TROP2 promotes PINK1-mediated mitophagy and apoptosis to accelerate the progression of senile chronic obstructive pulmonary disease by up-regulating DRP1 expression.

Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease characterised by irreversible airflow limitation. The elderly are a vulnerable population for developing COPD. With the growth of age, physiological degenerative changes occur in the thorax, bronchus, lung and vascular wall, which can lead to age-related physiological attenuation of lung function in the elderly, so the prevalence of COPD increases with age. Its pathogenesis has not yet been truly clarified. Mitophagy plays an important role in maintaining the stability of mitochondrial function and intracellular environment by scavenging damaged mitochondria. Currently, studies have shown that trophoblast antigen 2 (TROP2) expression is up-regulated in airway basal cells of patients with COPD, suggesting that TROP2 is involved in the progression of COPD. However, whether it is involved in disease progression by regulating mitochondrial function remains unclear. In this study, compared with non-smoking non-COPD patients, the expression of TROP2 in lung tissues of smoking non-COPD patients and patients with COPD increased, and TROP2 expression in patients with COPD was higher than that in smoking non-COPD patients. To further explore the role of TROP2, we stimulated BEAS-2B with cigarette smoke to construct an in vitro model. We found that TROP2 expression increased, whereas TROP2 silencing reversed the cigarette smoke extract-induced decrease in mitochondrial membrane potential, increased reactive oxygen species content, decreased adenosine triphosphate (ATP) production, increased inflammatory factor secretion and increased apoptosis. In addition, we searched online bioinformatics and screened the gene dynamin-related protein 1 (DRP1) related to mitophagy as the research object. Co-IP assay verified the binding relationship between DRP1 and TROP2. Further study found that TROP2 promoted mitophagy and apoptosis of BEAS-2B cells by up-regulating the expression of DRP1. In addition, PTEN-induced putative kinase 1 (PINK1) is a potential binding protein of DRP1, and DRP1 accelerated mitophagy and apoptosis of BEAS-2B cells by promoting the expression of PINK1. We established a COPD SD rat model by cigarette smoke exposure and LPS instillation and treated it by intraperitoneal injection of si-TROP2. The results showed that TROP2 silencing restored lung function and reduced the secretion of inflammatory factors in bronchoalveolar lavage fluid. In conclusion, TROP2 can be used as a new reference for COPD treatment.

HuR-positive stress granules: Potential targets for age-related osteoporosis.

Aging impairs osteoblast function and bone turnover, resulting in age-related bone degeneration. Stress granules (SGs) are membrane-less organelles that assemble in response to stress via the recruitment of RNA-binding proteins (RBPs), and have emerged as a novel mechanism in age-related diseases. Here, we identified HuR as a bone-related RBP that aggregated into SGs and facilitated osteogenesis during aging. HuR-positive SG formation increased during osteoblast differentiation, and HuR overexpression mitigated the reduction in SG formation observed in senescent osteoblasts. Moreover, HuR positively regulated the mRNA stability and expression of its target ß-catenin by binding and recruiting ß-catenin into SGs. As a potential therapeutic target, HuR activator apigenin (API) enhanced its expression and thus aided osteoblasts differentiation. API treatment increased HuR nuclear export, enhanced the recruitment of ß-catenin into HuR-positive SGs, facilitated ß-catenin nuclear translocation, and contributed osteogenesis. Our findings highlight the roles of HuR and its SGs in promoting osteogenesis during skeletal aging and lay the groundwork for novel therapeutic strategies against age-related skeletal disorders.

Engineering CAR-NK cell derived exosome disguised nano-bombs for enhanced HER2 positive breast cancer brain metastasis therapy.

HER2-positive breast cancer brain metastasis (HER2+ BCBM) is a refractory malignancy with a high recurrence rate and poor prognosis. The efficacies of conventional treatments, including radiation and the FDA-approved drug trastuzumab, are compromised due to their significant obstacles, such as limited penetration through the blood-brain barrier (BBB), off-target effects on HER2+ tumor cells, and systemic adverse reactions, ultimately resulting in suboptimal therapeutic outcomes. In order to address these challenges, a novel biomimetic nanoplatform was created, which consisted of a combination of chimeric antigen receptor-natural killer (CAR-NK) cell-derived exosomes (ExoCAR), and a nanobomb (referred to as Micelle). This nanoplatform, known as ExoCAR/T7@Micelle, was designed to enhance the effectiveness of antitumor treatment by disrupting ferroptosis defense mechanisms. Due to the transferrin receptor binding peptide (T7) modification and CAR expression on the exosome surface, the nanoplatform successfully traversed the blood-brain barrier and selectively targeted HER2+ breast cancer cells. Moreover, integration of the reactive oxygen species (ROS) -amplified and photodynamic therapy (PDT)-based nanobomb facilitated the spatiotemporal release of the cargos at specific sites. Upon systemic administration of ExoCAR/T7@Micelle, mice with orthotopic HER2+ BCBM demonstrated a robust antitumor response in vivo, leading to a significant extension in survival time. Furthermore, histological analyses and blood index studies revealed no discernible side effects. Collectively, this study is the first to indicate the possibility of HER2+ BCBM therapy with a CAR-NK cell-derived biomimetic drug delivery system.

A novel recombinant ORF7-siRNA delivered by flexible nano-liposomes inhibits varicella zoster virus infection.

BACKGROUND: Varicella zoster virus (VZV), which is a human restricted alpha-herpesvirus, causes varicella (chickenpox) and zoster (shingles). The subsequent post-herpetic neuralgia (PHN) due to VZV infection is excruciating for most patients. Thus, developing specific therapeutics against VZV infection is imperative. RNA interference (RNAi) represents an effective approach for alternative antiviral therapy. This study aimed to develop a novel anti-VZV therapeutics based on RNAi. RESULTS: In this study, we screened and found the open reading frame 7 (ORF7) of the VZV genome was an ideal antiviral target based on RNAi. Therefore, a novel siRNA targeting ORF7 (si-ORF7) was designed to explore the potential of RNAi antiviral treatment strategy toward VZV. We used a bio-engineering approach to manufacture recombinant siRNA agents with high yield in E. coli. Then, the efficacy of recombinant ORF7-siRNA (r/si-ORF7) in inhibiting VZV infection both in cellular level and 3D human epidermal skin model was evaluated. The r/si-ORF7 was proved to inhibit the VZV replication and reduce the virus copy numbers significantly in vitro. Furthermore, flexible nano-liposomes were established to deliver r/si-ORF7 to 3D human epidermal skin model and found r/si-ORF7 also could inhibit the VZV infection, thus maintaining normal skin morphology. CONCLUSIONS: Taken together, our results highlighted that transdermal administration of antiviral r/si-ORF7 was a promising therapeutic strategy for functional cure of VZV infection.

Co-Polymer Carrier with Dual Advantages of Cartilage-Penetrating and Targeting Improves Delivery and Efficacy of MicroRNA Treatment of Osteoarthritis.

Osteoarthritis (OA) is a debilitating joint disease affecting nearly 400 million people with no efficient etiological therapies. OA is primarily identified by cartilage destruction, and gradual degeneration of the whole joint would happen when the OA progresses. Hence, cartilage has been identified as the primary therapeutic target of OA. Unfortunately, numerous barriers block the delivery of therapeutic agents into cartilage, including avascular traits and high hardness of the extracellular matrix. Herein, a cartilage-targeting peptide (CAP) modified polyvinylamine (PVAm)- poly (lactic-co-glycolic acid) (PLGA) copolymer (CAP-PVAm-PLGA) is designed, which can form spherical nanoparticles with the r-miR-140 (CPP-NPs). CPP-NPs possessed enhanced mechanical properties due to the introduction of PLGA to vehicles. Meanwhile, CAP endowed the cartilage targeting which facilitated CPP-NPs localization in cartilage. With such dual advantages, CPP-NPs exhibited outstanding penetrability and accumulation in cartilage even subchondral bone, and can penetrate to a depth of 1000 µm into human cartilage. The degeneration area of cartilage is reduced by 65% and synovial inflammation score by 80% in OA mice, and the microarchitecture of subchondral bone is also ameliorated. These studies established a promising platform for therapeutic RNA delivery in OA therapy that overcame the cartilage barriers.

A lipid-polymer hybrid nanoparticle (LPN)-loaded dissolving microneedle patch for promoting hair regrowth by transdermal miR-218 delivery.

Alopecia is the most common multifactorial hair loss disorder, affecting almost 50% of the population and even having a serious psychological impact on the patients. miR-218 has therapeutic potential for alopecia since it can activate the Wnt/ß-catenin channel by down-regulating SFRP2, which is a key channel in hair follicle cycle transformation for hair regrowth. Although miR-218 has the potential to treat this disease, several barrier properties of the skin challenge miRNA's delivery to the target location, such as passing through the corneum and resistant enzymatic degradation. To address these challenges, we evaluated a device that combined the use of hyaluronic acid (HA)-based dissolving microneedle (MN) to enhance corneum permeability with the lipid polymer hybrid nanoparticles (LPNs) as a miRNA delivery carrier to protect miR-218 from degradation. The MN patches could promote LPNs/miR-218 diffusing in the dermis region, and significantly increase the bioavailability of miR-218. Furthermore, in the shaved mouse model, the MN patches showed higher efficacy in promoting hair growth than the topical smear treatment, while avoiding the safety concern. This work established a novel and effective combination device with MN and LPNs that can be used for localized transdermal miRNA delivery to promote hair regrowth.

Flexible nano-liposomes-based transdermal hydrogel for targeted delivery of dexamethasone for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that can lead to synovitis, cartilage destruction, and even joint damage. Dexamethasone (DEX) is a commonly used agent for RA therapy on inflammation manage. However, the traditional administering DEX is hampered by low efficiency and obvious adverse effects. Therefore, in order to efficiently deliver DEX to RA inflamed joints and overcome existing deficiencies, we developed transdermal formation dextran sulfate (DS) modified DEX-loaded flexible liposome hydrogel (DS-FLs/DEX hydrogel), validated their transdermal efficiency, evaluated its ability to target activated macrophages, and its anti-inflammatory effect. The DS-FLs/DEX exhibited excellent biocompatibility, sustainable drug release, and high uptake by lipopolysaccharide (LPS)-activated macrophages. Furthermore, the DS-FLs/DEX hydrogel showed desired skin permeation as compared with regular liposome hydrogel (DS-RLs/DEX hydrogel) due to its good deformability. In vivo, when used the AIA rats as RA model, the DS-FLs/DEX hydrogel can effectively penetrate and accumulate in inflamed joints, significantly improve joint swelling in RA rats, and reduce the destructive effect of RA on bone. Importantly, the expression of inflammatory cytokines in joints was inhibited and the system toxicity did not activate under DS-FLs/DEX hydrogel treatment. Overall, these data revealed that the dextran sulfate (DS) modified DEX-loaded flexible liposome hydrogel (DS-FLs/DEX hydrogel) can prove to be an excellent drug delivery vehicle against RA.

Pulmonary toxicity in driver gene positive non-small cell lung cancer therapy.

Molecular targeted therapy significantly improved the therapeutic efficacy in non-small cell lung cancer (NSCLC) patients with driver gene mutations but also with new toxicity profiles. Although most patients treated with these drugs developed relatively controllable toxicity, significant pulmonary toxicity events, including interstitial lung disease, occurred in a small proportion of patients and can lead to discontinuation or even be life-threatening. Pulmonary toxicity associated with these anti-tumor drugs is a problem that cannot be ignored in clinical practice. The prompt diagnosis of drug-related lung injury and the consequent differential diagnosis with other forms of pulmonary disease are critical in the management of pulmonary toxicity. Current knowledge of the pathophysiology and management of pulmonary toxicity associated with these targeted drugs is limited, and participants should be able to identify and respond to the development of drug-induced pulmonary toxicity. This review offers information about the potential pathogenesis, risk factors and management for the development of these events based on the available literature. This review focused on pulmonary toxicities in driver gene-positive NSCLC therapy by describing the related adverse events to promote the awareness and management of this important toxicity related to antitumor-targeted therapy.

Polyvinylamine with moderate binding affinity as a highly effective vehicle for RNA delivery.

Polymeric carriers for RNA therapy offer potential advantages in terms of low immunogenicity, promoting modifiability and accelerating intracellular transport. However, balancing high transfection efficacy with low toxicity remains challenging with polymer-based vehicles; indeed, polyethyleneimine (PEI) remains the "gold standard" polymer for this purpose despite its significant toxicity limitations. Herein, we demonstrate the potential of polyvinylamine (PVAm), a commodity high-charge cationic polymer used in the papermaking industry and has similar structure with PEI, as an alternative carrier for RNA delivery. High levels of transfection of normal, tumor, and stem cells with a variety of RNA cargoes including small interfering RNA (siRNA), microRNA (miRNA), and recombinant RNA can be achieved in vitro under the proper complex conditions. While, both the anti-tumor effect achieved in a xenograft osteosarcoma model and lipid-lowering activity observed in a hyperlipidemia mice indicate the potential for highly effective in vivo activity. Of note, both the transfection efficiency and the cytotoxicity of PVAm compare more favorably with those of PEI, with PVAm offering the additional advantages of simpler purification and significantly lower cost. In addition, the mechanism for the difference in transfection efficiency between PVAm and PEI is explored by molecular docking as well as analyzing the process of association and dissociation between polymers (PVAm and PEI) and nucleic acids. Our research provides a novel, non-toxic, and cost-effective carrier candidate for next generation RNA therapy, and elucidates the potential mechanism of PVAm for its efficient delivery of RNA.

Bergamottin promotes osteoblast differentiation and bone formation via activating the Wnt/ß-catenin signaling pathway.

Osteoporosis is one of the most common bone disorders that seriously affect the health and life quality of elderly individuals. Reduced osteoblast differentiation and bone formation lead to changes in bone volume and microarchitecture, leaving the bones vulnerable to fracture. Bergamottin (BM) is a natural compound derived from various citrus fruits and possesses multiple biological activities including anti-adipogenesis function. This study aimed to evaluate the effects of BM on osteoblast differentiation and its potential anti-osteoporosis capacity, as well as to explore the underlying mechanism. We demonstrated that BM, as a positive regulator for osteogenesis, significantly promoted osteoblast differentiation and bone formation. Mechanically, BM activated the Wnt/ß-catenin signaling pathway and promoted the nuclear translocation of ß-catenin. In addition, BM dramatically upregulated the expression of ß-catenin, enhanced the transcriptional activation of T cell factor 7 (TCF7), and increased the expression of Runt-related transcription factor 2 (Runx2). Taken together, this study revealed that BM enhanced osteoblast differentiation and attenuated ovariectomy (OVX)-induced bone loss, possessing the potential to be developed into a food ingredient or supplement for preventing osteoporosis.

Association of serum vitamin C with liver fibrosis in adults with nonalcoholic fatty liver disease.

OBJECTIVE: This study aimed to investigate the association between serum vitamin C and liver fibrosis in patients with NAFLD in the US adults. METHODS: We conducted a cross-sectional analysis of data from the 2017 to 2018 cycle of National Health and Nutrition Examination Survey (NHANES). Serum vitamin C and transient elastography (TE)-accessed liver stiffness was taken as independent and dependent variables, respectively. Liver steatosis and fibrosis were detected by controlling attenuation parameter (CAP) and TE. NAFLD was defined by a CAP score of ≥248 dB/m without any indication of other causes of chronic liver disease. The median liver stiffness of ≥8.2 kPa was used to identify significant fibrosis (≥F2) among NAFLD patients. We calculated the adjusted odds ratio (OR) and 95% confidential intervals (CIs) for associations with significant NAFLD fibrosis using multivariable logistic regression models. RESULTS: Overall, 1926 individuals with NAFLD were included in the analysis and 267 subjects met the definition of significant fibrosis. Serum vitamin C was associated with lower odds of liver fibrosis in NAFLD after adjusting for potential confounders (OR = 0.60, 95% CI, 0.43-0.84), while in the subgroup analysis stratified by gender and body mass index (BMI), this association showed a difference after adjusting for confounders (males: OR = 0.43, 95% CI, 0.26-0.71; females: OR = 0.78, 95% CI, 0.49-1.24). There were no significant associations of serum vitamin C with liver fibrosis in NAFLD with underweight or normal (OR = 1.34, 95% CI, 0.19-9.34). CONCLUSIONS: This cross-sectional study indicated an association of serum vitamin C with significant fibrosis in men and overweight or obese patients with NAFLD.

Unmet health needs and associated factors among 1727 rural community-dwelling older adults: A cross-sectional study.

AIM: To investigate the needed, unneeded and unmet health care services among rural community-dwelling older adults in China and examine the influencing factors, aiming to facilitate the global development of the home care system for a healthier world. METHODS: This cross-sectional study investigated rural areas in three provinces in Western China. A total of 1727 rural community-dwelling older adults were enrolled. The needed, unneeded and unmet health care services were assessed by the Supply and Demand of Health Care Services (SD-HCS) questionnaire for older adults. RESULTS: Respect (73%, 1265/1727) was the most needed. The other top 9 needed mainly belonged to the divisions of health monitoring and information regarding chronic diseases. Re-employment or part-time jobs (71%, 1230/1727) was the most unneeded. All five protection and safety items were the most unmet but needed. Religion was the main influencing factor of those health care services that were less unmet but needed. CONCLUSIONS: Respect was basic for older adults, and chronic disease management was in great demand among rural community-dwelling older adults. Due to low willingness and the crisis workforce, a more flexible retirement policy is needed in rural China. It is urgent to improve the emergency care system in rural areas. Last but not least, more research is needed to explore the association between religion and health.

Long noncoding RNA AK039312 and AK079370 inhibits bone formation via miR-199b-5p.

Osteoporosis caused by aging and menopause had become an emerging threat to human health. The reduction of osteoblast differentiation has been considered to be an essential cause of osteoporosis. Osteoblast differentiation could be regulated by LncRNAs, and increasing evidences have proved that LncRNAs may be adopted as potential therapeutic targets for osteoporosis. However, reports on rescue effects of LncRNAs in vivo are relatively limited. In this study, two LncRNAs (AK039312 and AK079370) were screened as osteogenic related LncRNAs. Both AK039312 and AK079370 could inhibit osteoblast differentiation and bone formation through suppressing osteogenic transcription factors. This inhibitory effect was achieved via binding and sequestering miR-199b-5p, and enhanced GSK-3ß which further inhibited wnt/ß-catenin pathway. Moreover, the siRNAs of AK039312 and AK079370 significantly alleviated postmenopausal osteoporosis, and the combination of si-AK039312 and si-AK079370 was more efficient than applying one si-LncRNA alone. This study has provided new insights for the therapy of osteoporosis.

miR-129-5p Inhibits Bone Formation Through TCF4.

Osteoporosis is a frequently occurring bone disease in middle-aged and aged men and women. However, current therapies on this disease are still not ideal. MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNA with a length of 18-25 nucleotides. miRNAs have been identified as important regulators for development, metabolism, carcinogenesis, and bone formation. miR-129-5p has been reported as a regulator of cancer and neuroscience, whereas studies about its function on bone formation is still limited. In this study, we investigated the function and mechanism of miR-129-5p on osteoblast differentiation and bone formation. We have assessed the expression of miRNAs in bone mesenchymal stem cells from aging and menopause osteoporosis C57BL6 mice. The expression of miR-129-5p was altered in all osteoporosis models. Besides, the expression of miR-129-5p was negatively correlated with osteoblastic differentiation markers in the femur tissues of C57BL/6 mice of different ages. We further demonstrated that overexpression of miR-129-5p inhibited osteoblast differentiation in MC3T3-E1 cell line, as well as bone formation of C57BL/6 mice. On the other hand, down-regulation of miR-129-5p enhanced osteoblast differentiation and bone formation. We also found that miR-129-5p inhibited Wnt/ß-catenin pathway in osteoblast. The target gene of miR-129-5p has been forecasted and proved as Tcf4. We further found that plasmid containing Tcf4-3' UTR sequence enhanced osteoblast differentiation, as well as Wnt/ß-catenin pathway in MC3T3-E1 cells. To further investigate the rescue effect of miR-129-5p inhibitor, we manufactured bioengineered novel recombinant miR-129-5p inhibitor through Escherichia coli system and then tested its function. The results showed that the novel recombinant miR-129-5p inhibitor promoted osteoblast differentiation and greatly ameliorated menopause osteoporosis in C57BL6 mice. In conclusion, we have discovered miR-129-5p as an inhibitor of bone formation. miR-129-5p inhibited downstream transcription factors of Wnt/ß-catenin pathway through targeting Tcf4. Moreover, novel recombinant miR-129-5p inhibitor showed rescue effect on osteoporosis. This study has revealed a new mechanism of osteogenic differentiation and provided novel therapeutic strategies for treatment of skeletal disorders.

Silencing of lncRNA AK045490 Promotes Osteoblast Differentiation and Bone Formation via ß-Catenin/TCF1/Runx2 Signaling Axis.

Osteoporosis, a disease characterized by both loss of bone mass and structural deterioration of bone, is the most common reason for a broken bone among the elderly. It is known that the attenuated differentiation ability of osteogenic cells has been regarded as one of the greatest contributors to age-related bone formation reduction. However, the effects of current therapies are still unsatisfactory. In this study we identify a novel long noncoding RNA AK045490 which is correlated with osteogenic differentiation and enriched in skeletal tissues of mice. In vitro analysis of bone-derived mesenchymal stem cells (BMSCs) showed that AK045490 inhibited osteoblast differentiation. In vivo inhibition of AK045490 by its small interfering RNA rescued bone formation in ovariectomized osteoporosis mice model. Mechanistically, AK045490 inhibited the nuclear translocation of ß-catenin and downregulated the expression of TCF1, LEF1, and Runx2. The results suggest that Lnc-AK045490 suppresses ß-catenin/TCF1/Runx2 signaling and inhibits osteoblast differentiation and bone formation, providing a novel mechanism of osteogenic differentiation and a potential drug target for osteoporosis.

[Living Arrangement Intentions of the Elderly and Its Influencing Factors in Western China].

BACKGROUND: China is the country with the largest population of elderly, accounting for more than 17.3% of the total population. The arrival of the so-called "silver wave" has generally reduced the abilities of daily life of the elderly and has continued to increase endowment pressures. Assisting the elderly in China to age successfully is an urgent problem. PURPOSE: To understand the living arrangement intentions of the elderly in Western China and to provide a reference for the reformation of the social endowment service system. METHODS: A self-designed questionnaire and Barthel self-care ability scale were conducted on 2,078 elderly people living in Guangxi and Ningxia Provinces in China. RESULTS: A total of 1,634 participants (78.6%) chose home-based care, 187 (9.0%) chose community care, and 257 (12.3%) chose institutional care. Differences in age, ethnic group, household registration, education level, family monthly income, family income and expenditure situation, and religion all significantly affected living arrangement intention (all p < .05). Logistic regression showed that age, ethnicity, household registration, religion, marital status, family monthly income, and length of hospital stay were all primary factors of influence on the home care intention of the elderly people (all p < .05). CONCLUSIONS: A significant majority of the elderly in this study expressed an intention to choose home-based care. It will be necessary to build a home-based mode of care that incorporates medical-care functions. In addition, the health service functions of community and institutions should be improved and perfected, as the intention to live in these settings is also growing. Appropriate services should be provided to meet the living arrangement intentions of the elderly in order to start a new era of elderly care customization. Finally, the development and expansion of "Internet Plus" should be leveraged to build a social endowment service system that meets the comprehensive range of elderly-care needs.

Effects of penehyclidine hydrochloride on severe acute pancreatitis-associated acute lung injury in rats.

Penehyclidine hydrochloride (PHC) is a selective M1 and M3 receptor antagonist. This study was designed to investigate the effect of PHC on acute lung injury (ALI) induced by severe acute pancreatitis (SAP) and the expression of hypoxia-inducible factor-1α (HIF-1α) in rats. A total of 45 healthy adult male SD rats were randomly divided into 3 groups: an S group, sham operation; an ALI group, pancreatitis-associated acute lung injury (PALI); and a P group, PALI treated with PHC. Rats from the ALI and P groups were used to establish a model of acute lung injury associated with SAP by retrograde injection of 4% sodium taurocholate into the biliopancreatic duct. Rats in the P group, reflecting acute lung injury caused by SAP, were treated with PHC immediately following SAP. Rats in the S and ALI groups were injected with the same amount of 0.9% sodium chloride solution. After modeling, the rats were sacrificed at 12h. The wet/dry weight (W/D) ratios of lung tissue were calculated. Pathological changes in pancreatic and lung tissues were scored. The expression levels of TLR4 and NF-κB p65 in lung tissue were detected by Western blot. RT-PCR was used to detect HIF-1α mRNA in lung tissue. The HIF-1α, IL-1ß, and IL-6 expression levels in lung tissues and serum amylase levels were detected by ELISA. The results showed extensive infiltration of neutrophils, alveolar hemorrhage and necrosis and fat necrosis in the pancreatic tissue of rats in the PALI and P groups. Their pancreatic tissue injury scores were significantly higher than the score of the S group (P<0.01). However, no statistically significant difference was observed in the serum amylase levels of the P and ALI groups (P>0.05). The W/D ratios of lung tissue in the ALI and P group rats were significantly higher than those in the S group (P<0.05). Compared with those of the ALI group rats, the lung tissue pathological changes of the P group were significantly improved, and the lung W/D value was significantly lower than that of the ALI group (P<0.05). Compared with those of the S group, the TLR4, NF-κB p65, HIF-1α mRNA, and HIF-1α expression levels in the lung tissue of the ALI and P groups were significantly higher (P<0.01), and the TLR4, NF-κB p65, HIF-1α mRNA, HIF-1α, IL-1ß and IL-6 expression levels in the P group were significantly lower than those in the ALI group (P<0.05). The current work indicates that PHC could not alleviate the damage to pancreatic tissue caused by SAP. However, PHC did suppress HIF-1α, IL-1ß and IL-6 expression levels and reduced the acute lung injury induced by SAP in rats, which might depend on suppression of the expression of inflammatory factors, such as HIF-1α.

Specific alterations in gut microbiota are associated with prognosis of Budd-Chiari syndrome.

Gut microbiota is associated with liver diseases. However, gut microbial characteristics of Budd-Chiari syndrome (B-CS) have not been reported. Here, by MiSeq sequencing, gut microbial alterations were characterized among 37 health controls, 20 liver cirrhosis (LC) patients, 31 initial B-CS patients (B-CS group), 33 stability patients after BCS treatment (stability group) and 23 recurrent patients after BCS treatment (recurrence group). Gut microbial diversity was increased in B-CS versus LC. Bacterial community of B-CS clustered with controls but separated from LC. Operational taxonomic units (OTUs) 421, 502 (Clostridium IV) and 141 (Megasphaera) were unique to B-CS. Genera Escherichia/Shigella and Clostridium XI were decreased in B-CS versus controls. Moreover, nine genera, mainly including Bacteroides and Megamonas, were enriched in B-CS versus LC. Notably, Megamonas could distinguish B-CS from LC with areas under the curve (AUCs) of 0.7904. Microbial function prediction revealed that L-amino acid transport system activity was decreased in B-CS versus both LC and controls. Furthermore, OTUs 27 (Clostridium XI), 137 (Clostridium XIVb) and 40 (Bacteroides) were associated with B-CS stability. Importantly, genus Clostridium XI was enriched in stability group versus both recurrence group and B-CS group. Also, PRPP glutamine biosynthesis was reduced in stability group versus recurrence group, but was enriched in stability group versus B-CS group. In conclusion, specific microbial alterations associated with diagnosis and prognosis were detected in B-CS patients. Correction of gut microbial alterations may be a potential strategy for B-CS prevention and treatment.

Bone metastasis target redox-responsive micell for the treatment of lung cancer bone metastasis and anti-bone resorption.

In order to inhibit the growth of lung cancer bone metastasis and reduce the bone resorption at bone metastasis sites, a bone metastasis target micelle DOX@DBMs-ALN was prepared. The size and the zeta potential of DOX@DBNs-ALN were about 60 nm and -15 mV, respectively. DOX@DBMs-ALN exhibited high binding affinity with hydroxyapatite and released DOX in redox-responsive manner. DOX@DBMs-ALN was effectively up taken by A549 cells and delivered DOX to the nucleus of A549 cells, which resulted in strong cytotoxicity on A549 cells. The in vivo experimental results indicated that DOX@DBMs-ALN specifically delivered DOX to bone metastasis site and obviously prolonged the retention time of DOX in bone metastasis site. Moreover, DOX@DBMs-ALN not only significantly inhibited the growth of bone metastasis tumour but also obviously reduced the bone resorption at bone metastasis sites without causing marked systemic toxicity. Thus, DOX@DBMs-ALN has great potential in the treatment of lung cancer bone metastasis.

Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells.

Ferroptosis is a novel form of cell death, which is characterized by accumulation of reactive oxygen species (ROS). Sigma 1 receptor (S1R) has been suggested to function in oxidative stress metabolism. Both erastin and sorafenib significantly induced S1R protein expression. Haloperidol strongly promoted erastin- and sorafenib-induced cell death, which was blocked by ferrostatin-1 but not ZVAD-FMK or necrosulfonamide. During ferroptosis, haloperidol substantially increased the cellular levels of Fe2+, GSH and lipid peroxidation. Furthermore, several ferroptosis-related protein targets were up-regulated in the absence of haloperidol. Thus, Our study identified an association between haloperidol and ferroptosis for the first time. Our analyses of a combination of drugs may provide a novel strategy of hepatocellular carcinoma (HCC) therapy.