Chemotherapy exacerbates ovarian cancer cell migration and cancer stem cell-like characteristics through GLI1.

BACKGROUND: Despite the great clinical response to the first-line chemotherapeutics, metastasis still happens among most of the ovarian cancer patients within 2 years. METHODS: Using multiple human ovarian cancer cell lines, a transwell co-culture system of the carboplatin or VP-16-challenged feeder and receptor cells was established to demonstrate the chemotherapy-exacerbated migration. The migration and cancer stem cell (CSC)-like characteristics were determined by wound healing, transwell migration, flow cytometry and sphere formation. mRNA and protein expression were identified by qPCR and western blot. Bioinformatics analysis was used to investigate the differentially expressed genes. GLI1 expression in tissue samples was analysed by immunohistochemistry. RESULTS: Chemotherapy was found to not only kill tumour cells, but also trigger the induction of CSC-like traits and the migration of ovarian cancer cells. EMT markers Vimentin and Snail in receptor cells were upregulated in the microenvironment of chemotherapy-challenged feeder cells. The transcription factor GLI1 was upregulated by chemotherapy in both clinical samples and cell lines. Follow-up functional experiments illustrated that inhibiting GLI1 reversed the chemotherapy-exacerbated CSC-like traits, including CD44 and CD133, as well as prevented the migration of ovarian cancer cells. CONCLUSIONS: Targeting GLI1 may improve clinical benefits in the chemotherapy-exacerbated metastasis in ovarian cancer treatment.

Increased Serum Levels of Cortisol and Inflammatory Cytokines in People With Depression.

This cross-sectional study aimed at measuring the correlation and association between serum levels of cortisol, inflammatory cytokines, and depression and to measure the detection accuracy of serum levels of cortisol in serum samples. In total, 89 male participants were recruited into this study from June 15, 2017, to September 31, 2017. The Hamilton Depression Rating Scale, Beck Anxiety Inventory, and Pittsburgh Sleep Quality Index were used to investigate the mental health status of the participants. Serum concentrations of cortisol and inflammatory cytokines were determined. The serum cortisol concentration, anxiety level, and sleep quality were included in the final logistic regression model. Serum cortisol was able to accurately distinguish between patients with depression and those without depression. There was a significant positive correlation between serum cortisol levels and Hamilton Depression Rating Scale scores.

The effects of visual art therapy on adults with depressive symptoms: A systematic review and meta-analysis.

Depression constitutes a pervasive global mental health concern and stands as a principal determinant of elevated suicide rates worldwide. Recent empirical investigations have showcased the significant potential of visual art therapy (VAT) in ameliorating symptoms among individuals with depression. Nevertheless, specific studies have yielded findings marked by inconclusiveness, underscoring the imperative need for further research to comprehensively establish its efficacy. This study is a systematic review and meta-analysis of extant research, to ascertain the efficacy and effect size of VAT as an intervention for adults with depressive symptoms. A comprehensive search was conducted across 10 databases. The search encompassed articles published from the inception of these databases up until October 18, 2023. Two researchers screened the literature in accordance with inclusion and exclusion criteria and performed a thorough quality assessment. The original data and the data obtained from the literature were extracted for further analysis. The statistical analysis of the data was performed using Stata 17.0 software. fifteen studies were included, encompassing a total of 932 participants. The outcomes of meta-analysis unveiled a statistically significant effect of VAT in diminishing depressive symptoms among adults (SMD = -0.73; 95% CI, -1.07 to -0.39; p < 0.001; 15 randomised controlled trials (RCTs); low-quality evidence). The subgroup analysis indicated that VAT exhibited heightened effectiveness among adults below 65 years of age, with interventions lasting ≤12 weeks demonstrating superior efficacy. Additionally, sensitivity analysis underscored the robustness and reliability of the findings. VAT appears to alleviate depressive symptoms among adults. Existing research indicates that the effectiveness of VAT is influenced by factors, such as intervention population characteristics and intervention duration. However, to comprehensively probe the efficacy of VAT, future studies should strive for larger sample sizes, multicentre collaborations, and long-term follow-ups.

Dietary aluminium intake disrupts the overall structure of gut microbiota in Wistar rats.

Approximately, 40% of ingested dietary aluminium accumulates in the intestine, which has been considered a target organ for dietary aluminium exposure. The gut microbiota may be the first protective barrier against the toxic metal aluminium and a crucial mediator of the bioavailability of metal aluminium. We previously evaluated dietary aluminium intake and its health risks in a population from Jilin Province, China, and found that the average daily intake of aluminium in the diet of residents in Jilin Province was 0.163 mg/kg after the total diet survey. In the present study, the equivalent concentration of aluminium in rats was extrapolated by the average dietary aluminium intake in the population of Jilin Province based on body surface area. Furthermore, healthy adult Wistar rats were randomly divided into four groups (n = 15 for each group): a control group and three groups treated with aluminium solution (1, 10, and 100 mg/kg/day, intragastrically) for 28 days. Following treatment, necrosis of renal tubular epithelial cells, hyperplasia of bile ducts and hyperplasia of heart tissue, as well as fiber in the liver, kidney, and heart tissues of aluminium-treated rats were observed, although there were no significant changes in the spleen and brain. Subsequently, fecal samples were withdrawn for 16S rRNA gene sequence analysis. It was found that aluminium decreased the microbiota diversity and changed the overall community structure of the gut microbiota, including three phyla and four genera, together with the regulation of 12 signaling pathways. Collectively, treatment with aluminium markedly altered the structure of the gut microbiota, suggesting that the disorders of intestinal flora induced by aluminium may be an important mechanism for aluminium toxicity.

Biomimetic co-assembled nanodrug of doxorubicin and berberine suppresses chemotherapy-exacerbated breast cancer metastasis.

Chemotherapy is a major approach for treating breast cancer patients. Paradoxically, it can also induce cancer progression. Understanding post-chemotherapy metastasis mechanism will help the development of new therapeutic strategies to ameliorate chemotherapy-induced cancer progression. In this study, we deciphered the role of HMGB1 in the regulation of TLR4-mediated epithelial to mesenchymal transitions (EMT) process on doxorubicin (Dox)-treated 4T1 breast cancer cells. Berberine (Ber), a clinically approved alkaloid has been demonstrated as an HMGB1-TLR4 axis regulator to Dox-exacerbated breast cancer metastasis in vitro and in vivo. Hypothesizing that combination of Dox and Ber would be beneficial for breast cancer chemotherapy, we engineered self-assembled nanodrug (DBNP) consisting of Dox and Ber without the aid of additional carriers. After cloaking with 4T1 cell membranes, DBNP@CM exhibited higher accumulation at tumor sites and prolonged blood circulation time in 4T1 orthotopic tumor-bearing mice than DBNP. Importantly, DBNP@CM not only effectively inhibited tumor growth with fewer side effects, but also remarkably suppressed pulmonary metastasis via blocking HMGB1-TLR4 axis. Together, our results have provided a promising combination strategy to dampen chemotherapy-exacerbated breast cancer metastasis and shed light on the development of biomimetic nanodrug for efficient and safe breast cancer chemotherapy.

Contamination and health risk assessment of lead, arsenic, cadmium, and aluminum from a total diet study of Jilin Province, China.

Lead (Pb), arsenic (As), cadmium (Cd) and aluminum (Al) are the four most common heavy metals and can cause serious harm to human health. To evaluate contamination levels and associated safety issues of the four common heavy metals of the residents in Jilin Province, China, a total diet study (TDS) method was used. Concentration and consumption data of the four heavy metals were collected from the fifth Chinese TDS of Jilin province. In total, 12 food groups were studied and two regions were selected for comparison. According to the results, the mean concentration of lead, arsenic, cadmium, and aluminum was 0.0189, 0.0691, 0.0085, and 9.309 mg/kg, respectively. Aluminum in deep-fried dough sticks exceeded the national limit standard. Pollution of the Songhua River Basin is not very different from that of other areas. The average consumer exposure to the four heavy metals in the 2 to 6-year-old group was the highest among all age-groups. Potatoes and their products were the primary sources of dietary exposure to lead. Aquatic products and their related commodities had the highest contribution to arsenic exposure. Vegetables and vegetable products were the main sources of dietary exposure to cadmium. The highest contributor to aluminum in the diet was from cereals and cereal products. In general, there might be some potential risks to the 2 to 6-year-old population due to exposure to lead and aluminum. Contamination of aluminum in cereals and cereal products needs further consideration.

Treatment of severe sepsis with nanoparticulate cell-free DNA scavengers.

Severe sepsis represents a common, expensive, and deadly health care issue with limited therapeutic options. Gaining insights into the inflammatory dysregulation that causes sepsis would help develop new therapeutic strategies against severe sepsis. In this study, we identified the crucial role of cell-free DNA (cfDNA) in the regulation of the Toll-like receptor 9-mediated proinflammatory pathway in severe sepsis progression. Hypothesizing that removing cfDNA would be beneficial for sepsis treatment, we used polyethylenimine (PEI) and synthesized PEI-functionalized, biodegradable mesoporous silica nanoparticles with different charge densities as cfDNA scavengers. These nucleic acid-binding nanoparticles (NABNs) showed superior performance compared with their nucleic acid-binding polymer counterparts on inhibition of cfDNA-induced inflammation and subsequent multiple organ injury caused by severe sepsis. Furthermore, NABNs exhibited enhanced accumulation and retention in the inflamed cecum, along with a more desirable in vivo safety profile. Together, our results revealed a key contribution of cfDNA in severe sepsis and shed a light on the development of NABN-based therapeutics for sepsis therapy, which currently remains intractable.

Janus nanocarrier-based co-delivery of doxorubicin and berberine weakens chemotherapy-exacerbated hepatocellular carcinoma recurrence.

Despite the rapid progress which has been made in hepatocellular carcinoma (HCC) chemotherapeutics, recurrence of liver cancer still remains a barrier to achieve satisfying prognosis. Herein, we aimed to decipher the role of berberine (BER) in chemotherapy-exacerbated HCC repopulation via developing a nanocarrier co-deliveries doxorubicin (DOX) and BER to achieve a synergic effect in HCC treatment. The underlying fact of chemotherapy that promotes HCC repopulation was firstly examined and corroborated by clinical samples and murine repopulation model. Then, hyaluronic acid (HA)-conjugated Janus nanocarrier (HA-MSN@DB) was developed to load DOX and BER simultaneously. The HCC targeting efficiency, pH-controlled drug-release and anti-cancer property of HA-MSN@DB were assessed in CD44-overexpressed HCCs and normal liver cells. Magnet resonance imaging, bio-distribution, biocompatibility, tumor and recurrence inhibition studies were performed in H22 tumor-bearing mice. BER significantly reduced doxorubicin (DOX)-triggered HCC repopulation in vitro and in vivo through inhibiting Caspase-3-iPLA2-COX-2 pathway. The delivery of HA-MSN@DB into HCCs through CD44 receptor-mediated targeting effect was demonstrated. The controlled release of DOX and BER in response to acidic tumor microenvironment was validated. Importantly, HA-MSN@DB drastically enhanced the antitumor activity of DOX and suppressed DOX-exacerbated HCC repopulation in vitro and in vivo. Furthermore, HA-MSN@DB exhibited enhanced tumor accumulation and biocompatibility. Our findings revealed the pivotal role of BER in overcoming chemotherapy-exacerbated HCC repopulation through Caspase-3-iPLA2-COX-2 pathway, thereby providing a promising and stable nanocarrier integrating DOX and BER for effective HCC chemotherapy without repopulation. STATEMENT OF SIGNIFICANCE: In this work, we have first demonstrated the fact that berberine (Ber) reduces chemotherapy-exacerbated HCC recurrence and studied its mechanism by the aid of a doxorubicin-induced mice HCC relapse model. We then developed a promising strategy that simultaneously inhibits HCC and its recurrence with an HCC-targeted co-delivery nanocarrier HA-MSN@DB and revealed that such an inhibition was related with the suppression of Caspase-3-iPLA2-COX-2 pathway by berberine.

Morita therapy for depression in adults: A systematic review and meta-analysis.

Morita therapy is a systematic psychological therapy that aims to improve everyday functioning rather than target specific symptoms. However, there has been no systematic review evaluating the evidence of the effectiveness of Morita therapy in the treatment of depression. The aim of this study was to assess the clinical efficacy of Morita therapy in combination with pharmacotherapy in patients 18 and older who were diagnosed with current depressive disorder. A total of 840 patients with depression from 11 randomized controlled trial (RCT) studies were included in this meta-analysis after a literature search of 10 databases was performed from database inception to July 1, 2017. All the eligible studies were determined to have an unclear or high risk of bias. Morita therapy plus pharmacotherapy was significantly superior to pharmacotherapy alone in reducing depression severity. The remission rate of the Morita therapy plus pharmacotherapy group was better than that of the pharmacotherapy alone group. Morita therapy significantly reduced depression severity symptoms and improved the remission rate. Due to the relatively weak quality of the included studies, definitive conclusions cannot be made. Thus, multi-center, well-designed clinical trials with larger cohorts are urgently needed to support the clinical application of Morita therapy.

Gram-scale production of carrier-free fluorescent berberine microrods for selective liver cancer therapy.

Berberine, a widely used isoquinoline alkaloid in traditional Chinese medicine, has been proved to be a potential candidate in liver cancer therapy. However, the low therapeutic dose in the tumor target which is due to the poor solubility and oral bioavailability has limited its clinical application. In this study, fluorescent self-carried Berberine microrods (Ber-MRs) were prepared in gram-scale through a facile and cheap antisolvent precipitation method. Ber-MRs exhibited good optical properties, pH-responsive drug release behavior and selective and safe antitumor performance in vitro and in vivo without obvious toxicity. These findings have demonstrated that Ber-MRs are promising for efficient and safe liver cancer therapy. © 2018 BioFactors, 44(5):496-502, 2018.

Self-assembled dual fluorescence nanoparticles for CD44-targeted delivery of anti-miR-27a in liver cancer theranostics.

Despite the vital role miRNA-27a plays in driving the development and progress of liver cancer, miRNA-based inhibition therapy is hampered due to its undesired degradation and off-target effects. Herein, a multifunctional nanoparticle for noninvasive tracking of targeted delivery of anti-miR-27a oligonucleotides against liver cancer was constructed. Methods: Dual-fluorescent conjugates (QD-HA-PEI) were first fabricated through crosslinking hyaluronic acid (HA), polyethyleneimine (PEI) and near-infrared (NIR) fluorescent quantum dots (QDs) via a facile one-pot approach. Antisense oligonucleotide was then encapsulated by QD-HA-PEI to form anti-miR-27a/QD-HA-PEI via electrostatic interactions. Targeting, biodistribution, bioimaging, in vitro cytotoxicity and in vivo anti-tumor effects were evaluated and the underlying mechanism was studied. Results: The NIR fluorescence of anti-miR-27a/QD-HA-PEI could be employed to monitor CD44 receptor-targeted cellular uptake and tumor accumulation. Importantly, the intrinsic fluorescence of anti-miR-27a/QD-HA-PEI remained in the "ON" state in extracellular or blood environment, but switched to the "OFF" state in the intracellular environment, indicating pH-responsive oligonucleotide release. Furthermore, anti-miR-27a/QD-HA-PEI exhibited effective and selective anti-cancer effects in vitro and in vivo with fewer side effects via the direct down-regulation of oncogenic transcription factors FOXO1 and PPAR-γ. Conclusion: Our findings validate the dual-fluorescent nanoparticles as delivery vectors of therapeutic miRNA, capable of simultaneous tumor imaging and tracking of miRNA-based modulation therapy, thereby providing an efficient and safe approach for liver cancer theranostics.

Berberine inhibits the chemotherapy-induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer.

OBJECTIVES: Cytotoxic chemotherapy is an effective and traditional treatment of ovarian cancer. However, chemotherapy-induced apoptosis may also trigger and ultimately accelerate the repopulation of the small number of adjacent surviving cells. This study mainly focused on the tumour cell repopulation caused by chemotherapy in ovarian cancer and the adjunctive/synergistic effect of Berberine on the prevention of tumour repopulation. MATERIALS AND METHODS: The transwell system was used to mimic the co-culture of surviving ovarian cancer cells in the microenvironment of cytotoxic chemotherapy-treated dying cells. Tumour cell proliferation was observed by crystal violet staining. AA and PGE2 levels were measured by ELISA, and changes of protein expression were analysed by Western blot. RESULTS: Chemotherapy drug VP16 treatment triggered AA pathway, leading to the elevated PGE2 level, and ultimately enhanced the repopulation of ovarian cancer cells. Berberine can block the caspase 3-iPLA2 -AA-COX-2-PGE2 pathway by inhibiting the expression of iPLA2 and COX-2. Berberine can also reverse the increased phosphorylation of FAK caused by abnormal PGE2 level and thus reverse the repopulation of ovarian cancer cells after VP16 treatment. CONCLUSIONS: Our observation suggested that Berberine could inhibit the chemotherapy-induced repopulation of ovarian cancer cells by suppressing the AA pathway and phosphorylation of FAK. And these findings implicated a novel combined use of Berberine and chemotherapeutics, which might prevent ovarian cancer recurrence by abrogating early tumour repopulation.

Chemotherapy induces ovarian cancer cell repopulation through the caspase 3-mediated arachidonic acid metabolic pathway.

Recurrence is one of the major causes of high mortality in ovarian cancer. However, the mechanism of ovarian cancer recurrence after chemotherapy has not been fully understood. In the present study, we investigated the effect of chemotherapy-induced tumor microenvironment on the proliferation of SKOV3 cells. We have shown that SKOV3 cells repopulated faster in the culture medium from apoptotic SKOV3 ovarian cancer cells after 24 h of etoposide phosphate (VP-16) treatment. We found that during apoptosis, cleaved caspase 3 could activate cytosolic calcium-independent phospholipase A2, which stimulated the release of arachidonic acid (AA) and triggered the production of prostaglandin E2 (PGE2). An increased level of phosphorylated focal adhesion kinase (FAK) subsequently facilitated the reproliferation of SKOV3 cells, and VP-16-induced repopulation effects were partially reversed by the FAK inhibitor PF562271. Furthermore, the plasma AA-to-PGE2 ratio and tumoral FAK expression of ovarian cancer patients after chemotherapy were significantly lower than those before chemotherapy. Taken together, our results indicate that chemotherapy-induced apoptotic cancer cells can produce PGE2-enriched microenvironment through caspase 3-mediated AA metabolic pathway, which could lead to the abnormal activation of FAK and eventually accelerate the repopulation of SKOV3 cells. Our study provides novel insight into a mechanism that may be utilized to prevent ovarian cancer recurrence in response to chemotherapy.