Bone-Targeted Supramolecular Nanoagonist Assembled by Accurate Ratiometric Herbal-Derived Therapeutics for Osteoporosis Reversal.

Developing novel strategies for defeating osteoporosis has become a world-wide challenge with the aging of the population. In this work, novel supramolecular nanoagonists (NAs), constructed from alkaloids and phenolic acids, emerge as a carrier-free nanotherapy for efficacious osteoporosis treatment. These precision nanoagonists are formed through the self-assembly of berberine (BER) and chlorogenic acid (CGA), utilizing noncovalent electrostatic, π-π, and hydrophobic interactions. This assembly results in a 100% drug loading capacity and stable nanostructure. Furthermore, the resulting weights and proportions of CGA and BER within the NAs are meticulously controlled with strong consistency when the CGA/BER assembly feed ratio is altered from 1:1 to 1:4. As anticipated, our NAs themselves could passively target osteoporotic bone tissues following prolonged blood circulation, modulate Wnt signaling, regulate osteogenic differentiation, and ameliorate bone loss in ovariectomy-induced osteoporotic mice. We hope this work will open a new strategy to design efficient herbal-derived Wnt NAs for dealing with intractable osteoporosis.

The optimal blood glucose is significantly associated with lower mortality in critically ill patients with cardiogenic shock: an analysis revealed with time series blood glucose records.

BACKGROUND: The optimal blood glucose (BG) level for patients with cardiogenic shock in the intensive care unit (ICU) remains unclear. Studies have found that both excessively high and low BG levels contribute to adverse cardiovascular events. Our study aims to investigate the optimal BG level for critically ill patients with cardiogenic shock and evaluate the effects of optimal BG on the prognosis of patients. METHODS: A total of 2013 patients with cardiogenic shock obtained from the Medical Information Mart for Intensive Care (MIMIC) IV database were included in the final cohort for our retrospective observational study for data analysis. The exposure was time-weighted average BG (TWA-BG), which was calculated by the time-series BG records and corresponding time stamps of patients with cardiogenic shock during their stay in the ICU. The cut-off value of TWA-BG was identified by the restricted cubic spline curve and included patients were categorized into three groups: low TWA-BG group (TWA-BG ≤ 104 mg/dl), optimal TWA-BG group (104 < TWA-BG ≤ 138 mg/dl), and high TWA-BG group (TWA-BG > 138 mg/dl). The primary outcome was 28-day mortality, and the secondary outcomes were ICU and in-hospital mortality. We performed the log-rank test to detect whether there is a difference in mortality among different groups in the original cohort. Multiple distinct models were employed to validate the robustness of the results. RESULTS: Our study revealed that the optimal BG level for critically ill patients with cardiogenic shock is 104-138 mg/dl. Compared to the optimal TWA-BG group, the low TWA-BG group (hazard ratio (HR): 1.67, 95% confidence interval (CI): 1.19-2.33, p = 0.002) and high TWA-BG group (HR: 1.72, 95% CI: 1.46-2.03, p < 0.001) exhibited higher 28-day mortality. Similarly, the low TWA-BG group and high TWA-BG group demonstrated higher risks in terms of ICU mortality (low TWA-BG group: HR: 2.30, 95% CI: 1.40-3.79, p < 0.001; high TWA-BG group: HR: 1.77, 95% CI: 1.45-2.17, p < 0.001) and in-hospital mortality (low TWA-BG group: HR: 1.73, 95% CI: 1.19-2.51, p = 0.001; high TWA-BG group: HR: 1.64, 95% CI: 1.38-1.95, p < 0.001). Sensitivity analysis conducted through propensity score matching and the subgroup analysis further substantiated the robustness of the results. CONCLUSION: The optimal BG level for patients with cardiogenic shock is 104-138 mg/dl. BG levels below 104 mg/dl and above 138 mg/dl were associated with a less favorable prognosis.

Systemic Administration with Bacteria-Inspired Nanosystems for Targeted Oncolytic Therapy and Antitumor Immunomodulation.

Malignant tumors represent a formidable global health challenge, compelling the pursuit of innovative treatment modalities. Oncolytic therapy has emerged as a promising frontier in antitumor strategies. However, both natural agents (such as oncolytic bacteria or viruses) and synthetic oncolytic peptides confront formidable obstacles in clinical trials, which include the delicate equilibrium between safety and efficacy, the imperative for systemic administration with targeted therapy, and the need to counteract oncolysis-induced immunosuppression. To overcome these dilemmas, we have developed biomimetic nanoengineering to create oncolytic bacteria-inspired nanosystems (OBNs), spanning from hierarchical structural biomimicry to advanced bioactive biomimicry. Our OBNs harbor inherent oncolytic potential, including functionalized oligosaccharides mimicking bacterial cell walls for optimal blood circulation and tumor targeting, tumor acidity-switchable decoration for tumor-specific oncolysis, stereospecific tryptophan-rich peptides for robust oncolytic activity, encapsulated tumor immunomodulators for enhanced immunotherapy, and innate multimodal imaging potential for biological tracing. This work elucidates the efficacy and mechanisms of OBNs, encompassing primary tumor suppression, metastasis prevention, and recurrence inhibition. Systemic administration of d-chiral OBNs has demonstrated superior oncolytic efficacy, surpassing intratumoral injections of clinical-grade oncolytic peptides. This work heralds an era in biomimetic engineering on oncolytic agents, promising the revolutionization of contemporary oncolytic therapy paradigms for clinical translation.

Effect of greenhouse gas emissions on the life cycle of biomass energy production and conversion under different straw recycling modes.

With the gradual growth of greenhouse gas (GHG) emissions during the agricultural cultivation cycle, GHG emissions specific to the production and conversion of biomass energy is becoming increasingly problematic. Current studies lack analysis of net GHG emissions generated during full life cycle of agricultural cultivation, straw use and bioenergy production. This study measures the global warming potential of biomass energy production and conversion processes under different agricultural cultivation cycle systems based on life cycle approach, accompanied by four straw treatment methods: fast pyrolysis, slow pyrolysis, flash pyrolysis and anaerobic fermentation. The demonstration of Heilongjiang Province showed that the net GHG emissions of rice and soybean over 52.39% and 101.57% higher than those of corn, respectively. The amount of standard coal saved by fast pyrolysis treatment, slow pyrolysis treatment and anaerobic fermentation treatment of straw was only 38.38%, 78.02% and 61.98% of that of flash pyrolysis treatment. The relationship between environmental pressure and economic growth was decoupled during 2011-2017 and coupled in 2017-2020. This study contributes to green production of biomass energy. The methodology in this paper can be used to account for and assess the carbon effect of the entire straw recycling chain in any region.

Enantiomeric Virus-Inspired Oncolytic Particles for Efficient Antitumor Immunotherapy.

Synthesizing biomimetic systems with stereospecific architectures and advanced bioactivity remains an enormous challenge in modern science. To fundamentally eliminate biosafety issues of natural oncolytic viruses, the development of synthetic virus-inspired particles with high oncolytic activity is urgently needed for clinical antitumor treatments. Here, we describe the design and synthesis of enantiomeric virus-inspired particles for efficient oncolytic therapy from homochiral building blocks to stereospecific supramolecular constructions. The L-virus-inspired oncolytic particles (L-VOPs) and D-VOPs possess similar biomimetic nanostructures but mirror-imaged enantiomeric forms. It is important that both L-VOPs and D-VOPs successfully mimic the pharmacological activity of oncolytic viruses, including direct tumor lysis and antitumor immune activation. D-VOPs provide quite better oncolytic efficacy than that of clinical-grade oncolytic agents (LTX-315, IC50 = 53.00 µg mL-1) with more than 5-fold decrease in IC50 value (10.93 µg mL-1) and close to 100% tumor suppression (98.79%) against 4T1 tumor-bearing mice, attributed to the chirality-dependent tumor recognition, interaction, antidegradation, and immunotherapy. This work provides a strategy for the synthesis of stereospecific biomimetic material systems as well as develops an advanced candidate for biomimetic oncolytic agents without biosafety risks.

Bio-Responsive Macromolecular Drug and Small-Molecular Drug Conjugates: Nanoparticulate Prodrugs for Tumor Microenvironment Heterogeneity Management and Therapeutic Response Enhancement.

How to break through the poor response of current drug therapy, which often resulted from tumor microenvironment heterogeneity (TMH), remains an enormous challenge in the treatment of critical diseases. In this work, a practical solution on bio-responsive dual-drug conjugates for overcoming TMH and improving antitumor treatment, which integrates the advantages of macromolecular drugs and small-molecular drugs, is proposed. Nanoparticulate prodrugs based on small-molecular drug and macromolecular drug conjugates are designed as a robust weapon for programmable multidrug delivery at tumor-specific sites: the tumor microenvironment acid condition triggers delivery of macromolecular aptamer drugs (AX102) to manage TMH (including tumor stroma matrix, interstitial fluid pressure, vasculature network, blood perfusion, and oxygen distribution), and intracellular lysosomal acid condition activates rapid release of small-molecular drugs (doxorubicin and dactolisib) to enhance curative effects. As compared with doxorubicin chemotherapy, the tumor growth inhibition rate is enhanced by 47.94% after multiple tumor heterogeneity management. This work verifies that the nanoparticulate prodrugs facilitate TMH management and therapeutic response enhancements, as well as elucidates synergetic mechanisms for drug resistance reversal and metastasis inhibition. It is hoped that the nanoparticulate prodrugs will be an excellent demonstration of the co-delivery of small-molecular drugs and macromolecular drugs.

Tendency of dynamic vasoactive and inotropic medications data as a robust predictor of mortality in patients with septic shock: An analysis of the MIMIC-IV database.

Background: Septic shock patients fundamentally require delicate vasoactive and inotropic agent administration, which could be quantitatively and objectively evaluated by the vasoactive-inotropic score (VIS); however, whether the dynamic trends of high-time-resolution VIS alter the clinical outcomes remains unclear. Thus, this study proposes the term VIS Reduction Rate (VRR) to generalise the tendency of dynamic VIS, to explore the association of VRR and mortality for patients with septic shock. Methods: We applied dynamic and static VIS data to predict ICU mortality by two models: the long short-term memory (LSTM) deep learning model, and the extreme gradient boosting (XGBoost), respectively. The specific target cohort was extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database by the sophisticated structured query language (SQL). Enrolled patients were divided into four groups by VRR value: ≥50%, 0 ~ 50%, -50% ~ 0, and < -50%. Statistical approaches included pairwise propensity score matching (PSM), Cox proportional hazards regression, and two doubly robust estimation models to ensure the robustness of the results. The primary and secondary outcomes were ICU mortality and in-hospital mortality, respectively. Results: VRR simplifies the dosing trends of vasoactive and inotropic agents represented by dynamic VIS data while requiring fewer data. In total, 8,887 septic shock patients were included. Compared with the VRR ≥50% group, the 0 ~ 50%, -50% ~ 0, and < -50% groups had significantly higher ICU mortality [hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.17-1.50, p < 0.001; HR 1.79, 95% CI 1.44-2.22, p < 0.001; HR 2.07, 95% CI 1.61-2.66, p < 0.001, respectively] and in-hospital mortality [HR 1.43, 95% CI 1.28-1.60, p < 0.001; HR 1.75, 95% CI 1.45-2.11, p < 0.001; HR 2.00, 95% CI 1.61-2.49, p < 0.001, respectively]. Similar findings were observed in two doubly robust estimation models. Conclusion: The trends of dynamic VIS in ICU might help intensivists to stratify the prognosis of adult patients with septic shock. A lower decline of VIS was remarkably associated with higher ICU and in-hospital mortality among septic shock patients receiving vasoactive-inotropic therapy for more than 24 h.

Weather-driven synergistic water-economy-environment regulation of farmland ecosystems.

Farmland ecosystems (FEs) constitute the most important source of food production, and water is one of the most important factors influencing FEs. The amount of water can affect the yield and thus the economic efficiency. Water migration can generate environmental effects through the migration of fertilizers. Interlinkages and constraints exist between the water, economy and environment, which require synergistic regulation. Meteorological elements influence the reference crop uptake amount and thus the water cycle processes and are key drivers of regulation at the water-economy-environment nexus. However, the weather-driven, synergistic water-economy-environment regulation of FEs has not been sufficiently researched. As such, this paper employed a dynamic Bayesian prediction of the reference evapotranspiration (ETo) and a quantitative characterization of the total nitrogen (TN) and total phosphorus (TP) contents in agricultural crops and soils via field monitoring and indoor experimental analysis. Consequently, multiobjective optimization modeling was conducted to weigh the mutual trade-offs and constraints between water, the economy and the environment. The proposed method was verified via an example involving the modern agricultural high-tech demonstration park in Harbin, Heilongjiang Province, China. The results indicated that (1) the effect of meteorological factors gradually decreased over time, but the prediction results were very accurate, and the higher the delay order of the dynamic Bayesian network (DBN) was, the more accurate the predictions; (2) ETo was significantly driven by meteorological elements, and the most important meteorological factor influencing ETo throughout the year was average temperature. When the average temperature was reduced by 10.0 %, ETo was reduced by 1.4 %, the required amount of irrigation water was reduced by 4.9 %, and the economic benefits of a single cube of water increased by 6.3 %; (3) resource-economy-environment multidimensional synergy enabled a 12.8 % reduction in agricultural ecosystem pollutant emissions, while the economic benefits per unit of water increased by 8.2 % and the system synergy increased by 23.2 %.

Guanidinium-Rich Lipopeptide-Based Nanoparticle Enables Efficient Gene Editing in Skeletal Muscles.

Genome editing mediated by the CRISPR-Cas system holds great promise for the treatment of genetic diseases. However, safe and efficient in vivo delivery of CRISPR genome editing machinery remains a challenge. Here, we report a lipopeptide-based nanoparticle (LNP) that can efficiently deliver the CRISPR Cas9/sgRNA ribonucleoprotein (RNP) and enable efficient genome editing both in vitro and in vivo. An artificial lipopeptide, GD-LP, was constructed by linking a hydrophilic guanidinium-rich head to an oleic acid-based hydrophobic tail via a disulfide bond. LNP formed by the self-assembly of GD-LP can easily form a complex with RNP with a loading content of up to 20 wt %. The resulting RNP-LNP nanocomplex led to 72.6% gene editing efficiency in GFP-HEK cells with negligible cytotoxicity. The LNP also showed significantly higher transfection efficiencies than Lipofectamine 2000 for the delivery of mRNA in NIH 3T3 and RAW 264.7 and the delivery of plasmid DNA in B78 cells. In vivo studies showed that intramuscular injection of the RNP-LNP nanocomplex in Ai14 mice induced efficient gene editing in muscular tissues. Moreover, the delivery of Cas9 RNP and donor DNA by LNP (i.e., RNP/ssODN-LNP nanocomplex) restored dystrophin expression, reduced skeletal muscle fibrosis, and significantly improved muscle strength in a Duchenne muscular dystrophy (DMD) mouse model.

Dynamic-responsive virus-mimetic nanocapsules facilitate protein drug penetration and extracellular-specific unpacking for antitumor treatment.

Protein-based drugs have been demonstrating great potential for the treatment of various diseases, but most of them encounter many difficulties in clinical trials or uses, such as instability, low bioavailability, and poor in vivo efficacy. In this work, we developed virus-mimetic nanocapsules (VMNs) for improving protein systemic delivery and pharmaceutical effects through bioinspired macromolecular and supramolecular engineering. These VMNs possessed hierarchical nanostructures including artificial capsids, encapsulated proteins, and synthetic envelopes. These dynamic-responsive VMNs can harbor protein drugs, resist protein adsorption, target solid tumors, penetrate into deep tissue, and site-specifically unpack protein drugs. Through surmounting the sequential physio-pathological barriers, protein-loaded VMNs successfully maximized the in vitro and in vivo therapeutic efficacy of proteins, giving a promising strategy to address dilemmas on clinical TRAIL therapy. This study is expected to promote in vivo treatment outcomes and clinical transformation of protein drugs.

Risk regulation of water allocation in irrigation areas under changing water supply and demand conditions.

The uncertainty of the hydrological environment and unbalanced water resource allocation result in a high risk of irrigation water shortages in regional agriculture, which seriously affects the sustainable development of agricultural systems. In this paper, we propose a risk regulation based modeling approach for the optimal allocation of agricultural water resources in a complex stochastic environment. The approach includes a conditional value-at-risk (CVaR) model, two-stage stochastic programming (TSP) model, two-dimensional joint distribution probability (JP) model, fractal criteria, and a multiple forms of chance-constrained programming (CCP) model. The model can weigh the contradiction between the intended target and associated penalties attributed to unknown hydrological events, measure the risk between system benefits and expected losses in agricultural water allocation at different confidence levels, and address the randomness in the objective function and constraints (including the left end term, right end term, and left and right end terms). To verify the applicability of the method, it is applied to the Jinxi Irrigation District in China to optimize the allocation and risk regulation of limited water resources under the variable runoff conditions of the Songhua River and crop water demands in the irrigation area. By adjusting parameters such as risk preference and probability of violation, the risk of water shortages in the irrigation area can be regulated, and the multidimensional impacts of different water allocation schemes on agricultural economic benefits, social benefits, ecology and environment can be determined. The case study reveals that the CTSP-CCJP method is sensitive, applicable to complex and uncertain environments and important for the efficient use of agricultural water resources and risk reduction.

Profiling the influence of physicochemical parameters on the microbial community and flavor substances of zaopei.

BACKGROUND: Strong-flavor baijiu is a traditional distilled alcoholic beverage with a long history in China. The fermented grains play a pivotal role in the production of baijiu. The purpose of this study was to evaluate and compare the microbiota and flavor substances present in fermented zaopei (ZP) from pits of different ages. High-throughput sequencing, headspace solid-phase microextraction gas chromatography-mass spectrometry, principal component analysis, community composition analysis, and redundancy analysis were used to analyze and evaluate the impact of environmental factors on microbial communities and flavor substances. RESULTS: Six genera of bacteria (e.g., Caproiciproducens, Syntrophaceticus, Sedimentibacter, Hydrogenispora, Pelotomaculum and Bacillus) and seven genera of fungi (Cladosporium, Debaryomyces, Dipodascus, Auxarthron, Cephalotrichum, unclassified Stachybotryaceae, unclassified Microascaceae and Cephalotrichum) notably affected the production of hexanoic acid (an important flavor compound). Moisture and alcohol content also had considerable effects on the production of the flavor compounds such as ethyl lactate, hexanoic acid, and ethyl hexanoate. The profiles of volatile compounds present in ZP were different between the aged and new pits; these profiles were mainly reflected in the concentration and types of alcohols, aldehydes, esters, and aromatic compounds. CONCLUSIONS: This paper provides a comprehensive overview of the physicochemical parameters, flavor substances, and microbial population distribution of ZP. Characterization of various ZP samples help to elucidate the fermentation mechanisms and offer a theoretical reference to control and enhance the quality of Baijiu. © 2021 Society of Chemical Industry.

Comparative evaluation of the bispectral index (BIS) and BISpro during propofol anaesthesia.

OBJECTIVE: To compare the accuracy, correlation and agreement between the bispectral index (BIS) and BISpro during propofol anaesthesia. METHODS: The BIS, BISpro, heart rate, target-concentration of propofol and Observer's Assessment of Alertness and Sedation (OAA/S) score were recorded every 30 s in female patients scheduled for hysteroscopic surgery. Propofol anaesthesia was induced by an initial target-controlled concentration (1.0 µg/ml) followed by a stepwise increase (0.5 µg/ml) until the patient was unresponsive. Spearman's correlation coefficient and prediction probability were calculated for the association between sedation levels and the above parameters. The ability of investigated parameters to distinguish between OAA/S scores was analysed. Bland-Altman analysis was used to compare the agreement between BIS and BISpro. The BIS and BISpro cut-off values for lost response were also determined. RESULTS: Out of 30 patients in total, a high correlation was found between BIS and BISpro, and both correlated well with OAA/S score. Only BIS was able to distinguish all investigated OAA/S states accurately, but the ability to predict OAA/S score 5 to loss of response was comparable between BIS and BISpro. The calculated cut-off values were 68 for BIS and 70 for BISpro. CONCLUSION: BISpro and BIS are reliable monitors of general anaesthesia during sedation.Trial registration number: Chinese Clinical Trial Registry (URL: www.chictr.org.cn): ChiCTR1900024037 (retrospectively registered).

Controllable mixed-charged co-assembly of dendritic lipopeptides into invisible capsid-like nanoparticles as potential drug carriers.

The feature of invisibility is vital in drug nanocarriers for prolonging blood transportation, with this generating excellent resistance to protein adsorption and clearance from the body. In this work, we report a well-designed molecular and supramolecular strategy for precisely developing mixed-charged nanoparticles with resistance to protein adsorption. We constructed anionic dendritic lipopeptides (ADLs) and cationic dendritic lipopeptides (CDLs) with eight carboxyl or amino groups as terminal groups. By regulating the molar ratio between ADLs and CDLs, amphiphilic dendritic lipopeptides were assembled into nanoparticles (NPs) with adjustable surface charge. Notably, the co-assembly of equivalent amounts of ADLs and CDLs generated neutral mixed-charged NPs as invisible capsid-like NPs (ICNPs). ICNPs were able to resist protein adsorption and serve as stealth nanocarriers for harboring guest molecules.

An association between cumulative exposure to light at night and the prevalence of hyperuricemia in steel workers.

OBJECTIVES: Exposure to light at night (LAN) can disturb circadian endocrine and metabolic rhythms. Hyperuricemia (HUA) is an early-onset metabolic disorder. However, it is still not clear whether LAN exposure increases the prevalence of HUA. MATERIAL AND METHODS: The authors used crosssectional data on the Beijing-Tianjin-Hebei occupational populations cohort from March-July 2017. A total of 7664 steel workers were finally selected to investigate the relationship between LAN exposure and the prevalence of HUA among steel workers. The authors collected demographic and socio-economic data, as well as information on lifestyle factors, anthropometric measures, and laboratory tests. The restricted cubic spline method was used to analyze the dose-response relationship between cumulative LAN exposure and the prevalence of HUA. Logistic regression analyses were used to fit the relationship between them. RESULTS: The average age of the participants was 43.5±8.6 years; 7051 (91.7%) of them were males, 2749 (35.9%) reported to suffer from HUA, and 1241 (16.2%) were not exposed to LAN. There was a significant non-linear dose-response relationship between them. After adjustment for the confounding factors, including demographic data, lifestyle factors, etc., the lower LAN exposure was significantly associated with HUA (0-1931.7 days, OR = 1.180, and the 95% CI: 1.000-1.394; 1931.7-4343 days, OR = 1.215, 95% CI: 1.035-1.426). CONCLUSIONS: This study revealed that a certain amount of exposure to LAN is independently related to the prevalence of HUA in steel workers in China. Int J Occup Med Environ Health. 2021;34(3):385-401.

Corneal curvature, asphericity, and aberrations after transepithelial photorefractive keratectomy and femtosecond laser-assisted in situ keratomileusis for myopia: A prospective comparative study.

PURPOSE: We aimed to compare transepithelial photorefractive keratectomy (TPRK) and femtosecond laser-assisted in situ keratomileusis (FS-LASIK) for myopia treatment by analyzing corneal curvature, asphericity (Q-value), and corneal aberration. METHODS: Corneal topography was measured before and 6 months after the TPRK or FS-LASIK surgery. We measured and compared corneal curvature (sagittal curvature in the 1- to 7-mm zones), change in keratometric measurements (Kmpost - Kmpre, ΔK), Q-values (from the vertex of the 6-, 7-, 8-, and 9-mm zones), higher-order aberration (HOA), vertical and horizontal trefoil (Z3-3 and Z33), vertical and horizontal coma (Z3-1 and Z31), and spherical aberration (Z40) between the two surgery groups. RESULTS: The sagittal curvature Δ K in the 1-mm zone after TPRK was significantly higher than after FS-LASIK. The Δ K/ΔSE (ΔSE [spherical equivalent] = SEpre - SEpost) ratio in the 1- to 4-mm diameter zones was significantly higher after TPRK than after FS-LASIK. The preoperative Q-values of the 6- and 7-mm zones did not differ between the treatment groups, but postoperative values were significantly higher following FS-LASIK than following TPRK. HOA, Z40, and Z3-1 were all significantly higher after surgery in both groups. Postoperative Z3-3 was significantly higher following TPRK but not following FS-LASIK. There were no postoperative differences in aberrations in either group; however, the change in HOA and Z3-1 was significantly greater following FS-LASIK. CONCLUSION: TPRK changes the corneal curvature to a greater extent and the visual quality (Q-value, aberrations) to a lesser extent than FS-LASIK.

Hyaluronic Acid-Pluronic®F127-Laden Soft Contact Lenses for Corneal Epithelial Healing: In Vitro and In Vivo Studies.

Hyaluronic acid (HA) is widely used to treat various ocular diseases like dry eye syndrome, keratoconus, and other corneal epithelial injuries. The currently available eye drop solutions need frequent doses affecting the routine life style of patients. In this work, the silicone contact lens was designed to entrap HA and Pluronic®F127 to improve the wettability of the contact lens to treat various ocular diseases. The soaking method (HA-SM) was compared with the direct entrapment (DL-HA-PI) technique. The HA-Pluronic®F127-laden contact lenses (DL-HA-PI) showed acceptable optical transmittance with improved swelling (water content) properties. The in vitro release data showed high burst release with HA-SM contact lenses (12-36 h), while DL-HA-PI contact lenses showed prolong release up to 96 h. The in vivo release in the rabbit tear fluid showed high HA concentration (tear fluid) with DL-HA-PI contact lenses in comparison to the HA-SM contact lenses. The DL-HA-PI-3 batch with Pluronic®F127 showed more promising results in schirmer strip study in comparison to DL-HA-3 batch (without Pluronic®F127). The presence of Pluronic®F127 with HA showed high potential to improve hydration property of the contact lens. The corneal healing model showed reduction in the ocular inflammatory symptoms with DL-HA-PI-3 batch, thus demonstrating the potential of HA and Pluronic®F127 to be used in various ocular diseases.

Nanomedicine solutions to intricate physiological-pathological barriers and molecular mechanisms of tumor multidrug resistance.

Cancer multidrug resistance (MDR) has been a fatal factor for the failure of clinical chemotherapy, accompanying with tumor metastasis and recurrence. The mechanisms of MDR are extremely complicated, diversifying from tumor physiological-pathological barriers to molecular mechanisms of cellular factors. Especially, certain hard biological barriers (such as tumor tissue barriers and tumor subcellular compartments) are found to have close relationship with multidrug resistance, and increasing attentions are paid to address the MDR-related physiopathologic barriers for optimal drug distribution and bioavailability. Molecular and genetic factors of multidrug resistance are also gradually disclosed, such as decreased drug influx, increased drug efflux, altered drug targets, aberrant apoptotic pathway and activated DNA repair. To cope with these challenges, diverse nanomedicine solutions have been developed for overcoming physiological-pathological barriers and molecular mechanisms in the treatment of drug-resistant tumors. This review first introduces that multifunctional nanomedicines break through sequential physiological-pathological barriers to reverse MDR, including prolonged in vivo blood circulation, improved drug tumor penetration and intratumoral distribution, increased cellular internalization, optimized subcellular targeting and sufficient drug release. For another, nanomedicine solutions also show immense potentials on provoking multiple mechanisms for MDR reversal, such as decreasing drug efflux, strengthening tumor apoptosis and suppressing anti-apoptosis.