The excitatory transmission from basolateral nuclues of amygdala to nucleus accumbens shell regulates propofol self-administration through AMPA receptors.

Propofol addictive properties have been demonstrated in humans and rats. The glutamatergic transmission from basolateral nucleus of amygdala (BLA) to the nucleus accumbens (NAc) modulates reward-seeking behaviour; especially, NAc shell (NAsh) is implicated in reward-seeking response. Previous studies indicated the interactions between AMPA receptors (AMPARs) and dopamine D1 receptor (D1R) in NAc mediated drug addiction, but whether the circuit of BLA-to-NAsh and AMPARs regulate propofol addiction remains unclear. We trained adult male Sprague-Dawley rats for propofol self-administration to examine the changes of action potentials (APs) and spontaneous excitatory postsynaptic currents (sEPSCs) in the NAsh. Thereafter, optogenetic stimulation with adeno-associated viral vectors microinjections in BLA was used to explore the effect of BLA-to-NAsh on propofol self-administration behaviour (1.7 mg/kg/injection). The pretreatment effects with NBQX (0.25-1.0 µg/0.3 µl/site) or vehicle in the NAsh on propofol self-administration behaviour, the expressions of AMPARs subunits and D1R/ERK/CREB signalling pathway in the NAc were detected. The results showed that the number of APs, amplitude and frequency of sEPSCs were enhanced in propofol self-administrated rats. Propofol self-administration was inhibited in the NpHR3.0-EYFP group, but in the ChR2-EYFP group, there was a promoting effect, which could be weakened by NBQX pretreatment. NBQX pretreatment also significantly decreased the expressions of GluA2 subunit and D1R in the NAc but did not change the expressions of GluA1 and ERK/CREB signalling pathway. The evidence supports a vital role of BLA-to-NAsh circuit in regulating propofol self-administration and suggests this central reward processing may function through the interaction between AMPARs and D1R in the NAsh.

Design and synthesis of novel 3,4-dihydrocoumarins as potent and selective monoamine oxidase-B inhibitors with the neuroprotection against Parkinson's disease.

The monoamine oxidase-B (MAO-B) inhibitors with neuroprotective effects are better for Parkinson's disease (PD) treatment, due to the complicated pathogenesis of PD. To develop new hMAO-B inhibitors with neuroprotection, a novel series of 3,4-dihydrocoumarins was designed as selective and reversible hMAO-B inhibitors to treat PD. Most compounds showed potent and selective inhibition for hMAO-B over hMAO-A with IC50 values ranging from nanomolar to sub-nanomolar. Among them, compound 4d was the most potent hMAO-B inhibitor (IC50 = 0.37 nM) being about 20783-fold more active than iproniazid, and exhibited the highest selectivity for hMAO-B (SI > 270,270). Kinetic studies revealed that compound 4d was a reversible and competitive inhibitor of hMAO-B. Neuroprotective studies indicated that compound 4d could protect PC12 cells from the damage induced by 6-OHDA and rotenone. Besides, compound 4d did not exhibit acute toxicity at a dose up to 2500 mg/kg (po), and could cross the BBB in parallel artificial membrane permeability assay. More importantly, compound 4d was able to significantly prevent the motor deficits in the MPTP-induced PD model. These results indicate that compound 4d is an effective and promising candidate against PD.

Design, synthesis and evaluation of novel ferulic acid derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease.

A series of new ferulic acid derivatives were designed, synthesized and evaluated as multi-target inhibitors against Alzheimer's disease. In vitro studies indicated that most compounds showed significant potency to inhibit self-induced ß-amyloid (Aß) aggregation and acetylcholinesterase (AChE), and had good antioxidant activity. Specifically, compound 4g exhibited the potent ability to inhibit cholinesterase (ChE) (IC50, 19.7 nM for hAChE and 0.66 µM for hBuChE) and the good Aß aggregation inhibition (49.2% at 20 µM), and it was also a good antioxidant (1.26 trolox equivalents). Kinetic and molecular modeling studies showed that compound 4g was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, compound 4g could remarkably increase PC12 cells viability in hydrogen peroxide-induced oxidative cell damage and Aß-induced cell damage. Finally, compound 4g had good ability to cross the BBB using the PAMPA-BBB assay. These results suggested that compound 4g was a promising multifunctional ChE inhibitor for the further investigation.

A near-infrared Nile red fluorescent probe for the discrimination of biothiols by dual-channel response and its bioimaging applications in living cells and animals.

Biothiols, including cysteine (Cys), homocysteine (Hcy), glutathione (GSH) and H2S, play important roles in human physiological processes. However, it is a great difficulty to distinguish biothiols from each other because of their similar chemical properties. Based on Nile red, we have designed and synthesized a near-infrared fluorescent probe for discriminating Cys/Hcy from GSH/H2S by a dual-channel detection method. Using an ether bond, near-infrared Nile red was attached to 7-nitrobenzofurazan to construct the probe. Due to the photo-induced electron transfer, the probe showed almost no fluorescence from the green to red emission band. But upon the addition of Cys (0-150 µM) or Hcy (0-200 µM), the probe exhibited a noteworthy fluorescence "turn-on" signal in two unique emission bands (Green and Red) with a fast response (within 30 min). In contrast, the probe displayed an increase in fluorescence only in the red channel when encountering GSH (0-70 µM) or H2S (0-50 µM), and GSH/H2S could be tested respectively by different response time. The limit of detection was calculated to be 0.09 µM (Cys), 0.30 µM (Hcy), 0.24 µM (GSH), and 0.04 µM (H2S), respectively (based on S/N = 3). The desirable dual-channel detection could be achieved in serum samples and living cells. Moreover, the probe could be applied for bioimaging in mice, which indicated its potential application in the clinic.

Impact of hemodynamic goal-directed resuscitation on mortality in adult critically ill patients: a systematic review and meta-analysis.

The effect of hemodynamic optimization in critically ill patients has been challenged in recent years. The aim of the meta-analysis was to evaluate if a protocolized intervention based on the result of hemodynamic monitoring reduces mortality in critically ill patients. We performed a systematic review and meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions. The study was registered in the PROSPERO database (CRD42015019539). Randomized controlled trials published in English, reporting studies on adult patients treated in an intensive care unit, emergency department or equivalent level of care were included. Interventions had to be protocolized and based on results from hemodynamic measurements, defined as cardiac output, stroke volume, stroke volume variation, oxygen delivery, and central venous-or mixed venous oxygenation. The control group had to be treated without any structured intervention based on the parameters mentioned above, however, monitoring by central venous pressure measurements was allowed. Out of 998 screened papers, thirteen met the inclusion criteria. A total of 3323 patients were enrolled in the six trials with low risk of bias (ROB). The mortality was 22.4% (374/1671 patients) in the intervention group and 22.9% (378/1652 patients) in the control group, OR 0.94 with a 95% CI of 0.73-1.22. We found no statistically significant reduction in mortality from hemodynamic optimization using hemodynamic monitoring in combination with a structured algorithm. The number of high quality trials evaluating the effect of protocolized hemodynamic management directed towards a meaningful treatment goal in critically ill patients in comparison to standard of care treatment is too low to prove or exclude a reduction in mortality.

The efficacy and safety of mivacurium in pediatric patients.

BACKGROUND: Mivacurium is the shortest acting nondepolarizing muscle relaxant currently available; however, the effect of different dosages and injection times of intravenous mivacurium administration in children of different ages has rarely been reported. This study was aimed to evaluate the muscle relaxant effects and safety of different mivacurium dosages administered over different injection times in pediatric patients. METHODS: Six hundred forty cases of pediatric patients, aged 2 m-14 years, ASA I or II, were divided into four groups (Groups A, B, C, D) according to the age class (2-12 m, 13-35 m, 3-6 years and 7-14 years) respectively, also each group were divided into four subgroups by induction dose (0.15, 0.2 mg/kg in 2-12 m age class; 0.2, 0.25 mg/kg in other three age classes), and mivacurium injection time (20 s, 40 s), totally 16 subgroups. Neuromuscular transmission was monitored with supramaximal train-of-four stimulation of the ulnar nerve. Radial artery blood (1 ml) was sampled to quantify plasma histamine concentrations before and 1, 4, and 7 min after mivacurium injection (P0, P1, P2 and P3). RESULTS: Five hundred sixty-two cases completed the study. There were no demographic differences within the four groups. The onset time of 0.2 mg/kg groups in 2-12 m aged patients were shorter than those of 0.15 mg/kg groups (189 ± 64 s vs. 220 ± 73 s, 181 ± 60 s vs. 213 ± 71 s, P <0.05), and the recovery times were no statistical differences. The T1 25% recovery time of 0.2 mg/kg in 3-6 years aged patients was shorter than that of 0.25 mg/kg group (693 ± 188 s vs. 800 ± 206 s, P <0.05). The onset and recovery times of mivacurium were not different in 13-35 m and 7-14 years aged patients. The plasma concentrations of histamine at P0, P1, P2 and P3 were not different within four groups. CONCLUSIONS: The induction dose and injection time of mivacurium had mostly insignificant effects on onset and recovery times. The main exception to this was that in 2-12 m aged patients, increasing the dose of mivacurium from 0.15 to 0.2 mg/kg accelerated the onset time by about 30 s. Mivacurium produced no significant release of histamine in any age group at the doses studied. TRIAL REGISTRATION: ClinicalTrials.gov Identifier- NCT02117401 , July 14, 2014. (Retrospectively registered).

Can noninvasive hemoglobin measurement reduce the need for preoperative venipuncture in pediatric outpatient surgery?

BACKGROUND: Noninvasive measurements of hemoglobin in the pediatric perioperative setting could be helpful to avoid venipunctures in children. The present study aims to evaluate this by using a noninvasive device for hemoglobin determination. We compared noninvasively obtained hemoglobin with laboratory hemoglobin concentrations in children during their preoperative assessment. METHODS: In an observational study, 122 nonanemic children (age 4.2 ± 1.6 years) who were scheduled to undergo different surgical procedures under general anesthesia were included. In their preoperative preparations, single invasive blood samples for laboratory hemoglobin concentrations were routinely taken following hospital policy and compared to simultaneous noninvasive determinations of hemoglobin. A preoperative invasive value ≤9 g/dL would have caused cancelation of surgery and implied further investigations. RESULTS: A Bland-Altman plot showed that the average difference between noninvasively obtained hemoglobin and laboratory hemoglobin concentration was -0.44 g/dL (bias) with a standard deviation of the mean bias of 1.04 g/dL. A hemoglobin error grid showed that the noninvasive device could identify almost all invasive hemoglobin values >9 g/dL. In total, there were 4 false-positive values where noninvasively obtained hemoglobin observations were below while the paired invasive values were above 9 g/dL. CONCLUSION: The data in this pediatric setting suggest that the device may eliminate the need for venipuncture in nonanemic children.

A Fluorescent Coumarin-Based Probe for the Fast Detection of Cysteine with Live Cell Application.

A new coumarin-based fluorescent probe, containing an allylic esters group, has been designed and synthesized for sensing cysteine in physiological pH. In this fluorescent probe, the coumarin was applied as the fluorophore and an allylic esters group was combined as both a fluorescence quencher and a recognition unit. The probe can selectively and sensitively detect cysteine (Cys) over homocysteine, glutathione, and other amino acids, and has a rapid response time of 30 min and a low detection limit of 47.7 nM. In addition, the probe could be applied for cell imaging with low cytotoxicity.

The use of a noninvasive hemoglobin monitor for determining fluid distribution and elimination in pediatric patients undergoing minor surgery.

In pediatric fluid therapy it would be preferable to describe distribution and elimination a fluid bolus based on repetitive hemoglobin (Hb) according to kinetic principles. Pulse CO-Oximetry is a recent advancement in patient monitoring that allows for the continuous noninvasive measurement of Hb (SpHb). The aim of this study was to describe the distribution and elimination of hydroxyethylstarch (HES) 130/0.4 in combination with crystalloids using a noninvasive Hb monitor in two cohorts of young children undergoing minor surgeries under general anesthesia. Two cohorts, 16 children aged 1-3 years and 12 aged 4-6 years, were investigated during anesthesia and minor surgical procedures. They were given a maintenance solution of lactated Ringer's and a fluid bolus of HES 130/0.4, 6 mL/kg over a period of 20 min. The whole procedure lasted 120 min, and SpHb values were measured every 10 min. The SpHb values were used to calculate plasma dilution, net volume, and mean residence time (MRT) of the infused fluid. A total of 377 measured SpHbs generated individual dilution plots that showed variability, particularly for the older cohort. Distribution and elimination rates of the infused fluid were calculated. Mean dilution plots were generated. There were no significant differences in dilution, net volume or MRT between groups. A non invasive Hb analyzer could be used to calculate fluid distribution. The variability in the data can probably be explained by reactions to anesthetic drugs, variability in measurement technique, variability in generating the complex capillary signals, and individual variability in baseline fluid status. The latter finding is important because this is a prerequisite for perioperative fluid planning for each individual.

Dose requirements of remifentanil for intubation in nonparalyzed Chinese children.

BACKGROUND: The objective of this study was to determine ED50 and ED95 of remifentanil for intubation combined with propofol in nonparalyzed Chinese children. METHODS: Forty-seven American Society of Anesthesiologists Class I children aged 4-11 years weighing 14-33.5 kg underwent general anesthesia with 2.5 mg·kg(-1) of intravenous propofol followed by remifentanil in Wenzhou, China. The initial dose of remifentanil was 2.5 µg·kg(-1) injected over 60 s. Intubation was attempted 30 s after the completion of remifentanil injection. Level of difficulty to intubate was graded on a scoring system. If the initial intubation condition was deemed satisfactory, subsequent remifentanil doses were decreased by 0.25 µg·kg(-1). If the intubating condition was deemed unsatisfactory, subsequent remifentanil doses were increased by 0.25 µg·kg(-1). Mean arterial pressure, heart rate, and pulse oximetry were documented before and after induction, immediately after intubation, and 1 min after intubation. RESULTS: The ED50 of remifentanil used to render a satisfactory intubating condition used in combination with 2.5 mg·kg(-1) of propofol in nonparalyzed Chinese children was 2.30 µg·kg(-1) (95% confidence interval: 2.28-2.31 µg·kg(-1)), and the ED95 is 2.75 µg·kg(-1) (95% confidence interval: 2.59-3.35 µg·kg(-1)). These doses were lower than previously reported. CONCLUSION: When used in combination with 2.5 mg·kg(-1) of intravenous propofol, ED50 and ED95 of remifentanil for adequate intubation in nonparalyzed children were lower than previously reported, at 2.30 and 2.75 µg·kg(-1), respectively.

[Effect of single-dose dexmedetomidine on recovery profiles after sevoflurane anesthesia with spontaneous respiration in pediatric patients undergoing cleft lip and palate repair].

OBJECTIVE: To explore the effect of single-dose dexmedetomidine on recovery period after sevoflurane anesthesia with spontaneous respiration in pediatric patients undergoing cleft lip and palate repair. METHODS: A total of 60 American Society of Anesthesiologists (ASA) I-II pediatric patients undergoing cleft lip and palate repair from October to December 2013 were randomly divided into groups D and C (n = 30 each) . Dexmedetomidine 0.5 µg/kg (group D) or an equal volume of normal saline (group C) was ad ministered intravenously over a period of 10 min at 30 min before the end of surgery. Anesthesia was induced and maintained with sevoflurane under spontaneous ventilation. Heart rate, mean arterial pressure (MAP), hemoglobin oxygen saturation (SpO2), respiratory rate, tidal volume (VT) and pressure of end-tidal carbon dioxide (PETCO2) were recorded at the time before induction (T0), 30 min before the end of surgery (T1) , 20 min before the end of surgery (T2), 15 min before the end of surgery (T3), 10 min before the end of surgery (T4), the end of surgery (T5), extubation (T6), 5 min after transferal into post-anesthesia care unit (PACU) (T7) , 1 h after surgery (T8) , extubation time, length of PACU stay, fentanyl consumption and adverse events were all recorded. The incidence and severity of coughing and emergence agitation were assessed. RESULTS: Compared to T0, MAP and heart rate at T1 to T5 all decreased in two groups (P < 0.05). MAP and heart rate at T6 both increased in two groups and group C was higher than group D (P < 0.05). No inter-group differences existed in SpO2, respiratory rate, VT or PETCO2. The incidence of coughing and emergence agitation (30% and 13.3%), fentanyl consumption of group D (0.8 ± 2.1 µg) were all significantly lower than that of group C [(66.7% vs 56.7%) and (4.9 ± 6.50) µg, P < 0.05]. Length of PACU stay in group D was shorter than that in group C [(15 ± 6) vs (23 ± 19) min, P < 0.05]. No inter-group difference existed in extubation time or adverse events. CONCLUSION: A single intravenous dose of dexmedetomidine is effective in reducing emergence agitation and coughing, shortening length of PACU stay and improving the quality of recovery period after sevoflurane anesthesia in pediatric patients undergoing cleft lip and palate repair.

Knowledge and attitude of surgical patients and their families toward anesthesia.

Introduction: Anesthesia plays a critical role in modern surgical procedures by ensuring patient pain management and safety. This study aimed to investigate the knowledge and attitude of surgical patients and their families toward anesthesia. Methods: This prospective, cross-sectional study included patients and their families in Wenzhou, China. Data collection and the measurement of knowledge and attitude scores were administered using a self-administered questionnaire. Results: 503 participants (69.98% patients, 30.02% families) were included. The mean knowledge and attitude scores were 7.93 ± 6.11 (possible range: 0-26), and 32.64 ± 2.59 (possible range: 8-40), respectively, indicating an inadequate knowledge and positive attitude. Moreover, a multivariable logistic regression analysis showed that age [odd ratio (OR) = 0.394, p = 0.018], residence (OR = 0.424, p = 0.002), household income per month (OR = 0.297 ~ 0.380, p < 0.05), gender (OR = 1.680, p = 0.017), education (OR = 2.891, p = 0.017), and experienced anesthesia (OR = 4.405, p = 0.001) were independently associated with knowledge score. Additionally, knowledge score (OR = 1.096, p < 0.001), relationship with the patient (OR = 1.902, p = 0.009), and household income per month (OR = 0.545, p < 0.031) were independently associated with attitude score. Discussion: In conclusion, surgical patients and their families in Wenzhou, China had inadequate knowledge while positive attitude towards anesthesia, which might be influenced by their sociodemographic characteristics, including age, gender, residence, education, household income, relationship with patient, and experienced anesthesia. These findings emphasize the necessity of customized educational programs aimed at improving anesthesia knowledge and attitudes of patients and their families, especially among those with older age and lower socioeconomic status.

Transforming Cancer Treatment with Nanotechnology: The Role of Berberine as a Star Natural Compound.

Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. This review introduced the expansive spectrum of BBR's anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery. Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. Nano-delivery systems increase drug concentration at the tumor site by improving pharmacological activity and tissue distribution, enhancing drug bioavailability. Organic nanocarriers have advantages for berberine delivery including biocompatibility, encapsulation, and controlled release of the drug. While the advantages of inorganic nanocarriers for berberine delivery mainly lie in their efficient loading ability of the drug and their slow release ability of the drug. This review introduced the expansive spectrum of BBR's anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery.

Mesoporous polydopamine (MPDA)-based drug delivery system for oral chemo-photothermal combinational therapy of orthotopic colon cancer.

Oral nano-drug delivery systems offering combination therapy have garnered significant interest in colon cancer treatment due to their precision in targeting tumors and minimizing peripheral tissue exposure. However, challenges such as the complex gastrointestinal environment and effective retention of nanoparticles in the colon have impeded further advancement. We developed a novel oral drug delivery system designed for localized treatment of colon cancer via chemotherapy and photothermal therapy (PTT). This system utilized mesoporous polydopamine (MPDA) as a photothermal carrier for doxorubicin hydrochloride (DOX), with surface modification using folic acid (FA) to enhance systemic tumor targeting. Additionally, to ensure gastrointestinal retention and precise colon localization, the nanoparticles were coated with an enteric-soluble material, ES100, resulting in the formulation MPDA-FA-DOX/ES100. This formulation exhibited high photothermal conversion efficiency, robust photothermal stability, and responsive drug release under near-infrared (NIR) laser stimulation. FA modification significantly enhanced the cellular uptake of nanoparticles by CT26 cells, promoting greater cytotoxic effects through combined chemotherapy and PTT. In vivo, MPDA-FA-DOX/ES100 demonstrated superior accumulation in colon tumor tissues and substantial photothermal effects, and notably, the CT/PTT group demonstrated significant tumor growth inhibition along with excellent biocompatibility. Collectively, these findings highlight the clinical potential of MPDA-FA-DOX/ES100 as an effective platform for localized and synergistic CT/PTT of colon cancer.

Multifunctional Biomimetic Liposomes with Improved Tumor-Targeting for TNBC Treatment by Combination of Chemotherapy, Antiangiogenesis and Immunotherapy.

Triple negative breast cancer (TNBC) featuring high relapses and metastasis shows limited clinical therapeutic efficiency with chemotherapy for the extremely complex tumor microenvironment, especially angiogenesis and immunosuppression. Combination of antiangiogenesis and immunotherapy holds promise for effective inhibition of tumor proliferation and invasion, while it remains challenging for specific targeting drug delivery to tumors and metastatic lesions. Here, a multifunctional biomimetic liposome loading Gambogic acid (G/R-MLP) is developed using Ginsenoside Rg3 (Rg3) to substitute cholesterol and cancer cell membrane coating, which is designed to increase long-circulating action by a low immunogenicity and specifically deliver gambogic acid (GA) to tumor site and metastatic lesions by homologous targeting and glucose transporter targeting. After G/R-MLP accumulates in the primary tumors and metastatic nodules, it synergistically enhances the antitumor efficacy of GA, effectively suppressing the tumor growth and lung metastasis by killing tumor cells, inhibiting tumor cell migration and invasion, achieving antiangiogenesis and improving the antitumor immunity. All in all, the strategy combining chemotherapy, antiangiogenesis, and immunotherapy improves therapeutic efficiency and prolonged survival, providing a new perspective for the clinical treatment of TNBC.

A rapid quantitative UPLC-MS/MS method for analysis of key regulatory oxysterols in biological samples for liver cancer.

An UPLC-APCI-MS/MS method was developed for the simultaneous determination of cholesterol, 7-dehydrocholesterol (7DHC) and eight oxysterols including 27-hydroxycholesterol (27OHC), 7α-hydroxycholesterol (7αOHC), 7ß-hydroxycholesterol (7ßOHC), 24S-hydroxycholesterol (24SOHC), 25-hydroxycholesterol (25OHC), 7α,24S-dihydroxycholesterol (7α,24SdiOHC), 7α,25-dihydroxycholesterol (7α,25diOHC), and 7α,27-dihydroxycholesterol (7α,27diOHC). It has been used for quantitative analysis of cholesterol, 7DHC and eight oxysterols in hepatocellular carcinoma (HCC) cells, plasma and tumor tissue samples. And the above compounds were extracted from the biological matrix (plasma and tissue) using liquid-liquid extraction with hexane/isopropanol after saponification to cleave the steroids from their esterified forms without further derivatization. Then cholesterol, 7DHC and oxysterols were separated on a reversed phase column (Agilent Zorbax Eclipse plus, C18) within 8 min using a gradient elution with 0.1 % formic acid in H2O and methanol and detected by an APCI triple quadrupole mass spectrometer. The lower limit of quantification (LLOQ) of the cholesterol, 7DHC and oxysterols ranged from 3.9 ng/mL to 31.25 ng/mL, and the recoveries ranged from 83.0 % to 113.9 %. Cholesterol, 7DHC and several oxysterols including 27OHC, 7αOHC and 7ßOHC were successfully quantified in HCC cells, plasma, tissues and urine of HCC mice. Results showed that 27OHC was at high levels in three kind of HCC cells and tumor tissues as well as plasma samples from both HepG2 and Huh7 bearing mice model，and the high levels of 27OHC in tumors were associated with HCC development. Moreover, the levels of cholesterol in HCC cells and tumor issues varied in different HCC cells and mice model. Oxysterols profiling in biological samples might provide complementary information in cancer diagnosis.

Biomimetic Nanomodulators With Synergism of Photothermal Therapy and Vessel Normalization for Boosting Potent Anticancer Immunity.

Combination therapy using photothermal therapy (PTT) and immunotherapy is one of the most promising approaches for eliciting host immune responses to ablate tumors. However, its therapeutic efficacy is limited due to inefficient immune cell infiltration and cellular immune responses. In this study, a biomimetic immunostimulatory nanomodulator, Tm@PDA-GA (4T1 membrane@polydopamine-gambogic acid), with homologous targeting is developed. The 4T1 membrane (Tm) coating reduced immunogenicity and facilitated uptake of Tm@PDA-GA by tumor cells. Polydopamine (PDA) as a drug carrier can induce PTT under near-infrared ray (NIR) irradiation and immunogenic cell death (ICD) to activate dendritic cells (DCs). Moreover, Tm@PDA-GA on-demand released gambogic acid (GA) in an acidic tumor microenvironment, inhibiting the expression of heat shock proteins (HSPs) for synergetic chemo-photothermal anti-tumor activity and increasing the ICD of 4T1 cells. More importantly, GA can normalize the vessels via HIF-1α and VEGF inhibition to enhance immune infiltration and alleviate hypoxia stress. Thus, Tm@PDA-GA induced ICD, activated DCs, stimulated cytotoxic T cells, and suppressed Tregs. Moreover, Tm@PDA-GA is combined with anti-PD-L1 to further augment the tumor immune response and effectively suppress tumor growth and lung metastasis. In conclusion, biomaterial-mediated PTT combined with vessel normalization is a promising strategy for effective immunotherapy of triple-negative breast cancer (TNBC).

Versatile Thermo-Sensitive liposomes with HSP inhibition and Anti-Inflammation for synergistic Chemo-Photothermal to inhibit breast cancer metastasis.

Photothermal therapy (PTT) is a prospective therapeutic method for breast cancer. However, excess inflammatory response induced by PTT may aggravate tumor metastasis. Meanwhile, the overexpressed heat shock proteins (HSPs) by cancer cells can protect them from hyperthermia during PTT. Therefore, to attenuate the PTT-induced inflammation and inhibit tumor metastasis, a folate receptor-targeted thermo-sensitive liposome (BI-FA-LP) co-loading Berberine (BBR) and Indocyanine green (ICG) was developed. BI-FA-LP utilized enhanced permeability and retention (EPR) effect and FA receptor-mediated endocytosis to selectively accumulate at tumor, reducing off-target toxicity during the treatment. After targeting to the tumor site, BBR and ICG were released from BI-FA-LP upon laser irradiation, and ICG showed good photothermal performance, while BBR inhibited HSP70 and HSP90 expression during PTT, exerting chemo-photothermal synergetic anti-tumor effect. Moreover, BBR could suppress the PTT induced inflammation, thus inhibiting tumor metastasis and ameliorating tissue injury. Thus, this versatile liposome provided a new strategy to enhance PTT and anti-inflammatory effects for breast cancer treatment.

Unlocking the anticancer activity of gambogic acid: a shift towards ferroptosis via a GSH/Trx dual antioxidant system.

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in ferroptosis by regulating the cellular antioxidant response and maintaining redox balance. However, compounds that induce ferroptosis through dual antioxidant pathways based on Nrf2 have not been fully explored. In our study, we investigated the impact of Gambogic acid (GA) on MCF-7 cells and HepG2 cells in vitro. The cytotoxicity, colony formation assay and cell cycle assay demonstrated potent tumor-killing ability of GA, while its effect was rescued by ferroptosis inhibitors. Furthermore, RNA sequencing revealed the enrichment of ferroptosis pathway mediated by GA. In terms of ferroptosis indicators detection, evidences for GA were provided including reactive oxygen species (ROS) accumulation, alteration in mitochondrial membrane potential (MMP), disappearance of mitochondrial cristae, lipid peroxidation induction, malondialdehyde (MDA) accumulation promotion, iron ion accumulation as well as glutathione (GSH)/thioredoxin (Trx) depletion. Notably, Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) successfully rescued GA-induced MDA accumulation. In terms of mechanism, Nrf2 was found to play a pivotal role in GA-induced ferroptosis by inducing protein alterations through the iron metabolism pathway and GSH/Trx dual antioxidant pathway. Furthermore, GA exerted good antitumor activity in vivo through GSH/Trx dual antioxidant pathway, and Fer-1 significantly attenuated its efficacy. In conclusion, our findings first provided new evidence for GA as an inducer of ferroptosis, and Nrf2-mediated GSH/Trx dual antioxidant system played an important role in GA-induced ferroptosis.

Design, synthesis and bioactivity evaluation of 4-hydroxycoumarin derivatives as potential anti-inflammatory agents against acute lung injury and colitis.

Acute lung injury (ALI) and inflammatory bowel disease (IBD) are common inflammatory illnesses that seriously affect people's health. Herein, a series of 4-hydroxylcoumarin (4-HC) derivatives were designed and synthesized. The inhibitory effects of these compounds on LPS-induced interleukin-6 (IL-6) release from J774A.1 cells were then screened via ELISA assay, compound B8 showed 3 times more active than the lead compound 4-HC. The most active compound B8 had the IC50 values of 4.57 µM and 6.51 µM for IL-6 release on mouse cells J774A.1 and human cells THP-1, respectively. Furthermore, we also found that B8 could act on the MAPK pathway. Based on the target prediction results of computer virtual docking, kinase inhibitory assay was carried out, and it revealed that targeting IRAK1 was a key mechanism for B8 to exert anti-inflammatory activity. Moreover, B8 exerted a good therapeutic effect on the dextran sulfate sodium (DSS)-induced colitis model and liposaccharide (LPS)-induced ALI mouse models. The acute toxicity experiments indicated that high-dose B8 caused no adverse reactions in mice, confirming its safety in vivo. Additionally, the preliminary pharmacokinetic (PK) parameters of B8 in SD rats were also examined, revealing a bioavailability (F) of 28.72 %. In conclusion, B8 is a potential candidate of drug for the treatment of ALI and colitis.