A case of acute lung injury in a peripheral blood stem cell donor mobilized with pegylated recombinant human granulocyte colony-stimulating factor.

Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) has been introduced for the mobilization of peripheral blood stem cells (PBSCs). However, no cases of acute lung injury (ALI) in healthy donors have been reported, and the underlying mechanisms remain poorly understood. We first reported a case of ALI caused by PEG-rhG-CSF in a healthy Chinese donor, characterized by hemoptysis, hypoxemia, and patchy shadows. Ultimately, hormone administration, planned PBSC collection, leukocyte debridement, and planned PBSC collection resulted in active control of the donor's ALI. The donor's symptoms improved without any adverse effects, and the PBSC collection proceeded without incident. Over time, the lung lesion was gradually absorbed and eventually returned to normal. PEG-rhG-CSF may contribute to ALI in healthy donors via mechanisms involving neutrophil aggregation, adhesion, and the release of inflammatory mediators in the lung. This case report examines the clinical manifestations, treatment, and mechanism of lung injury induced by PEG-rhG-CSF-mobilized PBSCs.

Identification of Parkinson's disease subtypes with distinct brain atrophy progression and its association with clinical progression.

Background: Parkinson's disease (PD) patients suffer from progressive gray matter volume (GMV) loss, but whether distinct patterns of atrophy progression exist within PD are still unclear. Objective: This study aims to identify PD subtypes with different rates of GMV loss and assess their association with clinical progression. Methods: This study included 107 PD patients (mean age: 60.06 ± 9.98 years, 70.09% male) with baseline and ≥ 3-year follow-up structural MRI scans. A linear mixed-effects model was employed to assess the rates of regional GMV loss. Hierarchical cluster analysis was conducted to explore potential subtypes based on individual rates of GMV loss. Clinical score changes were then compared across these subtypes. Results: Two PD subtypes were identified based on brain atrophy rates. Subtype 1 (n = 63) showed moderate atrophy, notably in the prefrontal and lateral temporal lobes, while Subtype 2 (n = 44) had faster atrophy across the brain, particularly in the lateral temporal region. Furthermore, subtype 2 exhibited faster deterioration in non-motor (MDS-UPDRS-Part Ⅰ, ß = 1.26 ± 0.18, P = 0.016) and motor (MDS-UPDRS-Part Ⅱ, ß = 1.34 ± 0.20, P = 0.017) symptoms, autonomic dysfunction (SCOPA-AUT, ß = 1.15 ± 0.22, P = 0.043), memory (HVLT-Retention, ß = -0.02 ± 0.01, P = 0.016) and depression (GDS, ß = 0.26 ± 0.083, P = 0.019) compared to subtype 1. Conclusion: The study has identified two PD subtypes with distinct patterns of atrophy progression and clinical progression, which may have implications for developing personalized treatment strategies.

Oral application of magnesium-L-threonate alleviates radicular pain by inhibiting neuro-inflammation dependent central sensitization of rats.

BACKGROUND: We have reported neuro-inflammation is involved in radicular pain by enhancing the efficiency of pain synaptic transmission in spinal level. Recently, peers' studies have confirmed that magnesium deficiency leads to neuro-inflammation, thus contributes to memory and emotional deficits and pain hypersensitivity in antineoplastic agents treated rats. In this study, we explore the effect of oral application of magnesium-L-threonate (L-TAMS) in radicular pain induced by lumbar disc herniation (LDH) of rats and the possible mechanisms. METHODS: Rat model of LDH was induced by autologous nucleus pulposus (NP) implantation. Mechanical and thermal pain thresholds were assessed by von Frey filaments and hotplate test respectively. L-TAMS was applied from drinking water at dosage of 604 mg/kg/day from 2 day before NP implantation and until the end of the experiment. Free Mg2+ content in serum and cerebrospinal fluid (CSF) was measured by calmagite chromometry. Synaptic transmission efficiency was determined by C-fiber evoked field potentials recorded by electrophysiologic recording in vivo. The activation of microglia in spinal dorsal horn was displayed by immunofluorescence staining and western blotting. The expressions of pro-inflammatory cytokines and glutamic N-methyl-D-aspartate receptor (NMDAR) subunits (NR2A, NR2B) were assessed by western blotting and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: NP implantation induced mechanical allodynia and thermal hyperalgesia, accompanied by decreased Mg2+ concentration in serum and CSF which were both obscured by oral application of L-TAMS. L-TAMS inhibited spinal microglia activation and pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) expression of rats with NP. L-TAMS decreased C-fiber evoked potentials and NR2B protein level in rats with NP, which were rescued by extra intrathecal delivery of TNF-α or IL-6 or IL-1ß. CONCLUSIONS: Oral application of L-TAMS alleviates radicular pain by inhibiting neuro-inflammation dependent central sensitization of rats.

Overcoming the Low-Stability Bottleneck in the Clinical Translation of Liposomal Pressurized Metered-Dose Inhalers: A Shell Stabilization Strategy Inspired by Biomineralization.

Currently, several types of inhalable liposomes have been developed. Among them, liposomal pressurized metered-dose inhalers (pMDIs) have gained much attention due to their cost-effectiveness, patient compliance, and accurate dosages. However, the clinical application of liposomal pMDIs has been hindered by the low stability, i.e., the tendency of the aggregation of the liposome lipid bilayer in hydrophobic propellant medium and brittleness under high mechanical forces. Biomineralization is an evolutionary mechanism that organisms use to resist harsh external environments in nature, providing mechanical support and protection effects. Inspired by such a concept, this paper proposes a shell stabilization strategy (SSS) to solve the problem of the low stability of liposomal pMDIs. Depending on the shell material used, the SSS can be classified into biomineralization (biomineralized using calcium, silicon, manganese, titanium, gadolinium, etc.) biomineralization-like (composite with protein), and layer-by-layer (LbL) assembly (multiple shells structured with diverse materials). This work evaluated the potential of this strategy by reviewing studies on the formation of shells deposited on liposomes or similar structures. It also covered useful synthesis strategies and active molecules/functional groups for modification. We aimed to put forward new insights to promote the stability of liposomal pMDIs and shed some light on the clinical translation of relevant products.

Rivastigmine nasal spray for the treatment of Alzheimer's Disease: Olfactory deposition and brain delivery.

Alzheimer's disease (AD) is characterized by a gradual decline in cognitive function and memory impairment, significantly impacting the daily lives of patients. Rivastigmine (RHT), a cholinesterase inhibitor, is used to treat mild to moderate AD via oral administration. However, oral administration is associated with slow absorption rate and severe systemic side effects. RHT nasal spray (RHT-ns), as a nose-to-brain delivery system, is more promising for AD management due to its efficient brain delivery and reduced peripheral exposure. This study constructed RHT-ns for enhancing AD treatment efficacy, and meanwhile the correlation between drug olfactory deposition and drug entering into the brain was explored. A 3D-printed nasal cast was employed to quantify the drug olfactory deposition. Brain delivery of RHT-ns was quantified using fluorescence tracking and Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) analysis, which showed a good correlation to the olfactory deposition. F2 (containing 1% (w/v) viscosity modifier Avicel® RC-591) with high olfactory deposition and drug brain delivery was further investigated for pharmacodynamics study. F2 exhibited superiority in AD treatment over the commercially available oral formulation. In summary, the present study showed the successful development of RHT-ns with improved olfactory deposition and enhanced brain delivery. It might provide new insight into the design and development of nose-to-brain systems for the treatment of AD.

Editorial on Special Issue "Design and Optimization of Pharmaceutical Gels".

The efficacy of many bioactive agents, including drugs, food supplements, and vaccines, is limited because of their poor chemical stability, low water solubility, and low oral bioavailability [...].

Dual peptides-modified cationic liposomes for enhanced Lung cancer gene therapy by a gap junction regulating strategy.

BACKGROUND: Gene therapy for lung cancer has emerged as a novel tumor-combating strategy for its superior tumor specificity, low systematical toxicity and huge clinical translation potential. Especially, the applications of microRNA shed led on effective tumor ablation by directly interfering with the crucial gene expression, making it one of the most promising gene therapy agents. However, for lung cancer therapy, the microRNA treatment confronted three bottlenecks, the poor tumor tissue penetration effect, the insufficient lung drug accumulation and unsatisfied gene transfection efficiency. To address these issues, an inhalable RGD-TAT dual peptides-modified cationic liposomes loaded with microRNA miR-34a and gap junction (GJ) regulation agent all-trans retinoic acid (ATRA) was proposed, which was further engineered into dry powder inhalers (DPIs). RESULTS: Equipped with a rough particle surface and appropriate aerodynamic size, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs were expected to deposit into the deep lung and reach lung tumor lesions guided by targeting peptide RGD. Assisted by cellular transmembrane peptides TAT, the RGD-TAT-CLPs/ARTA@miR-34a was proven to be effectively internalized by cancer cells, enhancing gene transfection efficiency. Then, the GJ between tumor cells was upregulated by ARTA, facilitating the intercellular transport of miR-34a and boosting the gene expression in the deep tumor. CONCLUSION: Overall, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could enhance tumor tissue penetration, elevate lung drug accumulation and boost gene transfection efficiency, breaking the three bottlenecks to enhancing tumor elimination in vitro and in vivo. We believe that the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could serve as a promising pulmonary gene delivery platform for multiple lung local disease treatments.

Polymyxin B sulfate inhalable microparticles with high-lectin-affinity sugar carriers for efficient treatment of biofilm-associated pulmonary infections.

Pulmonary infections caused by multidrug-resistant bacteria have become a significant threat to human health. Bacterial biofilms exacerbate the persistence and recurrence of pulmonary infections, hindering the accessibility and effectiveness of antibiotics. In this study, a dry powder inhalation (DPI) consisting of polymyxin B sulfate (PMBS) inhalable microparticles and high-lectin-affinity (HLA) sugar (i.e., raffinose) carriers was developed for treating pulmonary infections and targeting bacterial lectins essential for biofilm growth. The formulated PMBS-HLA DPIs exhibited particle sizes of approximately 3 µm, and surface roughness varied according to the drug-to-carrier ratio. Formulation F5 (PMBS: raffinose = 10:90) demonstrated the highest fine particle fraction (FPF) value (64.86%), signifying its substantially enhanced aerosol performance, potentially attributable to moderate roughness and smallest mass median aerodynamic particle size. The efficacy of PMBS-HLA DPIs in inhibiting biofilm formation and eradicating mature biofilms was significantly improved with the addition of raffinose, suggesting the effectiveness of lectin-binding strategy for combating bacterial biofilm-associated infections. In rat models with acute and chronic pulmonary infections, F5 demonstrated superior bacterial killing and amelioration of inflammatory responses compared to spray-dried PMBS (F0). In conclusion, our HLA carrier-based formulation presents considerable potential for the efficient treatment of multidrug-resistant bacterial biofilm-associated pulmonary infections.

Supercritical antisolvent-fluidized bed for the preparation of dry powder inhaler for pulmonary delivery of nanomedicine.

The supercritical antisolvent-fluidized bed coating process (SAS-FB) shows great potential as a technique to manufacture dry powder inhaler (DPI) that incorporate nanodrugs onto micronized matrix particles, capitalizing on the merits of both nanoparticle and pulmonary delivery. In this study, naringin (NAR), a pharmacologically active flavonoid with low solubility and in vivo degradation issues, was utilized as a model active pharmaceutical ingredient to construct nanomedicine-based DPI through SAS-FB. It is showed that processed NAR exhibited a near-spherical shape and an amorphous structure with an average size of around 130 nm. Notably, SAS-FB products prepared with different fluidized matrices resulted in varying deposition patterns, particularly when mixed with a coarse lactose to enhance the fine particle fraction (FPF) of the formulations. The FPF was positively associated with specific surface area of the SAS-FB products, while the specific surface area was directly related to surface roughness and particle size. In vitro dissolution studies using simulated lung fluid revealed that the NAR nanoparticles coated on the products were released immediately upon contact with solution, with a cumulative dissolution exceeding 90% within the first minute. Importantly, compared to oral raw NAR, the optimized DPI formulation demonstrated superior in vivo plasmatic and pulmonary AUC0→∞ by 51.33-fold and 104.07-fold respectively in a Sprague-Dawley rat model. Overall, SAS- FB technology provides a practical approach to produce nanomedicine DPI product that combine the benefits of nanoparticles with the aerodynamics properties of inhaled microparticles.

Association of body fat distribution with all-cause and cardiovascular mortality in US adults: a secondary analysis using NHANES.

OBJECTIVE: To investigate the association of fat and lean mass in specific regions with all-cause and cardiovascular-related mortality. DESIGN: Population based cohort study. SETTING: US National Health and Nutrition Examination Survey (2003-2006 and 2011-2018). PARTICIPANTS: 22 652 US adults aged 20 years or older. EXPOSURES: Fat and lean mass in specific regions obtained from the whole-body dual-energy X-ray absorptiometry. MAIN OUTCOME MEASURES: All-cause and cardiovascular-related mortality. RESULTS: During a median of 83 months of follow-up, 1432 deaths were identified. Associations between body composition metrics and mortality risks were evident above specific thresholds. For all-cause mortality, Android fat mass showed elevated HRs above 2.46 kg (HR: 1.17, 95% CI 1.02 to 1.34), while Android lean mass (ALM) had similar trends above 2.75 kg (HR: 1.17, 95% CI 1.03 to 1.33), and Android total mass above 5.75 kg (HR: 1.08, 95% CI 1.01 to 1.16). Conversely, lower HRs were observed below certain thresholds: Gynoid fat mass (GFM) below 3.71 kg (HR: 0.72, 95% CI 0.56 to 0.93), Gynoid lean mass below 6.44 kg (HR: 0.77, 95% CI 0.64 to 0.92), and Gynoid total mass below 11.78 kg (HR: 0.76, 95% CI 0.70 to 0.84). Notably, below 0.722 kg, the HR of visceral adipose tissue mass (VATM) was 1.25 (95% CI 1.04 to 1.48) for all-cause mortality, and above 3.18 kg, the HR of total abdominal fat mass was 2.41 (95% CI 1.15 to 5.05). Cardiovascular-related mortality exhibited associations as well, particularly for Android fat mass (AFM) above 1.78 kg (HR: 1.22, 95% CI 1.01 to 1.47) and below 7.16 kg (HR: 0.50, 95% CI 0.36 to 0.69). HRs varied for Gynoid total mass below and above 10.98 kg (HRs: 0.70, 95% CI 0.54 to 0.93, and 1.12, 95% CI 1.02 to 1.23). Android per cent fat, subcutaneous fat mass (SFM), AFM/GFM, and VATM/SFM were not statistically associated with all-cause mortality. Android per cent fat, Gynoid per cent fat, AFM/GFM, and VATM/SFM were not statistically associated with cardiovascular-related mortality. Conicity index showed that the ALM/GLM had the highest performance for all-cause and cardiovascular-related mortality with AUCs of 0.785, and 0.746, respectively. CONCLUSIONS: The relationship between fat or lean mass and all-cause mortality varies by region. Fat mass was positively correlated with cardiovascular mortality, regardless of the region in which they located. ALM/GLM might be a better predictor of all-cause and cardiovascular-related mortality than other body components or body mass index.

Guard against internal and external: An antibacterial, anti-inflammation and healing-promoting spray gel based on lyotropic liquid crystals for the treatment of diabetic wound.

The diabetic wound is a prevalent and serious complication of diabetes, which easily deteriorates due to susceptibility to infection and difficulty in healing, causing a high risk of amputation and economic burden to patients. Bacterial infection, persistent excessive inflammation, and cellular and angiogenesis disorders are the main reasons for the difficulty of diabetic wound healing. In this study, glycerol monooleate (GMO) was used to prepare lyotropic liquid crystal hydrogel (LLC) containing the natural antimicrobial peptide LL37 and carbenoxolone (CBX) to achieve antibacterial, anti-inflammation, and healing promotion for the treatment of diabetic wounds. The shear-thinning properties of the LLC precursor solution allowed it to be administered in the form of a spray, which perfectly fitted the shape of the wound and transformed into a gel after absorbing wound exudate to act as a wound protective barrier. The faster release of LL37 realized rapid sterilization of wounds, controlled the source of inflammation, and accelerated wound healing. The inflammatory signaling pathway was blocked by the subsequently released CBX, and the spread of the inflammatory response was inhibited and then further weakened. In addition, CBX down-regulated connexin (Cx43) to assist LL37 to promote cell migration and proliferation better. Combined with the pro-angiogenic effect of LL37, the healing of diabetic wounds was significantly accelerated. All these advantages made LL37-CBX-LLC a promising approach for the treatment of chronic diabetic wounds.

Decreased in n-3 DHA enriched triacylglycerol in small extracellular vesicles of diabetic patients with cardiac dysfunction.

PURPOSE: Diabetic cardiomyopathy is the leading cause of death in diabetic patients, and the mechanism by which factors other than hyperglycemia contribute to the development of diabetic cardiomyopathy is unknown. Serum small extracellular vesicles (sEVs) carry bioactive proteins or nuclei, which enter into remote tissues and modulate cell functions. However, in diabetic conditions, the changes of lipids carried by sEVs has not been identified. Our study aims to explore the changes of lipids in sEVs in diabetic patients with cardiovascular disease, we hope to provide new ideas for understanding the role of lipid metabolism in the pathogenesis of diabetic cardiomyopathy. METHODS: SEVs samples derived from serum of health controls (Ctrl), diabetic patients without cardiovascular diseases (DM), and diabetic patients with cardiovascular diseases (DM-CAD) were used for lipidomics analysis. Because AC16 cells are also treated with those sEVs to confirm the entrance of cells and effects on insulin sensitivity, a lipidomics analysis on cells was also performed. RESULTS AND CONCLUSIONS: In this study, we found that docosahexaenoic acid (DHA)-triacylglycerides of sEVs from serums of DM-CAD patients decreased significantly, and those sEVs could enter into AC16 cells and diminish insulin sensitivity. In addition, DHA-triacylglycerides were also decreased in cells treated with sEVs from DM-CAD. Therefore, DHA-triacylglycerides carried by sEVs may mediate intercellular signaling and be associated with the incidence of diabetic cardiovascular complications.

Factors affecting nasal drug delivery and design strategies for intranasal drug delivery. / é¼»è ”è¯ç‰©é€’é€çš„å½±å“å› ç´ å’Œæé«˜é€’é€æ•ˆçŽ‡çš„è®¾è®¡ç­–ç•¥.

Intranasal drug delivery system is a non-invasive drug delivery route with the advantages of no first-pass effect, rapid effect and brain targeting. It is a feasible alternative to drug delivery via injection, and a potential drug delivery route for the central nervous system. However, the nasal physiological environment is complex, and the nasal delivery system requires "integration of medicine and device". Its delivery efficiency is affected by many factors such as the features and formulations of drug, delivery devices and nasal cavity physiology. Some strategies have been designed to improve the solubility, stability, membrane permeability and nasal retention time of drugs. These include the use of prodrugs, adding enzyme inhibitors and absorption enhancers to preparations, and new drug carriers, which can eventually improve the efficiency of intranasal drug delivery. This article reviews recent publications and describes the above mentioned aspects and design strategies for nasal intranasal drug delivery systems to provide insights for the development of intranasal drug delivery systems.

A Pilot Study Exploiting the Industrialization Potential of Solid Lipid Nanoparticle-Based Metered-Dose Inhalers.

BACKGROUND: Delivery of inhalable nanoparticles through metered-dose inhalers (MDI) is a promising approach to treat lung disease such as asthma and chronic obstructive pulmonary disease. Nanocoating of the inhalable nanoparticles helps in stability and cellular uptake enhancement but complicates the production process. Thus, it is meaningful to accelerate the translation process of MDI encapsulating inhalable nanoparticles with nanocoating structure. METHODS: In this study, solid lipid nanoparticles (SLN) are selected as a model inhalable nanoparticle system. An established reverse microemulsion strategy was utilized to explore the industrialization potential of SLN-based MDI. Three categories of nanocoating with the functions of stabilization (by Poloxamer 188, encoded as SLN(0)), cellular uptake enhancement (by cetyltrimethylammonium bromide, encoded as SLN(+)), and targetability (by hyaluronic acid, encoded as SLN(-)) were constructed upon SLN, whose particle size distribution and zeta-potential were characterized. Subsequently, SLN were loaded into MDI, and evaluated for the processing reliability, physicochemical nature, formulation stability, and biocompatibility. RESULTS: The results elucidated that three types of SLN-based MDI were successfully fabricated with good reproducibility and stability. Regarding safety, SLN(0) and SLN(-) showed negligible cytotoxicity on cellular level. CONCLUSIONS: This work serves as a pilot study for the scale-up of SLN-based MDI, and could be useful for the future development of inhalable nanoparticles.

Paraneoplastic stiff-person syndrome with lung cancer: a case report and literature review.

Stiff person syndrome is a rare autoimmune disease of the central nervous system that manifests as stiffness and painful spasms of the trunk axis and lower limb muscles. Benzodiazepines are the first choice for the clinical treatment of the disease. We reported a case of SPS. The patient presented with stiffness and convulsions of lower limbs, weakness after convulsions, falling off easily, abdominal muscle stiffness, and painful spasms lasting for several minutes and alleviating spontaneously. This was caused or aggravated by fatigue or mental stimulation. Left stiffness and weakness of the muscle after relief was present. A chest-enhanced computed tomography scan (CT) suggested two large ground glass nodules in the upper lobe of the left lung. Biopsy pathology indicated the nodules as adenocarcinoma in situ. The patient's symptoms were significantly relieved after treatment with clonazepam and diazepam combined with pregabalin. The clinical manifestations of SPS vary among patients. The symptoms of the disease are mild or severe. Early identification and treatment can improve the prognoses of these patients.

Association between cooking fuel and folate insufficiency among pregnant women in Northern China.

This study explored whether using a coal or biomass stove for cooking was associated with a greater risk of red blood cell (RBC) folate insufficiency among pregnant women compared to using clean energy. A researcher-designed questionnaire was used to collect information on exposure-related factors and confounding factors. RBC folate concentrations were examined by microbiological assay. Binary logistic regression analysis was used to identify factors related to RBC folate insufficiency. The use of coal or firewood for cooking was associated with an increased risk of RBC folate insufficiency (<906 nmol/L) compared to gas. In subgroup analyses, associations between the use of polluting cooking fuels and folate insufficiency were positive for both urban and rural residents and statistically significant for rural women. Efforts to promote the use of clean energy and proper ventilation, especially in rural areas, are recommended to improve the health of pregnant women and their offspring.