Artemisinin reduces PTSD-like symptoms, improves synaptic plasticity, and inhibits apoptosis in rats subjected to single prolonged stress.

Post-Traumatic Stress Disorder (PTSD) is a chronic mental disorder characterized by symptoms of panic and anxiety, depression, impaired cognitive functioning, and difficulty in social interactions. While the effect of the traditional Chinese medicine artemisinin (AR) on PTSD is unknown, its therapeutic benefits have been demonstrated by studies on models of multiple neurological disorders. This study aimed to extend such findings by investigating the effects of AR administration on a rat model of PTSD induced by a regimen of single prolonged stress (SPS). After rats were subjected to the SPS protocol, AR was administered and its impact on PTSD-like behaviors was evaluated. In the present study, rats were subjected to a multitude of behavioral tests to evaluate behaviors related to anxiety, memory function, and social interactions. The expression of hippocampal synaptic plasticity-related proteins was detected using Western blot and immunofluorescence. The ultrastructure of synapses was observed under transmission electron microscopy. The apoptosis of hippocampal neurons was examined with Western blot, TUNEL staining, and HE staining. The results showed that AR administration alleviated the PTSD-like phenotypes in SPS rats, including behavior indicative of anxiety, cognitive deficits, and diminished sociability. AR administration was further observed to improve synaptic plasticity and inhibit neuronal apoptosis in SPS rats. These findings suggest that administering AR after the onset of severe traumatic events may alleviate anxiety, cognitive deficits, and impaired social interaction, improve synaptic plasticity, and diminish neuronal apoptosis. Hence, the present study provides evidence for AR's potential as a multi-target agent in the treatment of PTSD.

The hepatoprotective effects of Herbt Tea Essences on phenanthrene-induced liver damage in mice.

Phenanthrene (Phe), one of the most frequently occurring pollutants in nature, can cause substantial damage to the human liver. Herbt Tea Essences (HTE), a kind of black tea extract with strong anti-inflammatory activity, can protect humans against disease. Currently, whether HTE can protect the liver from Phe-induced hepatotoxicity remains unclear. Herein, we explore the protective effects of HTE against Phe-induced hepatotoxicity. Our results showed that Phe exposure could significantly induce liver damage and increase serum hepatic enzyme levels in mice. HTE could prevent liver damage and recover the expression levels of inflammatory factors. Furthermore, we found that HTE suppressed the excessive activation of the nuclear transcription factor kappa-B and transforming growth factor-ß/SMAD signaling pathways to alleviate Phe-induced liver inflammation and fibrosis. Overall, our data showed that HTE treatment could be a new preventive means for Phe-induced liver disease.

Treatment options for unresectable hepatocellular carcinoma with hepatitis virus infection following sorafenib failure.

BACKGROUND: Currently, there are a few treatment options for unresectable hepatocellular carcinoma (HCC) after progression following sorafenib (SOR) therapy, but with limited benefit. The purpose of this study was to investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors (ICIs) as second-line treatment. METHODS: From May 2018 to May 2021, a total of 93 HCCs who failed SOR treatment were included in this study and divided into TKI group (n = 37) and TKI-ICI group (n = 56). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety were estimated among the two groups. In addition, univariate and multivariate Cox regression analyses were performed for OS and PFS to identify possible prognostic factors. RESULTS: With a median follow-up time of 13.7 months, the median age of patients was 56 (range, 50-64) years and most were male. All of the patients were hepatitis virus-related HCC. Both median OS (7.63 months vs 19.23 months, P < 0.001) and median PFS (2.97 months vs 8.63 months, P < 0.001) were significantly improved in the TKI-ICI group compared to the TKI group. A significant increase in DCR was demonstrated in the TKI-ICI group compared to the TKI group (83.9% vs 45.9%, P = 0.0003), although no significant difference in ORR was reported (21.4% vs 8.1%, P = 0.1552). Multivariate Cox regression analysis of OS and PFS revealed that second-line regimen was an independent protective factor affecting death and progression in HCCs after SOR failure. In addition, Child-Pugh B7 was an independent risk factor of OS. Finally, there was no significant difference in the incidence of any grade or grade 3/4 adverse events (AEs) between the two groups, and no treatment-related deaths were observed. CONCLUSION: This real-world study suggests that the combination of TKIs and ICIs benefits more than mono-TKIs and is well tolerated in HCCs with hepatitis virus infection after SOR failure.

Prediction of the Active Components and Mechanism of Forsythia suspensa Leaf against Respiratory Syncytial Virus Based on Network Pharmacology.

Objective: Forsythia suspensa leaf (FSL) has been used as a health tea in China for centuries. Previous experiments have proved that FSL extract has a good effect on the antirespiratory syncytial virus (RSV) in vitro, but its exact mechanism is not clear. Therefore, this study aims to determine the active components and targets of FSL and further explore its anti-RSV mechanism. Methods: UPLC-Q-Exactive-MS was used to analyze the main chemical components of FSL. The compound disease target network, PPI, GO, and KEGG were used to obtain key targets and potential ways. Then, the molecular docking was verified by Schrödinger Maestro software. Next, the cell model of RSV infection was established, and the inhibitory effect of each drug on RSV was detected. Finally, western blotting was used to detect the effect of the active components of FSL on the expression of PI3K/AKT signaling pathway-related protein. Results: UPLC-Q-Exactive-MS analysis showed that there were 67 main chemical constituents in FSL, while network pharmacological analysis showed that there were 169 anti-RSV targets of the active components in FSL, involving 177 signal pathways, among which PI3K/AKT signal pathway played an important role in the anti-RSV process of FSL. The results of molecular docking showed that cryptochlorogenic acid, phillyrin, phillygenin, rutin, and rosmarinic acid had higher binding activities to TP53, STAT3, MAPK1, AKT1, and MAPK3, respectively. In vitro experiments showed that phillyrin and rosmarinic acid could effectively improve the survival rate of RSV-infected cells, increase the expression level of PI3K, and decrease the expression level of AKT. Conclusion: The active ingredients of FSL, phillyrin, and rosmarinic acid can play an anti-RSV role by inhibiting PI3K/AKT signaling pathway. This study provides reliable theoretical and experimental support for the anti-RSV treatment of FSL.

Prognostic models for outcome prediction in patients with advanced hepatocellular carcinoma treated by systemic therapy: a systematic review and critical appraisal.

OBJECTIVE: To describe and analyze the predictive models of the prognosis of patients with hepatocellular carcinoma (HCC) undergoing systemic treatment. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase until December 2020 and manually searched references from eligible articles. ELIGIBILITY CRITERIA FOR STUDY SELECTION: The development, validation, or updating of prognostic models of patients with HCC after systemic treatment. RESULTS: The systematic search yielded 42 eligible articles: 28 articles described the development of 28 prognostic models of patients with HCC treated with systemic therapy, and 14 articles described the external validation of 32 existing prognostic models of patients with HCC undergoing systemic treatment. Among the 28 prognostic models, six were developed based on genes, of which five were expressed in full equations; the other 22 prognostic models were developed based on common clinical factors. Of the 28 prognostic models, 11 were validated both internally and externally, nine were validated only internally, two were validated only externally, and the remaining six models did not undergo any type of validation. Among the 28 prognostic models, the most common systemic treatment was sorafenib (n = 19); the most prevalent endpoint was overall survival (n = 28); and the most commonly used predictors were alpha-fetoprotein (n = 15), bilirubin (n = 8), albumin (n = 8), Child-Pugh score (n = 8), extrahepatic metastasis (n = 7), and tumor size (n = 7). Further, among 32 externally validated prognostic models, 12 were externally validated > 3 times. CONCLUSIONS: This study describes and analyzes the prognostic models developed and validated for patients with HCC who have undergone systemic treatment. The results show that there are some methodological flaws in the model development process, and that external validation is rarely performed. Future research should focus on validating and updating existing models, and evaluating the effects of these models in clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020200187 .

Transarterial chemoembolization plus lenvatinib versus transarterial chemoembolization plus sorafenib as first-line treatment for hepatocellular carcinoma with portal vein tumor thrombus: A prospective randomized study.

BACKGROUND: The efficacy and safety of transarterial chemoembolization (TACE) plus lenvatinib in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) have not been evaluated. METHODS: In this open-label, single-center, randomized trial (ClinicalTrials.gov identifier: NCT04127396), participants with previously untreated HCC and type I-IV PVTT were randomized 1:1 to receive TACE plus lenvatinib (arm L; orally once daily, 12 mg for body weight ≥60 kg or 8 mg for body weight <60 kg) or TACE plus sorafenib (arm S; 400 mg orally twice daily in 28-day cycles). The primary end point was time-to-progression (TTP; time from randomization to disease progression) and secondary end points included objective response rate and toxicity. Prognostic factors were evaluated using a multivariable Cox proportional hazards model. RESULTS: Between December 30, 2018 and May 31, 2020, 64 patients were randomized (arm L, n = 32; arm S, n = 32); most patients had type I/II PVTT (71.9%), and the median target tumor diameter was 9.8 cm (range, 3.8-21.8). After a median follow-up of 16.1 months, patients in arm L had a higher median TTP (4.7 vs 3.1 months; hazard ratio [HR], 0.55; 95% CI, 0.32-0.95; P = .029) and objective response rate (53.1% vs 25.0%, P = .039) versus arm S. Multivariable analysis showed that TACE plus lenvatinib was significantly associated with higher TTP versus TACE plus sorafenib (HR, 0.50; 95% CI, 0.28-0.90; P = .021). Comparable safety profiles were observed in arms L and S. CONCLUSIONS: TACE plus lenvatinib was safe, well tolerated, and had favorable efficacy versus TACE plus sorafenib in patients with advanced HCC with PVTT and large tumor burden. LAY SUMMARY: Hepatocellular carcinoma with portal vein tumor thrombus has a poor prognosis. In addition, most phase 3 trials of drugs for hepatocellular carcinoma exclude patients with major portal vein invasion, and treatment options for these patients are limited. Transarterial chemoembolization has shown promising efficacy in these patients, especially in combination with systemic treatment or radiotherapy. However, transarterial chemoembolization plus lenvatinib has not been investigated in this setting. This open-label, single-center, randomized trial showed that transarterial chemoembolization plus lenvatinib is safe, well tolerated, and has favorable efficacy versus transarterial chemoembolization plus sorafenib for the treatment of hepatocellular carcinoma with portal vein tumor thrombus.

Microbial taxonomic, nitrogen cycling and phosphorus recycling community composition during long-term organic greenhouse farming.

Understanding the interplay between the farming system and soil microbiomes could aid the design of a sustainable and efficient farming system. A comparative greenhouse experiment consisting of organic (ORG), integrated (INT) and conventional (CON) farming systems was established in northern China in 2002. The effects of 12 years of organic farming on soil microbiomes were explored by metagenomic and 16S rRNA gene amplicon sequencing analyses. Long-term ORG shifted the community composition of dominant phyla, especially Acidobacteria, increased the relative abundance of Ignavibacteria and Acidobacteria Gp6 and decreased the relative abundance of Nitrosomonas, Bacillus and Paenibacillus. Metagenomic analysis further revealed that relative abundance of ammonia oxidizing microorganisms (Bacteria and Archaea) and anaerobic ammonium oxidation bacteria decreased during ORG. Conversely, the relative abundance of bacteria-carrying periplasmic nitrate reductases (napA) was slightly higher for ORG. Long-term organic farming also caused significant alterations to the community composition of functional groups associated with ammonia oxidation, denitrification and phosphorus recycling. In summary, this study provides key insights into the composition of soil microbiomes and long-term organic farming under greenhouse conditions.

Sediment phosphorus speciation and retention process affected by invasion time of Spartina alterniflora in a subtropical coastal wetland of China.

In coastal wetland ecosystems, most phosphorus (P) accumulates in the sediments and becomes a major pollutant causing eutrophication by recycling to the water column in estuary areas, especially exotic plant invasions will change the nutrient cycling. In this study, a large wetland invaded by exotic species Spartina alterniflora for over 15 years was selected to study the sediment P fractionation and its retention for different plant invasion periods. The samples were collected from east to west in September and the sediment P was fractionated into total P (TP), inorganic P (IP), iron/aluminum-bound P (Fe/Al-P), calcium-bound P (Ca-P), and organic P (OP). Additionally, the effect of the invasion period on the wetland P fractionation based on space-time reciprocal principle was investigated. For different S. alterniflora invasion periods, the average TP concentration was 675.37 mg kg-1 with a range of 160.33-1071 mg kg-1. The IP concentration was in the range of 107.33-813.33 mg kg-1 (accounting for 54.4-79.5% of TP), of which Fe/Al-P and Ca-P represented up to 99.4%. In addition, the P retention (RP) was within 41.67-329.67 mg kg-1. We also found that TP, IP, Fe/Al-P, Ca-P, OP, and RP in sediments were negatively correlated with pH (p < 0.05), and were also significantly positively correlated (p < 0.01) with water content and electrical conductivity. There were positive correlations between the various forms of P in the sediments (p < 0.01). However, the most important finding was that invasion time of S. alterniflora had a direct effect on the P speciation and three stages were determined. In the first stage, S. alterniflora mainly consumed the OP of the sediment. In the second stage, S. alterniflora showed great vitality and biological immobilization led to the transforming of IP to OP. In the third stage, all P fractions greatly decreased to values even lower than for the bare beach which indicated that S. alterniflora growth had begun to degenerate. These three stages well explained the P seemingly contradictory increases and decreases apparent in previous studies and provide important information for understanding the effect of S. alterniflora invasion.

A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration.

Age-related macular degeneration (AMD) is one of the leading cause of blindness among the elderly; however, current therapy options are limited. Epidemiological studies have shown that a diet that is high in omega-3 polyunsaturated (n-3) fatty acids can slow disease progression in patients with advanced AMD. In this study, we evaluated the effect of such a diet on the retinas of Ccl2(-/-)/Cx3cr1(-/-) mice, a model that develops AMD-like retinal lesions that include focal deep retinal lesions, abnormal retinal pigment epithelium, photoreceptor degeneration, and A2E accumulation. Ccl2(-/-)/Cx3cr1(-/-) mice that ingested a high n-3 fatty acid diet showed a slower progression of retinal lesions compared with the low n-3 fatty acids group. Some mice that were given high levels of n-3 fatty acids had lesion reversion. We found a shunted arachidonic acid metabolism that resulted in decreased pro-inflammatory derivatives (prostaglandin E(2) and leukotriene B(4)) and an increased anti-inflammatory derivative (prostaglandin D(2)). We also measured lower ocular TNF-alpha and IL-6 transcript levels in the mice fed a diet of high n-3 fatty acids. Our findings in these mice are in line with human studies of AMD risk reduction by long-chain n-3 fatty acids. This murine model provides a useful tool to evaluate therapies that might delay the development of AMD.