Clinical, Imaging, and Pathological-Molecular Characteristics Associated with Stage IA Invasive Lung Adenocarcinoma Recurrence After Sub-lobar Resection.

RATIONALE AND OBJECTIVES: This study aimed to investigate the association of clinical, imaging, and pathological-molecular characteristics with the prediction of patient prognosis with stage IA invasive lung adenocarcinoma (ILADC) after sub-lobar resection. MATERIALS AND METHODS: This study assessed 360 patients, including 91 and 269 with and without recurrence 3 years postoperatively, respectively, with stage IA ILADC undergoing preoperative chest computed tomography (CT) scans and subsequent sub-lobar resection at our institution. Their clinical and CT features and histological subtypes and gene mutation status were compared. Binary logistic regression analysis was conducted to identify the independent risk factors for recurrence. An external validation cohort included 113 patients, used to test the model's efficiency. RESULTS: For clinical features, old age, male gender, smokers, and high age-adjusted Charlson comorbidity index (ACCI) were frequently observed in patients with recurrence than those without (all p < 0.05). For CT features, large tumor size, solid-predominant density, spiculation, peripheral fibrosis, type II pleural tag, and pleural adhesion were more common in recurrent patients than non-recurrent ones (all p < 0.05). The regression model revealed old age, large tumor size, solid-predominant density, spiculation, type II pleural tag, and pleural adhesion as independent risk factors for recurrence, with an area under the curve (AUC) of 0.942. The external validation cohort obtained an AUC of 0.958. For phological-molecular features, micropapillary/solid-predominant growth pattern, KRAS, ALK, and NRAS mutation or fusion were more common in the recurrent group, whereas EGFR mutation was more frequent in the non-recurrent group (all p < 0.05). CONCLUSION: Clinical and CT features help predict the prognosis of patients with stage IA ILADC after sub-lobar resection and decide for individualized treatment. Moreover, patients with different prognosis demonstrated different pathological-molecular features.

Efficacy of Polyethylene Glycol Electrolyte Powder Combined With Linaclotide for Colon Cleansing in Patients With Chronic Constipation Undergoing Colonoscopy: A Multicenter, Single-Blinded, Randomized Controlled Trial.

INTRODUCTION: Constipation is an independent risk factor for poor bowel preparation. This study aimed to evaluate the bowel cleansing efficacy and safety of polyethylene glycol (PEG) combined with linaclotide (lin) for colonoscopy in patients with chronic constipation (CC). METHODS: This single-blinded, randomized, controlled, and multicenter study was conducted from July 2021 to December 2022 at 7 hospitals. Patients with CC who underwent colonoscopies were enrolled and randomly assigned to 4 groups with split-PEG regimens: 4L-PEG group, 4L-PEG+1d-Lin group, 3L-PEG+1d-Lin group, and 3L-PEG+3d-Lin group. The primary outcome was rates of adequate bowel preparation, defined as a total BBPS score ≥6 and a score ≥2 for each segment. Secondary outcomes were adverse effects, sleep quality, willingness to repeat the colonoscopy, adenoma detection rate, and polyp detection rate. RESULTS: Five hundred two patients were enrolled. The rates of adequate bowel preparation (80.0% vs 60.3%, P < 0.001; 84.4% vs 60.3%, P < 0.001) and the total Boston Bowel Preparation Scale (BBPS) scores (6.90 ± 1.28 vs 6.00 ± 1.61, P < 0.001; 7.03 ± 1.24 vs 6.00 ± 1.61, P < 0.01) in the 4L-PEG+1d-Lin group and the 3L-PEG+3d-Lin group were superior to that in the 4L-PEG group. Compared with the 4L-PEG group, the 4L-PEG+1d-Lin group (66.7% vs 81.7%, P = 0.008) and the 3L-PEG+3d-Lin group (75.0% vs 81.7%, P = 0.224) had a lower percentage of mild adverse events. No statistically significant difference in willingness to repeat the colonoscopy, sleep quality, polyp detection rate, or adenoma detection rate was observed among groups. DISCUSSION: PEG combined with linaclotide might be an effective method for bowel preparation before colonoscopy in patients with CC.

The clinical application of transarterial embolization via radial artery in hemorrhagic diseases in obstetrics and gynecology.

Purpose: The present study aimed to explore the feasibility and safety of Transarterial embolization (TAE) in the treatment of obstetrics and gynecological hemorrhagic diseases transradial approach (TRA) compared to transfemoral approach (TFA). Methods: This cohort study was conducted on patients with obstetrics and gynecology bleeding diseases from June 2021 to November 2022. Clinical characteristics of the patients were comparable between the two groups. The success rate of puncture and embolization, radiation dose, operation time, fluoroscopy time (FT), as well as complications of each patient were recorded and then retrospectively analyzed the data. The European Five-dimensional Health Scale (ED-5Q) and visual analog scale (VAS) were used to assess the quality of life (QOL) on the day of discharge and 30 days after surgery between the two groups. Results: A total of 71 patients undergoing TAE were allocated to the TRA (n = 31) or TFA (n = 40) group in this study. Puncture and embolization were completed in all patients. Compared to the TFA group, the radiation dose of the TRA group (343.89 ± 108.81 mGy vs. 469.29 ± 198.66 mGy; p = 0.029) is significantly reduced. Minor complications occurred in only one patient (3.2%) in the TRA group. The surgery-related quality of life EQ-5D index score on the day of discharge in the TRA group (0.72 ± 0.12 vs. 0.65 ± 0.11; p = 0.017) was significantly higher than that in the TFA group, and the VAS score (2.55 ± 0.62 vs. 2.95 ± 0.85; p = 0.025) of catheter site discomfort was significantly lower in the TRA group were than in the TFA group, but no significant difference was observed in the QOL assessment at 30 days post-surgery. Conclusion: Transradial approach TAE has comparable efficacy and safety to TFA TAE in treating obstetrics and gynecological bleeding diseases. This access can improve patient QOL without affecting surgical safety.

Technique to match mesorectal lymph nodes imaging findings to histopathology: node-by-node comparison.

BACKGROUND: Lymph node status is critical for staging rectal cancer and determining neoadjuvant therapy regimens. Establishing a matching between imaging and histopathological lymph nodes is fundamental for predicting lymph node status. This study reports a technique to achieve node-by-node pairing of mesorectal lymph nodes between imaging findings and histopathology. METHODS: Fifty-two patients with histopathologically verified rectal cancer underwent magnetic resonance imaging before surgery. The status of each lymph node in the surgical specimens was analyzed histopathologically and matched with preoperative imaging after the operation. RESULTS: A total of 346 mesorectal lymph nodes were located on imaging evaluation, of which 313 were confirmed histopathologically, and 33 were unmatched. The total success rate of the technique was 90.5%. Node-by-node analysis revealed 280 benign and 33 malignant nodal structures. CONCLUSION: The technique to match mesorectal lymph node imaging findings to histopathology was feasible and effective. It simplified the technical method and had a reasonable success matching rate, which could provide a standardized approach for obtaining a prospective correlation between imaging and histological findings, supporting all subsequent related studies at the level of mesorectal lymph nodes.

Integration of pharmacodynamics and metabolomics reveals the therapeutic effects of 6-acetylacteoside on ovariectomy-induced osteoporosis mice.

BACKGROUND: 6-acetylacteoside (6-AA) is a phenylethanoid glycoside isolated from Cistanche deserticola which had been previously proven to possess anti-osteoporotic activity previously. Currently, it is still unknown whether 6-AA plays a crucial role on the anti-osteoporotic effects of C. deserticola. PURPOSE: To elucidate the therapeutic effect and mechanism of 6-AA on osteoporosis by employing an ovariectomized mouse model in vivo and RAW264.7 cells in vitro. METHODS: Sixty female ICR mice were randomly assigned into six groups: sham-operated control group (SHAM, vehicle), ovariectomized model group (OVX, vehicle), positive group (EV, 1 mg/kg/day of estradiol valerate), low dosage (10 mg/kg/day of 6-AA), medium dosage (20 mg/kg/day of 6-AA) and high dosage (40 mg/kg/day of 6-AA) treatment groups. All substances were administered daily by intragastric gavage. After 12 weeks of intervention, trabecular bone microarchitecture was estimated and bone biomechanics were determined. Bone formation and resorption factors were determined by using the corresponding Elisa kits. The related proteins and metabolites were estimated by using western-blot and metabolomics techniques. RESULTS: OVX mice demonstrated significant atrophy of the uterine and vagina, declined biomechanical parameters such as flexural strength and maximum load, deteriorated trabecular bone microarchitecture such as decreased BMD, BMC, TMC, TMD, BVF, Tb. N, and Tb. Th and increased Tb. Sp, as well as increased bone resorption factors such as TRAP, cathepsin K, and DPD, all after 12 weeks of ovariectomy operation. Following administration of 6-AA to OVX mice, parameters related to the bone microarchitecture, bone resorption activities as well as biomechanical properties were all significantly improved. Meanwhile, the levels of NF-κB, NFATc1, RANK, RANKL and TRAF6 were significantly downregulated, while OPG, PI3K and AKT were upregulated after 6-AA intervention. This indicates that, 6-AA could prevent bone resorption by regulating the RANKL/RANK/OPG mediated NF-κB and PI3K/AKT pathways. Furthermore, 26 different metabolites corresponding to 25 metabolic pathways were identified, and 5 of which were related to the formation of osteoporosis. Interestingly, 23 abnormal metabolites were recovered after 6-AA treatment. CONCLUSION: Our results revealed the significant anti-osteoporotic effects of 6-AA on ovariectomized mice which were probably exerted via suppression of osteoclast formation and bone resorption.

Establishment and validation of nomograms for predicting mesorectal lymph node staging and restaging.

BACKGROUND: Preoperative determination of lymph node (LN) status is crucial in treatment planning for rectal cancer. This study prospectively evaluated the risk factors for lymph node metastasis (LNM) at staging and restaging based on a node-by-node pairing between MRI imaging findings and histopathology and constructed nomograms to evaluate its diagnostic value. METHODS: From July 2021 to July 2022, patients with histopathologically verified rectal cancer who underwent MRI before surgery were prospectively enrolled. Histological examination of each LN status in the surgical specimens and anatomical matching with preoperative imaging. Taking histopathological results as the gold standard, federating clinical features from patients and LN imaging features on MRI-T2WI. Risk factors for LN metastasis were identified by multivariate logistic regression analysis and used to create a nomogram. The performance of the nomograms was assessed with calibration plots and bootstrapped-concordance index and validated using validation cohorts. RESULTS: A total of 500 target LNs in 120 patients were successfully matched with node-by-node comparisons. A total of 353 LNs did not receive neoadjuvant therapy and 147 LNs received neoadjuvant chemoradiotherapy (neoCRT). Characterization of LNs not receiving neoadjuvant therapy and multivariate regression showed that the short diameter, preoperative CEA level, mrT-stage, border contour, and signal intensity were associated with a high risk of LN metastasis (P < 0.05). The nomogram predicted that the area under the curve was 0.855 (95% CI, 0.794-0.916) and 0.854 (95% CI, 0.727-0.980) in the training and validation cohorts, respectively. In the neoadjuvant therapy group, short diameter, ymrT-stage, internal signal, and MRI-EMVI were associated with LN positivity (P < 0.05), and the area under the curves using the nomogram was 0.912 (95% CI, 0.856-0.968) and 0.915 (95% CI, 0.817-1.000) in two cohorts. The calibration curves demonstrate good agreement between the predicted and actual probabilities for both the training and validation cohorts. CONCLUSION: Our nomograms combined with preoperative clinical and imaging biomarkers have the potential to improve the prediction of nodal involvement, which can be used as an essential reference for preoperative N staging and restaging of rectal cancer.

Importance of Gedunin in Antagonizing Rheumatoid Arthritis via Activating the Nrf2/ARE Signaling.

Objective: This study assessed the anti-arthritic effect and protection of Gedunin (GDN) on joint tissues and revealed the possible mechanism in suppressing rheumatoid arthritis (RA). Methods: LPS-induced macrophages and TNF-α-stimulated synovial fibroblasts (MH7A) or IL-1ß-stimulated primary rheumatoid arthritis synovial fibroblasts (RASFs) were used to evaluate the antiinflammatory effect of GDN. In addition, CIA-induced arthritis was employed here to evaluate the anti-arthritic effect. MTT and BRDU assays were utilized to evaluate the cell viability and proliferation, Q-PCR was conducted to detect the mRNA expression of cytokines, FACS was adopted to monitor ROS production, while western blotting (WB) and siRNA interference were applied in confirming the anti-arthritic effects of GDN via the Nrf2 signaling. Results. In vitro, cell viability was inhibited in macrophages and MH7A cells, but not in RASFs; but the proliferation of RASFs was significantly suppressed in time- and dose-dependent manners. GDN suppressed cytokine levels in LPS-stimulated macrophages and TNF-α-stimulated MH7A cells or RASFs. GDN suppressed ROS expression. Furthermore, GDN treatment notably dose-dependently decreased the mRNA and protein expression of iNOS in LPS-induced macrophages. sip62 interference results showed that GDN cause the less expression of HO-1 and Keap1 and also fail to inhibit cytokines after sip62 interference. In vivo, GDN effectively inhibited paw swelling, arthritis score, and arthritis incidence and cytokines. Conclusions: Our study suggested that GDN exhibited strong antagonistic effect on arthritis both in vitro and in vivo via activation of Nrf2 signaling. Our work will provide a promising therapeutic strategy for RA.

Neobaicalein Inhibits Th17 Cell Differentiation Resulting in Recovery of Th17/Treg Ratio through Blocking STAT3 Signaling Activation.

Huangqin is the dried root of Scutellaria baicalensis Georgi, which has been widely utilized for heat-clearing (Qingre) and dewetting (Zaoshi), heat-killed (Xiehuo) and detoxifying (Jiedu) in the concept of Traditional Chinese Medicine and is used for treating inflammation and cancer in clinical formulas. Neobaicalein (NEO) is of flavonoid isolated from Huangqin and has been reported to possess prominent anti-inflammatory effects in published work. Th17/Treg balance shift to Th17 cells is an essential reason for autoimmune inflammatory diseases. However, the role NEO plays in Th17 and Treg and the underlying mechanism has not been elucidated yet. Network pharmacology-based study revealed that NEO predominantly regulated IL-17 signaling pathway. Moreover, our result shown that NEO (3-30 µmol/L) down-regulated Th17 differentiation and cellular supernatant and intracellular IL-17A level and tumor necrosis factor α production in a concentration-dependent manner. The further mechanism research revealed that NEO also specifically inhibited phosphorylation of STAT3(Tyr725) and STAT4 (Y693) without influence on activation of STAT5 and STAT6 in splenocytes. Immunofluorescence results illuminated that NEO effectively blocked STAT3 translocated into nucleus. Interestingly, NEO at appreciated dose could only inhibit Th17 cell differentiation and have no effect on Treg differentiation. The present study revealed that NEO effectively inhibited Th17 cell differentiation through specifically blocking the activation of STAT3 signaling without inactivation of STAT5 and STAT6. Additional inhibitory effect on activation of STAT4 by NEO also suggested the potential for antagonism against Th1 differentiation. All work suggested that NEO may be a potential candidate for immunoregulation and treating autoimmune inflammatory diseases through inhibiting immune cell viability and T cell differentiation.

Progress in the Medicinal Value, Bioactive Compounds, and Pharmacological Activities of Gynostemma pentaphyllum.

Gynostemma pentaphyllum (Thunb.) Makino (GP), also named Jiaogulan in Chinese, was known to people for its function in both health care and disease treatment. Initially and traditionally, GP was a kind of tea consumed by people for its pleasant taste and weight loss efficacy. With the passing of the centuries, GP became well known as more than just a tea. Until now, numbers of bioactive compounds, including saponins (also named gypenosides, GPS), polysaccharides (GPP), flavonoids, and phytosterols were isolated and identified in GP, which implied the great medicinal worth of this unusual tea. Both in vivo and in vitro tests, ranging from different cell lines to animals, indicated that GP possessed various biological activities including anti-cancer, anti-atherogenic, anti-dementia, and anti-Parkinson's diseases, and it also had lipid-regulating effects as well as neuroprotection, hepatoprotective, and hypoglycemic properties. With the further development and utilization of GP, the research on the chemical constituents and pharmacological properties of GP were deepening day by day and had made great progress. In this review, the recent research progress in the bioactive compounds, especially gypenosides, and the pharmacological activities of GP were summarized, which will be quite useful for practical applications of GP in the treatment of human diseases.

Biological Activity, Hepatotoxicity, and Structure-Activity Relationship of Kavalactones and Flavokavins, the Two Main Bioactive Components in Kava (Piper methysticum).

Kava (Piper methysticum Forst) is a popular and favorable edible medicinal herb which was traditionally used to prepare a nonfermented beverage with relaxant beneficial for both social and recreational purposes. Numerous studies conducted on kava have confirmed the presence of kavalactones and flavokawains, two major groups of bioactive ingredients, in this miraculous natural plant. Expectedly, both kavalactone and flavokawain components exhibited potent antianxiety and anticancer activities, and their structure-activity relationships were also revealed. However, dozens of clinical data revealed the hepatotoxicity effect which is indirectly or directly associated with kava consumption, and most of the evidence currently seems to point the compounds of flavokawains in kava were responsible. Therefore, our aim is to conduct a systematic review of kavalactones and flavokawains in kava including their biological activities, structure-activity relationships, and toxicities, and as a result of our systematic investigations, suggestions on kava and its compounds are supplied for future research.

Exposure to a mixture of cigarette smoke carcinogens disturbs gut microbiota and influences metabolic homeostasis in A/J mice.

An increased risk of developing lung cancer has been associated with exposure to cigarette smoke carcinogens and alteration in the gut microbiota. However, there is limited understanding about the impact of exposure to NNK and BaP, the two important components of cigarette smoke carcinogens, on gut microbiota in lung cancer. The present study characterized the influence of exposure to a mixture of NNK plus BaP on lung cancer, feces metabolite composition, and gut microbiota in the A/J mice. The A/J mice were administered NNK plus BaP, and the changes in gut microbiota and feces metabolic profiles were characterized using 16S rRNA gene sequencing and metabolomics, respectively. Results presented here illustrated that a mixture of NNK plus BaP exposure triggered lung carcinogenesis as shown by light microscopy and histopathological evaluation. 16S rRNA sequencing of gut microbiota indicated that exposure to NNK plus BaP could modified fecal bacterial composition. Elevated levels of Actinobacteria, Bifidobacterium, and Intestinimonas and reduced levels of Alistipes, Odoribacter, and Acetatifactor are associated with NNK plus BaP triggered lung cancer. In addition, metabolomics profile revealed the regulation of metabolism including purine metabolism, phenylalanine metabolism, primary bile acid biosynthesis, steroid hormone biosynthesis, biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and others. In conclusion, the results provide some guidance for using gut microbes as biomarkers to assess the progression of lung cancer, and lead to interventional targets to control the development of the disease in the future.

Dual polymeric prodrug co-assembled nanoparticles with precise ratiometric co-delivery of cisplatin and metformin for lung cancer chemoimmunotherapy.

The combination therapy of cisplatin (CDDP) and metformin (MET) is a clinical strategy to enhance therapeutic outcomes in lung cancer. However, the efficacy of this combination is limited due to the asynchronous pharmacokinetic behavior of CDDP and MET, used as free drugs. Therefore, in this work, hyaluronic acid-cisplatin/polystyrene-polymetformin (HA-CDDP/PMet) dual-prodrug co-assembled nanoparticles were developed, with precise ratiometric co-delivery of CDDP and MET for chemo-immunotherapy against lung cancer. The HA-CDDP/PMet NPs showed a spherical morphology with an average particle size of 166.5 nm and a zeta potential of -17.4 mV at an HA-CDDP and PMet mass ratio of 1/1. The content of CDDP and MET in HA-CDDP/PMet NPs was 3.7% and 15.2%, respectively. In vitro antitumor effects of CDDP and MET resulted in an improved synergistic action on proliferation inhibition and apoptosis induction on Lewis lung cancer cells. Moreover, in vivo by co-delivered HA-CDDP/PMet NPs into tumor cells, with an excellent intracellular CDDP and MET cleavage. These nanoparticles exhibited significantly increased tumor accumulation and tumor growth inhibition and prolonged animal overall survival in Lewis lung cancer bearing mice without nephrotoxicity, excess of free drugs and homo-prodrugs. The synergistic effect of MET and CDDP in HA-CDDP/PMet NPs resulted in up-regulation of the cleaved poly(ADP)-ribose polymerase (PARP) protein to induce tumor cell apoptosis, and down-regulation of the excision repair cross-complementation group 1 (ERCC1) protein level to decrease the resistance to CDDP. The synergistic effect of MET and CDDP in HA-CDDP/PMet NPs also resulted in induction of the adenosine monophosphate (AMP)-activated protein kinase-α (AMPK-α) pathway and inhibition of the mammalian target of rapamycin (mTOR), finally exerting a chemotherapeutic effect and modulating a potent immunotherapeutic function with an increase in CD4+ and CD8+ T cells, a concomitant decrease in regulatory T (Treg) cells, and an increased expression of the cytokines IFN-γ and TNF-α. Therefore, the immunochemotherapy using CDDP and MET mediated by this dual prodrug co-assembled nano-platform might provide a promising treatment strategy against lung cancer.

The bioactive components as well as the nutritional and health effects of sea buckthorn.

Sea buckthorn (SB), also named sea berry, Hippophae rhamnoides L. or Elaeagnus rhamnoides L., has been used in daily life for centuries with kinds of purposes ranging from a beverage with a pleasant taste and flavor, to an agent for treatment of many disorders and diseases. SB is well known more than just a fruit. So far, a unique mixture of bioactive components was elucidated in SB including flavonoids, phenolic acids, proanthocyanidins, carotenoids, fatty acids, triterpenoids, vitamins and phytosterols, which implied the great medicinal worth of this seaberry. Both in vitro and in vivo experiments, ranged from cell lines to animals as well as a few in patients and healthy volunteers, indicated that SB possessed various biological activities including anti-inflammatory and immunomodulatory effects, antioxidant properties, anti-cancer activities, hepato-protection, cardiovascular-protection, neuroprotection, radioprotection, skin protection effect as well as the protective effect against some eye and gastrointestinal sickness. Furthermore, the toxicological results revealed neither the fruits, nor the seeds of SB were toxic. The present review summarizes the unique profile of the chemical compounds, the nutritional and health effects as well as the toxicological properties of SB, which lay the foundation for practical applications of SB in treatment of human diseases.

Protective Effect of Acteoside on Ovariectomy-Induced Bone Loss in Mice.

Acteoside, an active phenylethanoid glycoside compound isolated from herbs of Cistanche, was chosen for the investigation of anti-osteoporotic effect on postmenopausal osteoporosis by using an ovariectomized (OVX) mice model. The results from in vivo experiments showed that after daily oral administration of acteoside (20, 40, and 80 mg/kg body weight/day) for 12 weeks, bone mineral density and bone biomechanical properties of OVX mice were greatly enhanced, with significant improvement in bone microarchitecture. Furthermore, biochemical parameters of bone resorption markers as well as bone formation index, including tartrate-resistant acid phosphatase, cathepsin K, deoxypyridinoline, alkaline phosphatase, and bone gla-protein, were ameliorated by acteoside treatment, whereas the body, uterus, and vagina wet weights were seemingly not impacted by acteoside administration. Acteoside significantly affected osteoclastogenesis by attenuating nuclear factor kappa B (NF-κB) and stimulating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signal pathways through down-regulated levels of tumor-necrosis factor receptor-associated factor 6 (TRAF6), receptor activator of nuclear factor kappa B ligand (RANKL), RANK, NFKBIA, IκB kinase ß, nuclear factor of activated T-cells c2 (NFAT2), and up-regulated expressions of PI3K, AKT, and c-Fos. Accordingly, the current research validated our hypothesis that acteoside possesses potent anti-osteoporotic properties and may be a promising agent for the prevention of osteoporosis in the future.

Co-Delivery of Paclitaxel by a Capsaicin Prodrug Micelle Facilitating for Combination Therapy on Breast Cancer.

Poor anticancer ability, serious adverse reaction, and drug resistance against paclitaxel (PTX) have limited its clinical applications. When a mouse breast carcinoma cell line (4T1) was treated with both PTX and capsaicin (CAP), there was a synergistic anti-proliferative effect demonstrated with a combination index of 0.28. Therefore, a novel polyethylene glycol-derivatized CAP (PEG-Fmoc-CAP2) polymeric prodrug micellar carrier was developed and further encapsulated with PTX for antitumor combination treatment. The PEG-Fmoc-CAP2 polymeric micelles co-delivered with PTX achieved a 62.3% fraction of apoptotic cells in comparison to 45.4% fraction of apoptotic cells to that upon treatment with PTX alone. Comparable CAP amounts were found in the cell lysate treatment with PEG-Fmoc-CAP2-conjugated micelles to that of free CAP-treated 4T1 cells after 12 h treatment. Pharmacokinetic and biodistribution studies showed that the micelles possessed much longer circulation time in blood and preferential tumor tissue accumulation compared to the Taxol solution. Importantly, PTX/CAP-loaded micelles exhibited superior in vivo antitumor activity on the inhibition rate of tumor growth than other treatments (70.5% tumor growth reduction in PTX/CAP micelle-treated mice vs 57.8, 43.3, and 23.8% of tumor growth inhibition rate in PTX/PEG-Fmoc-OA2 micelles, Taxol, and PEG-Fmoc-CAP2 micelle-treated mice, respectively). Thus, the dual-functional PEG-Fmoc-CAP2 polymeric prodrug micelles are a promising co-delivery nanosystem for achieving synergistic antitumor efficacy of PTX and CAP.

Glycyrrhetinic acid-conjugated polymeric prodrug micelles co-delivered with doxorubicin as combination therapy treatment for liver cancer.

Significant synergy of doxorubicin (DOX) and glycyrrhizic acid (GA) in inhibiting the proliferation of cancer cells was demonstrated in the human hepatocellular carcinoma cell line, HepG2. A novel polymeric prodrug micellar carrier based on polyethylene glycol-derivatized GA (PEG-Fmoc-GA), was developed for co-delivery of DOX as a combined anti-cancer treatment. The PEG-Fmoc-GA polymeric prodrug micelles achieved a more effective synergistic action on cell proliferation inhibition and apoptosis induction, when co-delivered with DOX, which can be attributed to the dual effect of the cleaved GA and loaded DOX. PEG-Fmoc-GA conjugated micelles significantly facilitated the intracellular uptake of DOX by HepG2 cells, when compared to a DOX solution alone. In addition, DOX encapsulated in PEG-Fmoc-GA micelles displayed longer blood circulation time, larger drug concentration area under the curve, decreased volume distribution and clearance than DOX solution. Biodistribution studies showed that DOX/PEG-Fmoc-GA micelles were preferentially accumulated at the tumor site. Importantly, DOX/PEG-Fmoc-GA micelles demonstrated a more pronounced therapeutic efficacy in vivo compared with DOX alone with respect to both tumor growth inhibition and overall survival in a HepG2 xenograft model. Thus, PEG-Fmoc-GA polymeric prodrug micelles represent a promising dual-function co-delivery system to achieve anti-cancer synergistic activity of DOX and GA.

Cynomorium songaricum prevents bone resorption in ovariectomized rats through RANKL/RANK/TRAF6 mediated suppression of PI3K/AKT and NF-κB pathways.

AIM: Cynomorium songaricum Rupr., an edible and important Traditional Chinese medicine has long been used in folk for treatment of kidney deficiency, was chosen to estimate the antiosteoporotic activity and underlying molecular mechanism on rats induced by ovariectomy (OVX). MAIN METHODS: 9 of 45 rats were underwent bilateral laparotomy without removing the ovaries as sham group, remains were underwent bilateral ovariectomy and equally randomized into four groups: with vehicle (0.5% CMC-Na) as model group, estradiol valerate (1 mg/kg body weight/day) as positive control, with 100 and 300 mg/kg body weight/day of ethanol extracts of C. songaricum extract (CSE) as low and high dosage groups, respectively. KEY FINDINGS: After 12 weeks of continues orally intervention, the decreases of bone mineral density, bone mineral content, tissue mineral content, as well as the increases of bone trabecular separation and bone resorption markers were significantly reversed by CSE in the OVX rats, and in particular, a contradictory phenomenon on calcium and phosphorus contents was observed and elucidated. Mechanistically, the expressions of tumor-necrosis factor receptor-associated factor 6 (TRAF 6), nuclear factor kappa B (RANK) and its ligand (RANKL), as well as the nuclear factor kappa B (NF-κB), phosphoinositide 3­kinase (PI3K) and protein kinase B (AKT) levels were significantly down-regulated by CSE intervention, whereas the osteoprotegerin (OPG) was significantly up-regulated by CSE as compared to the control. SIGNIFICANCE: Concisely, C. songaricum exhibited potential therapeutic effect on bone metabolism of ovariectomized rats, and this effect was possibly exerted by RANKL/RANK/TRAF6 mediated down-regulation of NF-κB and PI3K/AKT pathways.

Syringin prevents bone loss in ovariectomized mice via TRAF6 mediated inhibition of NF-κB and stimulation of PI3K/AKT.

BACKGROUND: Syringin, also called eleutheroside B, is a main bioactive phenolic glycoside in Acanthopanax senticosus (Rupr. et Maxim.) Harms. Based on the "kidney dominates bone" theory of TCM, A. senticosus can strengthen bone and Syringin may be one of the responsibilities. PURPOSE: The objectives of this study were to estimate the osteoporotic activity of Syringin and reveal the possible molecular mechanisms in vivo. METHODS: Sixty female ICR mice were randomly assigned into sham operated group (SHAM, treated with vehicle) and five ovariectomized subgroups (n = 10 each), treated with vehicle as OVX group, estradiol valerate (EV, 1 mg/kg/day) as positive group, and Syringin (10, 20 and 40 mg/kg/day) as low, moderate and high dosage groups. The therapeutic effect of Syringin against osteoporosis was systematically analyzed by determining the bone mineral density (BMD), bone biomechanical properties, bone microarchitecture and serum biochemical parameters, and the molecular mechanism was also evaluated. RESULTS: After three months of orally administrated intervention, Syringin (10, 20 and 40 mg/kg/day) significantly improved the BMD, bone maximum load and trabecular bone microarchitecture in ovariectomized mice, evidenced by the increased bone mineral content, tissue mineral content, tissue mineral density, trabecular thickness and trabecular number, as well as the decreased trabecular separation in OVX mice. Meanwhile, the activities of tartrate-resistant acid phosphatase, deoxypyridinoline and cathepsin K in OVX mice were also inhibited by Syringin, while the increased body weight and decreased uterus weight seemed not influenced by Syringin administration. Concerning the underlying molecular mechanisms, Syringin significantly downregulated the expression of tumor-necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor kappa B (NF-κB) and receptor activator of nuclear factor kappa B ligand (RANKL) proteins levels, upregulated the expression of osteoprotegerin (OPG), phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) levels, suggesting that Syringin prevented bone lost by TRAF6-mediated inhibition of NF-κB and stimulation of PI3K/AKT, and subsequently increasing the OPG/RANKL ratio and inhibiting the osteoclastogenesis, finally promoting bone formation. CONCLUSIONS: All of the data implied Syringin possessed the potent anti-osteoporosis activity on ovariectomized mice, and the underlying molecular mechanism may be related to the NF-κB and PI3K/AKT signaling pathways.

Silymarin-Loaded Nanoparticles Based on Stearic Acid-Modified Bletilla striata Polysaccharide for Hepatic Targeting.

Silymarin has been widely used as a hepatoprotective drug in the treatment of various liver diseases, yet its effectiveness is affected by its poor water solubility and low bioavailability after oral administration, and there is a need for the development of intravenous products, especially for liver-targeting purposes. In this study, silymarin was encapsulated in self-assembled nanoparticles of Bletilla striata polysaccharide (BSP) conjugates modified with stearic acid and the physicochemical properties of the obtained nanoparticles were characterized. The silymarin-loaded micelles appeared as spherical particles with a mean diameter of 200 nm under TEM. The encapsulation of drug molecules was confirmed by DSC thermograms and XRD diffractograms, respectively. The nanoparticles exhibited a sustained-release profile for nearly 1 week with no obvious initial burst. Compared to drug solutions, the drug-loaded nanoparticles showed a lower viability and higher uptake intensity on HepG2 cell lines. After intravenous administration of nanoparticle formulation for 30 min to mice, the liver became the most significant organ enriched with the fluorescent probe. These results suggest that BSP derivative nanoparticles possess hepatic targeting capability and are promising nanocarriers for delivering silymarin to the liver.

Kartogenin, transforming growth factor-ß1 and bone morphogenetic protein-7 coordinately enhance lubricin accumulation in bone-derived mesenchymal stem cells.

Osteoarthritis, a common joint degeneration, can cause breakdown of articular cartilage with the presence of lubricin metabolic abnormalities. Lubricin is a multi-level chondroprotective mucinous glycoprotein in articular joints. Joint defect and infection is elevated and accompanied by accelerated cartilage lesions involving degradation and loss of lubricin. However, a novel, heterocyclic compound called kartogenin (KGN) was discovered to stimulate chondrogenic differentiation of bone-derived mesenchymal stem cells (BMSCs). And the synergistic effect of transforming growth factor-ß1 (TGF-ß1) and bone morphogenetic protein-7 (BMP-7) could provoke lubricin accumulation. This paper attempted to explore the connection between accumulation of lubricin and the effect of TGF-ß1, BMP-7 and/or KGN. Hence, we investigated the expression and secretion of lubricin in BMSCs treated with different combinations of TGF-ß1, BMP-7, and/or KGN. Using an in vitro BMSCs system, we observed the content of lubricin from BMSCs treated with TGF-ß1, BMP-7, and KGN was the highest at both the protein level and the gene level. The accumulation of lubricin was enhanced coordinately by the increase of synthesis and decrease of degradation possibly via c-Myc and adamts5 pathway. These results further suggested that supplementation of the defect parts with lubricin by using growth factors and small molecules showed a promising potential on preventing joint deterioration in patients with acquired or genetic deficiency of lubricin in the future of regenerative medicine.