri-cancerous adipose tissue browning.

BACKGROUND: The enrichment of peri-cancerous adipose tissue is a distinctive feature of colorectal cancer (CRC), accelerating disease progression and worsening prognosis. The communication between tumor cells and adjacent adipocytes plays a crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the mechanism of migration and invasion inhibitory protein (MIIP) downregulation in the remodeling of tumor cell-adipocyte communication and its role in promoting CRC. RESULTS: MIIP expression was found to be decreased in CRC tissues and closely associated with adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with MIIP-downregulated tumor supernatant exhibited aggravated browning and lipolysis. This finding was further confirmed in subcutaneously allografted mice co-injected with adipocytes and MIIP-downregulated murine CRC cells. Mechanistically, MIIP interacted with the critical lipid mobilization factor AZGP1 and regulated AZGP1's glycosylation status by interfering with its association with STT3A. MIIP downregulation promoted N-glycosylation and over-secretion of AZGP1 in tumor cells. Subsequently, AZGP1 induced adipocyte browning and lipolysis through the cAMP-PKA pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting CRC cell proliferation, invasion, and apoptosis resistance, accompanied by metabolic reprogramming. In a tumor-bearing mouse model, inhibition of ß-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in CRC with abnormal MIIP expression. CONCLUSIONS: Our data demonstrate that MIIP plays a regulatory role in the communication between CRC and neighboring adipose tissue by regulating AZGP1 N-glycosylation and secretion. MIIP reduction leads to AZGP1 oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of ß-adrenergic receptor or FFA uptake, combined with oxaliplatin, may represent a promising therapeutic strategy for CRC with aberrant MIIP expression.

Chemically engineered mTOR-nanoparticle blockers enhance antitumour efficacy.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. METHODS: Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. FINDINGS: Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. In vivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ+CD8+ T cells and CD8+ memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy. INTERPRETATION: The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents. FUNDING: This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).