Micronanoparticled risedronate exhibits potent vaccine adjuvant effects.

Micro/Nano-scale particles are widely used as vaccine adjuvants to enhance immune response and improve antigen stability. While aluminum salt is one of the most common adjuvants approved for human use, its immunostimulatory capacity is suboptimal. In this study, we modified risedronate, an immunostimulant and anti-osteoporotic drug, to create zinc salt particle-based risedronate (Zn-RS), also termed particulate risedronate. Compared to soluble risedronate, micronanoparticled Zn-RS adjuvant demonstrated increased recruitment of innate cells, enhanced antigen uptake locally, and a similar antigen depot effect as aluminum salt. Furthermore, Zn-RS adjuvant directly and quickly stimulated immune cells, accelerated the formulation of germinal centers in lymph nodes, and facilitated the rapid production of antibodies. Importantly, Zn-RS adjuvant exhibited superior performance in both young and aged mice, effectively protecting against respiratory diseases such as SARS-CoV-2 challenge. Consequently, particulate risedronate showed great potential as an immune-enhancing vaccine adjuvant, particularly beneficial for vaccines targeting the susceptible elderly.

[Comprehensive identification of metabolites and metabolic characteristics of luteolin and kaempferol in Simiao Yong'an Decoction in rats by UHPLC-LTQ-Orbitrap MS/MS].

Simiao Yong'an Decoction is a classic prescription for treating gangrene. Modern medical evidence has proven that Si-miao Yong'an Decoction has therapeutic effects on atherosclerosis(AS), vascular occlusion angeitides, and hypertension, while its pharmacodynamic mechanism remains unclear. The evidence of network pharmacology, molecular docking, literature review, and our previous study suggests that luteolin and kaempferol are two major flavonoids in Simiao Yong'an Decoction and can inhibit macrophage inflammation and exert anti-AS effects. However, due to lack of the metabolism studies in vivo, little is known about the metabolic characteristics of luteolin and kaempferol. This study employed ultra-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry(UHPLC-LTQ-Orbitrap MS/MS) and relevant software to identify the metabolites and metabolic pathways of luteolin and kaempferol in rat plasma, urine, and feces, after oral administration of luteolin and kaempferol, respectively. After the administration of luteolin, 10, 11, and 3 metabolites of luteolin were detected in the plasma, urine, and feces, respectively. After the administration of kaempferol, 9, 3, and 1 metabolites of kaempferol were detected in the plasma, urine, and feces, respectively. The metabolic pathways mainly involved methylation, glucuronidation, and sulfation. This study enriches the knowledge about the pharmacological mechanism of luteolin and kaempferol and supplies a reference for revealing the metabolic process of other flavonoids in Simiao Yong'an Decoction, which is of great significance for elucidating the pharmacological effects and effective substances of this decoction in vivo.

Treatment Outcomes in COVID-19 Patients with Brucellosis: Case Series in Heilongjiang and Systematic Review of Literature.

Objective: Clinical characteristics and outcome in COVID-19 with brucellosis patients has not been well demonstrated, we tried to analyze clinical outcome in local and literature COVID-19 cases with brucellosis before and after recovery. Methods: We retrospectively collected hospitalization data of comorbid patients and prospectively followed up after discharge in Heilongjiang Infectious Disease Hospital from January 15, 2020 to April 29, 2022. Demographics, epidemiological, clinical symptoms, radiological and laboratory data, treatment medicines and outcomes, and follow up were analyzed, and findings of a systematic review were demonstrated. Results: A total of four COVID-19 with brucellosis patients were included. One patient had active brucellosis before covid and 3 patients had nonactive brucellosis before brucellosis. The median age was 54.5 years, and all were males (100.0%). Two cases (50.0%) were moderate, and one was mild and asymptomatic, respectively. Three cases (75.0%) had at least one comorbidity (brucellosis excluded). All 4 patients were found in COVID-19 nucleic acid screening. Case C and D had only headache and fever on admission, respectively. Four cases were treated with Traditional Chinese medicine, western medicines for three cases, no adverse reaction occurred during hospitalization. All patients were cured and discharged. Moreover, one case (25.0%) had still active brucellosis without re-positive COVID-19, and other three cases (75.0%) have no symptoms of discomfort except one case fell fatigue and anxious during the follow-up period after recovery. Conducting the literature review, two similar cases have been reported in two case reports, and were both recovered, whereas, no data of follow up after recovery. Conclusion: These cases indicate that COVID-19 patients with brucellosis had favorable outcome before and after recovery. More clinical studies should be conducted to confirm our findings.

Effect of Animal-Assisted Therapy (AAT) on Social Interaction and Quality of Life in Patients with Schizophrenia during the COVID-19 Pandemic: An Experimental Study.

PURPOSE: Most patients with schizophrenia exhibit low willingness to return to society because of negative social experiences. The COVID-19 pandemic led to severe social isolation for schizophrenia patients. However, animal-assisted therapy (AAT) can improve individuals' empathy, social functions, and quality of life. The study aimed to evaluate the effectiveness of AAT in improving social interactions and quality of life in patients with chronic schizophrenia during the COVID-19 pandemic. METHODS: An experimental study was conducted, with six institutions for psychiatric rehabilitation in Taiwan as the case institutions. Patients in these institutions were randomly allocated to the experimental group, which received 60 minutes of AAT once a week for 12 weeks, or the control group, which engaged in routine discussion groups and watched short films about animals. Comparisons between the two groups were made before and after the intervention on social function, social adaptive function, and quality of life. Data were collected before the intervention (T1), immediately after the intervention (T2), and 3 months after the intervention (T3). RESULTS: Comparison between groups showed that social functioning was significantly higher in the experimental group than in the control group at T2. However, there was no sign of improvement in social adaptive functions of the experimental group. The experimental group exhibited significantly higher quality of life than the control group at T2 and T3. CONCLUSIONS: There was an impact of COVID-19 on the studied effects. AAT improved social functioning and quality of life in patients with chronic schizophrenia. The effect on quality of life lasted only up to 3 months after the intervention. AAT should be promoted for use as a community-based rehabilitation tool in patients with chronic schizophrenia. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2200061715. https://www.chictr.org.cn.

Characterization and difference of lipids and metabolites from Jianhe White Xiang and Large White pork by high-performance liquid chromatography-tandem mass spectrometry.

The quality of pork, such as intramuscular fat (IMF) content and flavor, can affect the acceptance of the consumer. Many studies have reported on the pork quality of Chinese local and commercial pigs (for example Large White (LW) pigs). The Jianhe White Xiang (JWX) pig, one of the Chinese Xiang pigs, is known for its high IMF and pork flavor. However, studies investigating the characterization and difference of lipids and metabolites between the JWX and LW pork are limited. Herein, we performed metabolomic and lipidomic profiling of JWX and LW pork by high-performance liquid chromatography-tandem mass spectrometry. The IMF and meat redness (a*) of the JWX pork were significantly higher than those of the LW pork. Metabolomic profiling revealed that 118 out of 501 polar metabolites, such as carnitine, amino acids, sugar, and dipeptide, were significantly different between the two types of pork. Additionally, the screened metabolites were mainly related to carnitine synthesis, phospholipid metabolism, sugar metabolism, and amino acid metabolism. Lipidomic profiling identified 100 of 376 lipids, which contained carnitine, diglyceride, triglyceride (TG), sphingomyelin, cardiolipin, fatty acid, phosphatidylcholine (PC), and phosphatidylethanolamine (PE), which were significantly different between the two types of pork under the positive and negative ion modes (variable importance in projection (VIP) > 1, p < 0.05, and fold change (FC) > 2 or FC < 0.5). All of the different TG substances were up-regulated in the JWX pork, and their carbon chain length was longer than that of the residual TGs. In addition, the JWX pork had more double bonds of PC and PE substances than LW pork. Thus, our findings provide comprehensive metabolomic and lipidomic profiles between the JWX and LW pork and a basic understanding on increasing the pork quality.

[Identification of chemical constituents in Simiao Yong'an Decoction based on UPLC-LTQ-Orbitrap-MS].

This study aims to identify the chemical constituents of Simiao Yong'an Decoction based on ultra-performance liquid chromatography coupled with linear quadrupole ion trap-orbitrap mass spectrometry(UPLC-LTQ-Orbitrap-MS). The elution was performed through a UPLC BEH C_(18) column(2.1 mm × 100 mm, 1.7 µm) with the mobile phase of water(containing 0.1% formic acid)-acetonitrile at a flow rate of 0.4 mL·min~(-1). LTQ-Orbitrap-MS with heat electrospray ion(HESI) source was employed to collect MS fragment information in the negative ion mode. A total of 72 compounds were identified based on reference substance comparison, fragmentation rules, accurate molecular weight, related reports and databases(MassBank and HMDB), including 30 iridoid glycosides, 9 organic acids, 15 flavonoids, 10 phenylpropanoids, 7 triterpenoids, and 1 saccharide. The method established in this study is comprehensive, rapid, and accurate, which can help summarize the fragmentation rules of constituents and provide reference for revealing the active constituents and pharmacodynamic mechanism of Simiao Yong'an Decoction.

The complete plastome sequence of Lilium primulinum var. burmanicum, an ornamental and medicinal plant endemic to China.

Lilium primulinum var. burmanicum (W. W. Smith) Stearn 1948 is an ornamental and medicinal plant that has an extremely limited distribution in Yunnan, China. Here, we obtained the complete plastome of L. primulinum var. burmanicum via next-generation sequencing, and conducted phylogenomic analyses with existing species from Lilium. The total length of L. primulinum var. burmanicum was 152,206 bp with a typical quadripartite structure. The whole plastome contained a pair of inverted repeats (IRa/IRb; 26,399 bp) which divided a large single-copy (LSC; 81,854 bp) and a small single-copy (SSC; 17,563 bp). The average GC content among the whole plastome sequence and the LSC, SSC, and IR regions were 37%, 34.8%, 30.6%, and 42.5%, respectively. There were 134 genes detected from the whole plastome sequence, including 87 protein-coding genes, 39 tRNAs, and 8 rRNAs. Phylogenetic analyses using maximum likelihood showed congruent results that L. primulinum var. burmanicum together with L. primulinum var. ochraceum formed a single branch. These results demonstrate a close relationship between these variation species. The newly characterized chloroplast genome presented here will provide essential data for further phylogenomic analyses of the intraspecific relationship among Lilium species and for conservation genetics research of L. primulinum var. burmanicum.

Comparative Pharmacokinetics of Seven Major Compounds in Normal and Atherosclerosis Mice after Oral Administration of Simiao Yong'an Decoction.

Simiao Yong'an decoction (SMYAD), a classic traditional Chinese medicine formula, has been used to treat atherosclerosis (AS) in clinical in China, but its therapeutic mechanism and pharmacodynamic material basis are not clear. In this study, the AS model was caused by a high-fat diet and perivascular carotid collar placement (PCCP), and SMYAD was orally administered to the model and normal mice. A rapid, sensitive, selective, and reliable method using ultrahigh-performance liquid chromatography (UHPLC) system combined with a Q Exactive HF-X mass spectrometer (UHPLC-Q Exactive HF-X MS) was established and validated for the simultaneous determination of seven compounds, including harpagide, chlorogenic acid, swertiamarin, sweroside, angoroside C, liquiritin, and isoliquiritigenin in the plasma of normal and AS mice. The specificity, linearity, precision, accuracy, recovery, and stability of the method were all within the acceptable criteria. The results showed that some pharmacokinetic behaviors of harpagide, chlorogenic acid, and isoliquiritigenin were significantly different among the two groups of mice. The specific parameter changes were harpagide (AUC0-t and AUC0-∞ were 11075.09 ± 2132.38 and 16221.95 ± 5622.42 ng·mL-1·h, respectively; CLz/F was 2.45 ± 0.87 L/h/mg), chlorogenic acid (t 1/2 was 21.59 ± 9.16 h; AUC0-∞ was 2637.51 ± 322.54 ng·mL-1·h; CLz/F was 13.49 ± 1.81 L/h/mg) and isoliquiritigenin (AUC0-t and AUC0-∞ were 502.25 ± 165.65 and 653.68 ± 251.34 ng·mL-1·h, respectively; CLz/F was 62.16 ± 23.35 L/h/mg) were altered under the pathological status of AS. These differences might be partly ascribed to the changes in gastrointestinal microbiota, nonspecific drug transporters, and cytochrome P450 activity under the AS state, providing research ideas and experimental basis for pharmacological effects and pharmacodynamic material basis.

Characterization of the complete chloroplast genome of Leucomeris decora Kurz (Asteraceae).

Leucomeris decora is a traditional medicinal plant that is listed as an endangered species in China. Recently, L. decora has become locally rare. Here the complete chloroplast genome of L. decora was assembled and reported for the first time. Its plastome was 151,491 bp in length, including a large single-copy region (LSC; 83,155 bp), a small single-copy region (SSC; 18,216 bp), and a pair of inverted repeated regions (IRa and IRb; 25,060 bp). The overall GC content was 37.8%, and the genome contains 134 genes, including 92 protein-coding genes, 8 rRNA genes, and 34 tRNA genes. Phylogenetic analysis of thirteen representative species from the family of Asteraceae showed that L. decora is clustered into one clade with Gerbera jamesonii with high bootstrap values, indicating a close relationship between these two species.

[Effects of Aromatherapy on Depression and Loneliness in Elderly With Frailty Living in Day-Care Centers].

BACKGROUND: In addition to playing significant role in the decline of physiological functions and the onset of depression, frailty is involved in a vicious circle with depression that has serious physical and mental impacts on sufferers. Furthermore, elderly people with frailty are less mobile, at increased risk of dissociative interpersonal relationships, and prone to develop a sense of loneliness, which also pose health threats. PURPOSES: This study was designed to explore the improvement effects of an aromatherapy intervention on depression and loneliness in the elderly with frailty living in daycare centers. METHODS: This study adopted a quasi-experimental, pre-and-post-test research design. This study enrolled 82 frail elderly people from six daycare centers in Taipei City as the research subjects. The subjects in the experimental group received aromatherapy twice a week for 30 minutes each session for four weeks. The researcher guided the experimental group in a small group setting to perform self-massage on the face and hands with lavender essential oil. The control group was guided in the same self-massage routine using pure base oil. RESULTS: Depression in the subjects was found to be positively correlated with degree of frailty. After the intervention, depression and loneliness was found to have decreased significantly in the experimental group (p < .05). CONCLUSIONS: The findings support the beneficial effects of aromatherapy interventions on depression and loneliness in the elderly with frailty living in daycare centers without adverse reactions. Aromatherapy may be used to improve depression and loneliness in elderly people with frailty.

[Respiratory infectious diseases and tissue "damage-repair" balance:pathological characteristics, treatment, and characteristics of traditional Chinese medicine].

Respiratory infectious diseases are important diseases causing major public safety events, posing a great threat to life, health, and social development. Effective control and scientific treatment of the diseases is the key basis for ensuring the stability and long-term development of the community of a shared future for human health. Although the pathogens of respiratory viral infectious diseases are diverse and the process is complex, the common pathological basis of their pathogenesis is characterized by the "damage-repair" functional imbalance of the immune microenvironment of the lesions, which leads to the subsequent structural and functional destruction of important organs. Therefore, the treatment should focus on antivirus and immunological regulation, strengthen the protection against immune injury, and promote the functional repair of damaged tissues. The above conclusions are the scientific core of host-directed therapies(HDT), which coincides with "human-disease co-treatment and healthy qi and pathogen interaction" in traditional Chinese medicine(TCM) theories. Under the support of TCM and western medicine theories, the complete pathological chain "infection-immunity-injury" of respiratory viral infectious diseases is integrated with dynamic change in "healthy qi-pathogen" in TCM to transform the treatment focus from the diseases to the patients. It is possible to fundamentally correct the "damage-repair" imbalance in the disease state, change the environment for disease development, and bring benefits to patients by strengthening human intervention, maintaining immune homeostasis, enhancing the protection of tissues and organs, and promoting the repair and regeneration of damaged tissues. This study focused on the common and key pathological processes of respiratory infectious diseases, especially the immune damage caused by the viral infection, to seek effective prevention and treatment strategies, review relevant theoretical progress, summarize effective drug candidates, prospect future research and development, and highlight the therapeutic characteristics of TCM.

Proteomic analysis of "Oriental Beauty" oolong tea leaves with different degrees of leafhopper infestation.

RATIONALE: Oriental Beauty, a type of oolong tea native to Taiwan, is highly prized by connoisseurs for its unique fruity aroma and sweet taste. Leaves of Oriental Beauty vary in appearance, aroma, and taste, depending on the degree of tea green leafhopper (Jacobiasca formosana) infestation. In this study, the aim is to investigate the differential expression of proteins in leaves with low, medium, and high degrees of leafhopper infestation. METHODS: Proteomic techniques 2DE (two-dimensional electrophoresis) and nanoscale liquid chromatography/tandem mass spectrometry (LC/MS/MS) were used to investigate the differential expression of proteins in tea leaves with different degrees of leafhopper infestation. RESULTS: A total of 89 proteins were found to exhibit significant differences in expression. In a gene ontology analysis, most of these proteins participated in biosynthesis, carbohydrate metabolism, transport, responses to stress, and amino acid metabolism. CONCLUSIONS: These results indicated that the unique aroma and taste of the leaves might be influenced by their protein expression profiles, as well as related factors such as defensive responses to tea green leafhopper saliva.

Dominant protozoan species in rhizosphere soil over growth of Beta vulgaris L. in Northeast China.

This paper identified the dominant protozoan species in the four layers of rhizosphere soil during the six growth stages of Beta vulgaris L. and analyzed the correlations of the abundance and diversity of the dominant protozoan species with soil properties at different growth stages and soil depth. A total of 15 species of protozoa were identified; among them, Colpoda sp., Bodo sp., two kinds of Oxytricha sp., and Tachysoma sp. were the most dominant species of Beta vulgaris L. rhizosphere soil. The Colpoda sp. was eurytopic species in the Beta vulgaris L. rhizosphere soil and Tachysoma sp., Vorticella sp., Colpoda sp., Oxytricha sp.1, and Oxytricha sp. 2 were noted closely related to the acceleration function of circulation of N and P elements in soils. These dominant protozoan species were proposed to play a significant role of fertilization on N supply in rhizosphere soil during the initial growth of Beta vulgaris L.

Homotypic targeting upconversion nano-reactor for cascade cancer starvation and deep-tissue phototherapy.

Cancer starvation therapy based on catalytic chemistry of glucose oxidase (GOx) offers great potential for multimodal treatment, benefiting from both nutrition shutting-off and the oxidization product hydrogen peroxide (H2O2). Herein, further optimization of such combined therapy was achieved by a cascade Nano-reactor, which was constructed by incorporating GOx into a bio-mimic upconversion nanosystem. The cascade began when GOx was delivered into tumor sites through homotypic targeting, facilitating selective starving of cancer cells and H2O2 generation. Then, upon 980 nm laser excitation, the 470 nm light emitted by upconversion nanoparticles (NaYF4: Yb, Tm) photolyzed H2O2 into hydroxyl radical for phototherapy, superior to direct photolysis by blue light with limited tissue penetration depth. Meanwhile, the 800 nm emission of UCNPs was used to track the in vivo fate and tumor targeting ability of the Nano-reactor. Radionuclide imaging further confirmed the targeting of the Nano-reactor to subcutaneous 4T1 tumor and lung metastasis. Significantly enhanced therapeutic efficacy of this cascade starvation-phototherapy was validated in vitro and in vivo, suggesting the Nano-reactor as a smart, simple and strong system for cancer multimodal therapy.

A Nd3+ sensitized upconversion nanosystem with dual photosensitizers for improving photodynamic therapy efficacy.

The efficacy of photodynamic therapy (PDT) was greatly hindered by the use of a 980 nm laser with undesired overheating effects as well as low reactive oxygen species (ROS) yields. Herein, we address these problems using a dual-photosensitizer (PS) loaded upconversion nanoparticle (UCNP) system. In detail, the NaYF4:Yb/Er/Nd@NaYF4:Nd core-shell UCNP system was designed to exhibit 808 nm laser excitation ability to avoid unfavorable thermal effects. More importantly, the co-encapsulation of dual PS, in terms of merocyanine 540 (MC540) and zinc phthalocyanine (ZnPc), could be respectively triggered by the dual emissions of UCNPs, which could generate sufficient ROS with improved efficiency. Furthermore, in vitro and in vivo studies were conducted to confirm the folate receptor (FR)-overexpressed cancer cell- or tumor-specific targeting ability with minimal side effects on normal tissue, by using this dual PS loaded UCNP system with the modification of the targeting group folic acid (FA). It is worth mentioning that the singlet oxygen production assay and PDT treatment demonstrated significantly enhanced PDT efficacy of the dual-PS approach, in comparison with the single PS method. In short, the FR-targeted dual-PS nanoconstructs maximized the anti-tumor efficacy of PDT by taking advantage of dual fluorescence emission and 808 nm excitation of UCNPs, which might inspire the future development of noninvasive deep-seated tumor treatment.

The effect of liraglutide on the proliferation, migration, and osteogenic differentiation of human periodontal ligament cells.

OBJECTIVE: Liraglutide (LIRA) is a novel antidiabetic therapy that may have anti-inflammatory and bone protective effects. Thus, we studied the potential therapeutic effect of LIRA on periodontitis by assessing the effects of LIRA on the proliferation, migration, inflammation, and osteogenic differentiation of human periodontal ligament cells (hPDLCs) after LPS stimulation. MATERIAL AND METHODS: The expression of glucagon like-peptide 1 receptor (GLP-1R) was measured using qRT-PCR. HPDLCs proliferation after LIRA were analyzed using MTT assays. Cell migration was quantified using a wound-healing assay. The expression of inflammatory (IL-6 and TNF-α) was measured by qRT-PCR and ELISA in hPDLCs. The effect of LIRA on the mineralization potential of hPDLCs was assessed by alizarin red S staining. Furthermore, the expression of Runx2 and ALP was measured by qRT-PCR and Western blot in hPDLCs. RESULTS: GLP-1R mRNA was present on hPDLCs, and LIRA increased the expression of GLP-1R mRNA. When cultured with 25, 50, 75, 100 and 125 nM LIRA for 24 h, hPDLCs proliferation was enhanced in a dose-dependent manner (P < 0.05), and 100 nM was optimal. LIRA promoted hPDLCs migration in a time-dependent manner. LPS significantly increased the expression of IL-6 and TNF-α (P < 0.01), decreased the formation of mineralization nodes (P < 0.01), and inhibited the expression of ALP and Runx2 (P < 0.05). LIRA treatment blocked the expression of IL-6 and TNF-α (P < 0.01), increased the formation of mineralization nodes (P < 0.01), and enhanced the expression of ALP and Runx2 (P < 0.05). CONCLUSION: LIRA can enhance the proliferation, migration, and osteogenic differentiation of hPDLCs and inhibit the inflammatory response. Thus, LIRA may have potential therapeutic use as an adjuvant treatment for human periodontitis, and this effect is independent of hypoglycemic activity.

Silica nanoparticle exposure inducing granulosa cell apoptosis and follicular atresia in female Balb/c mice.

Given that the effects of ultrafine fractions (< 0.1 µm) on reproductive diseases are gaining attention, this study aimed to explore the influence of silica nanoparticle (SiNP)-induced female reproductive dysfunction. In this study, 80 female mice were randomly divided into four groups including a control group and three concentrations of SiNP groups (7, 21, 35 mg/kg). Mice were exposed to the vehicle control and silica nanoparticles by tracheal perfusion every 3 days a total of five times in 15 days. Then, half of the mice in each group were sacrificed on 15 and 30 days after the first dose, respectively. Our findings indicated that SiNPs can result in ovarian damage, cause an imbalance of sex hormones, increase the number of atretic and primary follicles, and induce oxidative stress and DNA strand breaks in ovary by day 15. The protein expressions of ATM, CHK-2, P53, E2F1, P73, BAX, Caspase-9, and Caspase-3 were significantly increased, while expressions of RAD51 were down-regulated after SiNP exposure by days 15. Estradiol increased, while progesterone increased in low dose and decreased in high dose after SiNP exposure by 15 days. However, these changes were recovered by 30 days. The results suggest that SiNPs can cause reversible damage to follicles in mice. SiNPs could primarily cause DNA damage and DNA damage response through oxidative stress, while DNA damage repair failure because of severe DNA damage activated the mitochondrial apoptosis pathway and therefore resulted in apoptosis of granulosa cell. In addition, the disorder of reproductive endocrine function caused by SiNPs could be another reason for SiNP-induced reproductive dysfunction in mice. These events in turn induce the follicles to undergo atresia.

Silica nanoparticles induce autophagy dysfunction via lysosomal impairment and inhibition of autophagosome degradation in hepatocytes.

Autophagy dysfunction is considered as a potential toxic mechanism of nanomaterials. Silica nanoparticles (SiNPs) can induce autophagy, but the specific mechanism involved remains unclear. Therefore, the aim of this study was to confirm the effects of SiNPs on autophagy dysfunction and explore the possible underlying mechanism. In this article, we reported that cell-internalized SiNPs exhibited dose- and time-dependent cytotoxicity in both L-02 and HepG2 cells. Multiple methods verified that SiNPs induced autophagy even at the noncytotoxic level and blocked the autophagic flux at the high-dose level. Notably, SiNPs impaired the lysosomal function through damaging lysosomal ultrastructures, increasing membrane permeability, and downregulating the expression of lysosomal proteases, cathepsin B, as evidenced by transmission electron microscopy, acridine orange staining, quantitative reverse transcription-polymerase chain reaction, and Western blot assays. Collectively, these data concluded that SiNPs inhibited autophagosome degradation via lysosomal impairment in hepatocytes, resulting in autophagy dysfunction. The current study not only discloses a potential mechanism of autophagy dysfunction induced by SiNPs but also provides novel evidence for the study of toxic effect and safety evaluation of SiNPs.

mRECIST response combined with sorafenib-related adverse events is superior to either criterion alone in predicting survival in HCC patients treated with TACE plus sorafenib.

The mRECIST and dermatologic adverse events (AEs) can be used to assess the patient response to transarterial chemoembolization (TACE) and/or sorafenib for hepatocellular carcinoma (HCC). Here, we aimed to combine the two criteria to stratify the prognosis in patients with unresectable HCC receiving TACE plus sorafenib (TACE-S). In total, 176 consecutive HCC patients treated with TACE-S were enrolled. CT scans and laboratory tests were conducted pretreatment (at baseline, 5-7 days before the TACE-S) and post-treatment (at 1, 2 and 3 months). The radiological response was assessed according to mRECIST. Sorafenib-related AEs were recorded every 2 weeks after oral administration, and patients with dermatologic AEs of Grade 2 or more were defined as dermatologic responders. The earliest time at which mRECIST and dermatologic responses correlated with survival was 2 months after therapy. The mRECIST-dermatologic AE combination assessment stratified patients into three different prognoses; responders on both assessments exhibited the longest median overall survival (OS), followed by responders on one assessment and non-responders on both assessments (30.5, 17.4 and 8.3 months, respectively; p < 0.001). Achieving the highest C-index, the mRECIST-dermatologic AE combination showed better performance in predicting survival than either mRECIST or dermatologic AEs alone. Furthermore, the mRECIST-dermatologic AE combination remained a significant predictor of OS, even when the patients were stratified according to the BCLC stage, ECOG score or alpha-fetoprotein (AFP) value. This study showed that the combination of mRECIST response and dermatologic AEs is superior to either criterion used alone for predicting the survival of HCC patients treated with TACE-S.