Engineering Telodendrimer Nanocarriers for Monomeric Amphotericin B Delivery.

Systemic fungal infections are an increasingly prevalent health problem. Amphotericin B (AmB), a hydrophobic polyene antibiotic, remains the drug of choice for life-threatening invasive fungal infections. However, it has dose-limiting side effects, including nephrotoxicity. The efficacy and toxicity of AmB are directly related to its aggregation state. Here, we report the preparation of a series of telodendrimer (TD) nanocarriers with the freely engineered core structures for AmB encapsulation to fine-tune AmB aggregation status. The reduced aggregation status correlates well with the optimized antifungal activity, attenuated hemolytic properties, and reduced cytotoxicity to mammalian cells. The optimized TD nanocarrier for monomeric AmB encapsulation significantly increases the therapeutic index, reduces the in vivo toxicity, and enhances antifungal effects in mouse models with Candida albicans infection in comparison to two common clinical formulations, i.e., Fungizone and AmBisome.

Engineering Nanotrap Hydrogel for Immune Modulation in Wound Healing.

Imbalanced immune regulation leads to the abnormal wound healing process, e.g., chronic unhealing wound or hypertrophic scar formation. Thus, the attenuation of the overflowing inflammatory factors is a viable approach to maintain the homeostatic immune regulation to facilitate normal wound healing. A versatile telodendrimer (TD) nanotrap (NT) platform is developed for efficient biomolecular protein binding. The conjugation of TD NT in size-exclusive biocompatible hydrogel resin allows for topical application for cytokine scavenging. Fine-tuning the TD NT density/valency in hydrogel resin controls resin swelling, optimizes molecular diffusion, and improves cytokine capture for effective immune modulation. The hydrogel with reduced TD NT density allows for higher protein/cytokine adsorption capacity with faster kinetics, due to the reduced barrier of TD NT nano-assembly. The positively charged TD NT hydrogel exhibits superior removal of negatively charged proinflammatory cytokines from the lipopolysaccharide (LPS, a potent endotoxin) primed immune cell culture medium. The negatively charged TD NT hydrogel removes positively charged anti-inflammatory cytokines efficiently from cell culture medium. TD NT hydrogel effectively constrains the local inflammation induced by subcutaneous LPS injection in mice. These results indicate the great potential applications of the engineered TD NT hydrogel as topical immune modulatory treatments to attenuate local inflammation.

Facial Solid-Phase Synthesis of Well-Defined Zwitterionic Amphiphiles for Enhanced Anticancer Drug Delivery.

Serum protein adsorption on the nanoparticle surface determines the biological identity of polymeric nanocarriers and critically impacts the in vivo stability following intravenous injection. Ultrahydrophilic surfaces are desired in delivery systems to reduce the serum protein corona formation, prolong drug pharmacokinetics, and improve the in vivo performance of nanotherapeutics. Zwitterionic polymers have been explored as alternative stealth materials for biomedical applications. In this study, we employed facial solid-phase peptide chemistry (SPPC) to synthesize multifunctional zwitterionic amphiphiles for application as a drug delivery vehicle. SPPC facilitates synthesis and purification of the well-defined dendritic amphiphiles, yielding high-purity and precise architecture. Zwitterionic glycerylphosphorylcholine (GPC) was selected as a surface moiety for the construction of a ultrahydrophilic dendron, which was coupled on solid phase to a hydrophobic dendron using multiple rhein (Rh) molecules as drug-binding moieties (DBMs) for doxorubicin (DOX) loading via pi-pi stacking and hydrogen bonding. The resulting zwitterionic amphiphilic Janus dendrimer (denoted as GPC8-Rh4) showed improved stabilities and sustained drug release compared to the analogue with poly(ethylene glycol) (PEG) surface (PEG5k-Rh4). In vivo studies in xenograft mouse tumor models demonstrated that the DOX-GPC8-Rh4 nanoformulation significantly improved anticancer effects compared to DOX-PEG5k-Rh4, owing to the improved in vivo pharmacokinetics and increased tumor accumulation.

Amphiphilic Janus Twin Single-Chain Nanoparticles.

In these years, synthesis and self-assembly of nanoparticles with various sizes, geometries and compositions have aroused great interest due to their scientific significance and potential applications. The nanoparticles with asymmetric structures are able to self-assemble into hierarchical structures for constructing functional materials. To investigate the self-assembly behaviors of the nano-sized asymmetric polymer particles, synthesis and self-assembly of twin single-chain nanoparticles (TSCNPs), a type of covalently bonded SCNPs, are reported in this research. A block copolymer with pendant anthracene groups and bromines on two blocks were synthesized by two-step reversible addition-fragmentation chain transfer polymerization. After two-step intramolecular cross-linking reactions, anthracene photodimerization and atom transfer radical coupling, TSCNPs were prepared. The amphiphilic TSCNPs possess surfactant properties. Upon addition of the TSCNPs, the surface tension of water is reduced. In aqueous solution, the TSCNPs self-assemble into vesicles with the hydrophobic particles in the inner walls and the hydrophilic particles on the surfaces.

Nanoscale Proteinosomes Fabricated by Self-Assembly of a Supramolecular Protein-Polymer Conjugate.

Proteinosomes are a type of protein-based spherical capsules, which have potential applications in drug delivery, cell imaging, gene expression, and biocatalysis. In this research, a novel approach to the fabrication of proteinosomes entirely composed of protein molecules based on self-assembly of a supramolecular protein-polymer conjugate is proposed. A supramolecular protein-polymer conjugate was prepared by mixing ßCD-modified bovine serum albumin (BSA) and adamantane-terminated poly(N-isopropylamide) (Ad-PNIPAM) in aqueous solution. The BSA-PNIPAM bioconjugate self-assembled into micelles with PNIPAM cores and BSA coronae at a temperature above the lower critical solution temperature (LCST) of PNIPAM. After cross-linking of BSA in the coronae, and followed by addition of excess ßCD, PNIPAM chains were cleaved from the micellar structures, and nanoscale proteinosomes were prepared. The dual-responsive proteinosomes dissociated in the presence of trypsin or glutathione.

The natural product phyllanthusmin C enhances IFN-γ production by human NK cells through upregulation of TLR-mediated NF-κB signaling.

Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer-initiating cells, and clear viral infections. However, few reports describe a natural product that stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 ng/ml, and stimulated IFN-γ production in both human CD56(bright) and CD56(dim) NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C's activation of the NF-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12 and IL-15Rs and their related STAT signaling pathways were not responsible for the enhanced IFN-γ secretion by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively enhance human NK cell IFN-γ production. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted.

Preparation of Janus Graphene Oxide (GO) Nanosheets Based on Electrostatic Assembly of GO Nanosheets and Polystyrene Microspheres.

A facile and versatile method for the synthesis of Janus graphene oxide (GO) nanosheets with different structures is reported. Based on electrostatic assembly, Janus GO nanosheets can be easily functionalized with a template polymer or be defunctionalized by altering the ionic strength. By using this approach, Janus GO nanosheets are prepared successfully with hydrophobic polystyrene chains on one side and hydrophilic poly(2-(dimethylamino)ethyl methacrylate) chains on the other side.

Anti-sulfatide antibody-related Guillain-Barré syndrome presenting with overlapping syndromes or severe pyramidal tract damage: a case report and literature review.

Introduction: Anti-sulfatide antibodies are key biomarkers for the diagnosis of Guillain-Barré syndrome (GBS). However, case reports on anti-sulfatide antibody-related GBS are rare, particularly for atypical cases. Case description case 1: A 63 years-old man presented with limb numbness and diplopia persisting for 2 weeks, with marked deterioration over the previous 4 days. His medical history included cerebral infarction, diabetes, and coronary atherosclerotic cardiomyopathy. Physical examination revealed limited movement in his left eye and diminished sensation in his extremities. Initial treatments included antiplatelet agents, cholesterol-lowering drugs, hypoglycemic agents, and medications to improve cerebral circulation. Despite this, his condition worsened, resulting in bilateral facial paralysis, delirium, ataxia, and decreased lower limb muscle strength. Treatment with intravenous high-dose immunoglobulin and dexamethasone resulted in gradual improvement. A 1 month follow-up revealed significant neurological sequelae. Case description case 2: A 53 years-old woman was admitted for adenomyosis and subsequently experienced sudden limb weakness, numbness, and pain that progressively worsened, presenting with diminished sensation and muscle strength in all limbs. High-dose intravenous immunoglobulin, vitamin B1, and mecobalamin were administered. At the 1 month follow-up, the patient still experienced limb numbness and difficulty walking. In both patients, albuminocytologic dissociation was found on cerebrospinal fluid (CSF) analysis, positive anti-sulfatide antibodies were detected in the CSF, and electromyography indicated peripheral nerve damage. Conclusion: Anti-sulfatide antibody-related GBS can present with Miller-Fisher syndrome, brainstem encephalitis, or a combination of the two, along with severe pyramidal tract damage and residual neurological sequelae, thereby expanding the clinical profile of this GBS subtype. Anti-sulfatide antibodies are a crucial diagnostic biomarker. Further exploration of the pathophysiological mechanisms is necessary for precise treatment and improved prognosis.

Revealing the Impact of Gut Microbiota on Acne Through Mendelian Randomization Analysis.

Background: The association between acne and gut microbiota has garnered considerable attention; nevertheless, given the substantial diversity within gut microbiota, the precise cause-and-effect relationship linking specific microbial species to acne remains elusive. To address this gap in knowledge, our study utilized Mendelian randomization analysis to elucidate a potential causal link between gut microbiota composition and acne development while also investigating underlying mechanisms involving microbial factors associated with metabolic disorders. Materials and Methods: The independent single nucleotide polymorphisms (SNPs) closely associated with 196 gut microbiota samples (N=18340) were selected as variable tools. The relationship between gut microbiota and acne (N=212438) was analyzed using the Twosample package in R4.3.1, employing various methods including inverse variance weighting (IVW), weighted median, MR-Egger, Simple-mode, and Weighted-mode. To ensure the stability of the estimates, a series of sensitivity analyses were conducted, such as Cochran's Q-test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Additionally, the impact of each instrumental variable was calculated. Results: In the Mendelian randomization analysis, we identified twelve microbial taxa potentially associated with acne: family.Bacteroidaceae, family.Clostridiaceae1, genus.Allisonella, genus.Bacteroides, genus.Butyricimonas, genus.Clostridiumsensustricto1, and genus.Coprococcus3. These seven bacterial groups were found to be potential risk factors for acne. Conversely, family.Lactobacillaceae and genus.Ruminococcustorquesgroup along with genus.CandidatusSoleaferrea, genus.Fusicatenibacter, family.Lactobacillaceae, and genus.Lactobacillus exhibited a protective effect against acne. Furthermore, our investigation revealed that some of these microbial taxa have been implicated in metabolic diseases through previous studies. Importantly though, no causal relationship was observed in the reverse Mendelian randomization analysis.

"Click" amphotericin B in prodrug nanoformulations for enhanced systemic fungemia treatment.

Severe nephrotoxicity and infusion-related side effects pose significant obstacles to the clinical application of Amphotericin B (AmB) in life-threatening systemic fungal infections. In pursuit of a cost-effective and safe formulation, we have introduced multiple phenylboronic acid (PBA) moieties onto a linear dendritic telodendrimer (TD) scaffold, enabling effective AmB conjugation via boronate chemistry through a rapid, high yield, catalysis-free and dialysis-free "Click" drug loading process. Optimized AmB-TD prodrugs self-assemble into monodispersed micelles characterized by small particle sizes and neutral surface charges. AmB prodrugs sustain drug release in circulation, which is accelerated in response to the acidic pH and Reactive Oxygen Species (ROS) in the infection and inflammation. Prodrugs mitigate the AmB aggregation status, reduce cytotoxicity and hemolytic activity compared to Fungizone®, and demonstrate superior antifungal activity to AmBisome®. AmB-PEG5kBA4 has a comparable maximum tolerated dose (MTD) to AmBisome®, while over 20-fold increase than Fungizone®. A single dose of AmB-PEG5kBA4 demonstrates superior efficacy to Fungizone® and AmBisome® in treating systemic fungal infections in both immunocompetent and immunocompromised mice.

Telodendrimer functionalized hydrogel platform for sustained antibiotics release in infection control.

Wound infection commonly causes delayed healing, especially in the setting of chronic wounds. Local release of antibiotics is considered a viable approach to treat chronic wounds. We have developed a versatile telodendrimer (TD) platform for efficient loading of charged antibiotic molecules via a combination of multivalent and synergistic charge and hydrophobic interactions. The conjugation of TD in biocompatible hydrogel allows for topical application to provide sustained antibiotic release. Notably, a drug loading capacity as high as 20 % of the drug-to-resin dry weight ratio can be achieved. The payload content (PC) and release profile of the various antibiotics can be optimized by fine-tuning TD density and valency in hydrogel based on the charge and hydrophobic features of the drug, e.g., polymyxin B (PMB), gentamycin (GM), and daptomycin (Dap), for effective infection control. We have shown that hydrogel with moderately reduced TD density demonstrates a more favorable release profile than hydrogel with higher TD density. Antibiotics loaded in TD hydrogel have comparable antimicrobial potency and reduced cytotoxicity compared to the free antibiotics due to a prolonged, controlled drug release profile. In a mouse model of skin and soft tissue infection, the subcutaneous administration of PMB-loaded TD hydrogel effectively eliminated the bacterial burden. Overall, these results suggest that engineerable TD hydrogels have great potential as a topical treatment to control infection for wound healing. STATEMENT OF SIGNIFICANCE: Wound infection causes a significant delay in the wound healing process, which results in a significant financial and resource burden to the healthcare system. PEGA-telodendrimer (TD) resin hydrogel is an innovative and versatile platform that can be fine-tuned to efficiently encapsulate different antibiotics by altering charged and hydrophobic structural moieties. Additionally, this platform is advantageous as the TD density in the resin can also be fine-tuned to provide the desired antibiotic payload release profile. Sustained antibiotics release through optimization of TD density provides a prolonged therapeutic window and reduces burst release-induced cytotoxicity compared to conventional antibiotics application. Studies in a preclinical mouse model of bacteria-induced skin and soft tissue infection demonstrated promising therapeutic efficacy as evidenced by effective infection control and prolonged antibacterial efficacy of antibiotics-loaded PEGA-TD resin. In conclusion, the PEGA-TD resin platform provides a highly customizable approach for effective antibiotics release with significant potential for topical application to treat various bacterial wound infections to promote wound healing.

Research progress on the role of macrophages in acne and regulation by natural plant products.

Acne vulgaris is one of the most common skin diseases. The current understanding of acne primarily revolves around inflammatory responses, sebum metabolism disorders, aberrant hormone and receptor expression, colonization by Cutibacterium acnes, and abnormal keratinization of follicular sebaceous glands. Although the precise mechanism of action remains incompletely understood, it is plausible that macrophages exert an influence on these pathological features. Macrophages, as a constituent of the human innate immune system, typically manifest distinct phenotypes across various diseases. It has been observed that the polarization of macrophages toward the M1 phenotype plays a pivotal role in the pathogenesis of acne. In recent years, extensive research on acne has revealed an increasing number of natural remedies exhibiting therapeutic efficacy through the modulation of macrophage polarization. This review investigates the role of cutaneous macrophages, elucidates their potential significance in the pathogenesis of acne, a prevalent chronic inflammatory skin disorder, and explores the therapeutic mechanisms of natural plant products targeting macrophages. Despite these insights, the precise role of macrophages in the pathogenesis of acne remains poorly elucidated. Subsequent investigations in this domain will further illuminate the pathogenesis of acne and potentially offer guidance for identifying novel therapeutic targets for this condition.

Physical Therapy for at Least 6 Months Improves Motor Symptoms in Parkinson's Patients: A Meta-Analysis.

Objective: Long-term physical therapy helps to improve the motor symptoms of patients with Parkinson's disease, but the effectiveness is not clear. The purpose of this study was to evaluate the effect of long-term physical therapy on improving motor symptoms or daily activities in Parkinson's patients with drug use or discontinuation, as well as its impact on drug treatment dose. A subgroup analysis was conducted on different treatment methods to determine the most effective treatment method. Methods: The researchers independently searched databases, including PubMed, Medline, Embase, Ovid, Cochrane Library, and ISI Web of science. The search deadline was June 2022. A randomized controlled trial was conducted on Parkinson's disease patients with HY stages 1-3 who received continuous physical therapy for 6 months or more. Systematic evaluation and meta-analysis were carried out by using common clinical evaluation indicators, namely, MDS-UPDRS exercise score, daily activity (ADL) score, or LED dose. The quality of the literature was assessed using the modified Jadad scale of Cochrane's bias risk tool. Results: A total of 523 Parkinson's disease patients with HY stages of 1-3 were included in the study. The results showed that long-term physical therapy could improve patients' motor symptoms with combined antiparkinsonian drugs (Z = 2.61 and P = 0.009) and had a significant positive effect on the motor symptoms of patients with discontinued antiparkinsonian drugs (Z = 2.73 and P = 0.006). Meanwhile, it could reduce the LED dose of patients with Parkinson's disease. The difference was statistically significant (Z = 2.58 and P = 0.010). Conclusion: The results of this study indicated that physical therapy for at least 6 months or longer for patients with mild to moderate Parkinson's HY could effectively improve the motor symptoms of Parkinson's patients, whether or not combined with antiparkinson drugs. Meanwhile, long-term physical therapy reduced the LED dose of patients treated with drugs compared with patients in the control group who received short-term physical therapy, other types of intervention group, or no treatment.

Functionalized core-shell nanogel scavenger for immune modulation therapy in sepsis.

Sepsis is a complex, life-threatening hyperinflammatory syndrome associated with organ failure and high mortality due to lack of effective treatment options. Here we report a core-shell hydrogel nanoparticle with the core functionalized with telodendrimer (TD) nanotrap (NT) to control hyperinflammation in sepsis. The combination of multi-valent charged and hydrophobic moieties in TD enables effective binding with biomolecules in NT. The higher crosslinking in the shell structure of nanogel excludes the abundant large serum proteins and allows for size-selectivity in scavenging the medium-sized septic molecules (10-30 kDa), e.g., lipopolysaccharides (LPS, a potent endotoxin in sepsis), thus reducing cytokine production. At the same time, the core-shell TD NT nanogel captures the over-flowing proinflammatory cytokines effectively both in vitro and in vivo from biological fluids to further control hyperinflammation. Intraperitoneal injection of core-shell TD NT nanogel effectively attenuates NF-κB activation and cytokine production in LPS-induced septic mouse models. These results indicate the potential applications of the injectable TD NT core-shell nanogel to attenuate local or systemic inflammation.

Rational nanocarrier design towards clinical translation of cancer nanotherapy.

The past decades have witnessed an exponential growth in research of cancer nanomedicine, which has evolved into an interdisciplinary field involving chemistry, physics, biology, and pharmacology, pathophysiology, immunology and clinical science in cancer research and treatment. The application of nanoparticles in drug delivery increases the solubility and decreases the toxicity of free drug molecules. The unique feature of cancer pathophysiology, e.g. leaky blood vessel, presents a unique opportunity for nanocarriers to deliver therapeutics selectively to tumor sites based on size selectivity. However, the clinical translation of nanomedicine is mostly limited to the classical liposomal formulations and PEGylation of therapeutics. Numbers of reasons hinder the clinical translation of the novel nanoparticles developed in the last decades for drug delivery. Comprehensive understanding of the properties of nanocarriers and their interactions with the physiological and pathological interfaces is critical to design effective nanoformulations. In addition, understanding the general principles and concerns in pharmaceutical industries and clinical practice for nanotherapeutic development is essential to develop a translatable nanoformulations via rational nanocarrier designs. In this account, we will review the relationship between the physiochemical properties of nanocarriers and biodistribution, and interactions with biological and immunological systems for effective drug delivery and cancer treatments. Further, we review the strategies for rational design of nanocarriers via structure-based approach and bio-mimicking systems to facilitate the clinical translation in enhancing cancer treatment via both chemotherapy and immunotherapy.

Ligustrazine alleviates cyclophosphamide-induced hepatotoxicity via the inhibition of Txnip/Trx/NF-κB pathway.

AIMS: Cyclophosphamide (CP) is a common therapeutic drug for cancer, but exposure to CP can cause acute hepatotoxicity. This study aimed to elucidate the protective effects of Ligustrazine (2, 3, 5, 6-tetramethylpyrazine, TMP) on hepatotoxicity induced by CP or its active metabolite 4-hydroperoxycyclophosphamide (4-HC). MAIN METHODS: We presented a comprehensive investigation about the hepatoprotection of TMP on CP-induced mice and 4-HC-treated HSC-LX2 cells. Liver function was detected via enzyme-linked immunosorbent assay (ELISA). Hepatic histopathology analysis was performed via hematoxylin and eosin (H&E) and Masson staining. Survival of hepatocytes was detected by TUNEL assay. Related proteins in the thioredoxin (Trx)-interacting protein (Txnip)/Trx/Nuclear factor-kappa B (NF-κB) pathway were measured by western blotting. KEY FINDINGS: The results indicated that CP or 4-HC could increase the levels of alanine aminotransferase and aspartate aminotransferase, enhance inflammatory factors and oxidative indicators, and suppress the activity of oxidoreductases. Moreover, significant changes in liver histological structure, fibrosis, and cell death were observed through the activation of Txnip/Trx/NF-κB pathway. In contrast, administration of TMP significantly reversed these above changes. Furthermore, TMP intervention participated in the inhibition of NLRP3 inflammasome accompanied with pyroptosis, as well as upregulating Trx expression and downregulating p-NF-κB, while the protective effect of TMP was limited to the involvement of Txnip overexpression. SIGNIFICANCE: TMP treatment could significantly alleviate the hepatotoxicity process as evidenced by improving the structure and function of the liver, inhibiting oxidative stress and inflammation accompanied with pyroptosis, which was positively correlated with the inhibition of Txnip/Trx/NF-κB pathway.

Gender-dependent reproductive toxicity of copper metal-organic frameworks and attenuation by surface modification.

Metal-organic frameworks (MOFs) as promising materials have been widely used in drug delivery, disease diagnosis and therapy; however, their effects on the reproductive system remain unknown, which hinders their further clinical applications. Here we show that repeated subcutaneous injections of copper MOFs (HKUST-1) induce higher toxicity into the male reproductive system relative to the female reproductive system, with disrupted seminiferous tubule histology, sperm generation disorder, irreversible sperm morphological abnormities and reduced pregnancy rate but only slight follicle dysfunction and pregnancy complications in female mice. Interestingly, the modification of HKUST-1 with folic acid attenuates the reproductive toxicity and even improves pregnancy and fetus development. This study confirms the gender-dependent toxicity of HKUST-1 to the reproductive system, and that folic acid modification could relieve the reproductive toxicity, thus providing us a deep understanding of reproductive toxicity of copper MOFs, and also a guideline and feasible way to improve the biocompatibility of copper MOFs for potential medical use.

A Rationally Designed Micellar Nanocarrier for the Delivery of Hydrophilic Methotrexate in Psoriasis Treatment.

Methotrexate (MTX) is broadly applied in the clinic for the treatments of cancers and autoimmune diseases. Targeted delivery of MTX is attractive to improve its efficacy and reduce off-target toxicity. However, MTX encapsulation in nanoparticle is challenging due to its high water solubility. We rationally designed a well-defined telodendrimer (TD) nanocarrier based on MTX structure to sequester it in nanoparticles. Riboflavin (Rf) and positive charges groups were precisely conjugated on TD to form multivalent hydrogen bonds, π-π stacking and electrostatic interactions with MTX. A reverse micelle approach was developed to preset MTX and TD interactions in the core of micelles, which ensures the effective MTX loading upon dispersion into aqueous solution. As results, MTX loading capacity reaches over 20% (w/w) in the optimized nanocarrier with the particle size of 20-30 nm. The nanoformulations sustain the release of MTX in a controlled manner and exhibit excellent hemocompatibility. The in vitro cellular uptake of MTX was significantly improved by the nanoformulations. The potency of MTX nanoformulations is comparable to the free MTX in cytotoxicity. A psoriasis-like skin inflammation model was induced in mouse by imiquimod (IMQ) stimulation. MTX nanoformulations improved the psoriasis targeting and exhibited a superior long-lasting efficacy in reducing skin inflammation compared with the free MTX in psoriasis treatment.

[Effect of otopoint pellet-pressing combined with medication on clinical symptoms of migraine patients and changes of plasma 5-HT and CGRP contents].

OBJECTIVE: To investigate the short-term and long-term clinical effects of otopoint pellet-pressing combined with medication in the treatment of patients with migraine without aura and its impact on plasma 5-hydroxytryptamine(5-HT) and calcitonin gene-related peptide(CGRP) contents. METHODS: Patients with migraine without aura were randomly divided into medication(control) group(n=48) and otopoint pellet-pressing plus medication (treatment) group(n=49). Patients of the control group were given oral Flunarizine capsules(10 mg/time) twice a day, and those of the treatment group received same dosage of Flunarizine and pellet-pressing of otopoints Nao(Brain), Nie (Temporal), Shenmen(Shenmen), Jiaogan(Sympathy) and Pizhixia(Subcortex), 2 min/point, 3 times a day, simultaneously. The treatment was conducted for 1 month. The short-term and long-term clinical effects were evaluated according to Yang and colleagues' methods, and "Guiding principles for clinical research of new TCM drugs (trial)". The contents of plasma 5-HT and CGRP were detected by ELISA. RESULTS: After one month's treatment, of the 48 and 49 patients in the control and treatment groups, 10(20.83%)and 17(34.69%) were under control, 19(39.59%)and 23(46.94%) experienced marked improvement, 10(20.83%)and 7(14.29%)were effective, 9(18.75%) and 2(4.08%) failed, with the total effective rates being 81.25% and 95.92%, respectively. Six months' follow-up survey showed that of the 48 and 49 patients in the control and treatment groups, 4(8.33%)and 11(22.45%) were under control, 20(41.67%)and 24(48.98%)experienced marked improvement, 11(22.92%)and 9(18.37%)were effective, and 13(27.08%) and 5(10.20%)failed, with the total effective rates being 72.92% and 89.80%, respectively. The number of headache attacks, duration of each attack and the degree of headache were significantly decreased after 1 and 6 months' treatment in both groups in comparison with their own pre-treatment (P<0.05). The contents of plasma 5-HT at the time-points of 1 and 6 months were markedly increased (P<0.05), and those of plasma CGRP at the two time points markedly decreased in both groups in comparison with their own pre-treatment (P<0.05). The therapeutic effects of the treatment group were obviously superior to those of the control group in lowering the number of headache attacks, duration of each attack and the degree of headache and plasma CGRP content, as well as in increasing plasma 5-HT levels after 1 and 6 months' treatment (P<0.05). CONCLUSION: Otopoint pellet-pressing combined with oral administration of Flunarizine can significantly improve the clinical symptoms in patients with migraine without aura, and possess a stable long-term clinical effect, which may be associated with its effect in increasing plasma 5-HT and decreasing CGRP levels.

Anti-cancer effect of marchantin C via inducing lung cancer cellular senescence associated with less secretory phenotype.

BACKGROUND: Lung cancer is the leading cause of global cancer deaths. Current chemotherapeutic agents for lung cancer treatment are generally accompanied with severe side effects. Here, we report that marchantin C (Mar-C), a potential natural compound with little chemotherapeutic toxicity, exerts a well anti-tumor effect against lung cancer via inducing cellular senescence. METHODS: The antitumor activity of Mar-C was evaluated by MTT and colony formation in vitro cytotoxicity assays, and xenograft and homograft in vivo model. Antitumor mechanisms of Mar-C were investigated through SA-ß-gal staining, Q-PCR, immunoblotting, immunofluorescence, protein array and siRNA knocking-down analysis. RESULTS: Mar-C selectively induces senescence of lung cancer cells with limited cytotoxicity on normal or non-neoplastic cells. Mar-C-induced senescence was associated with the elevation of ROS and activation of DNA-damage, and largely dependent of prolonged p21CIP1 accumulation. The senescence-associated secretory phenotype (SASP) induced by Mar-C was distinct from doxorubicin-induced. Furthermore, Mar-C exhibited an inhibitory activity on tumor growth with little toxicity in animal studies, and significantly prolonged the survival time of tumor-bearing mice than that of doxorubicin or vehicle treatments. CONCLUSION: Mar-C selectively inhibited tumor growth via the induction of cancer cell senescence and had little chemotherapeutic toxicity, suggesting the potential of Mar-C as a promising anticancer agent. GENERAL SIGNIFICANCE: This study provided evidence to identify a novelty of Mar-C that exerted antitumor activity on lung cancer through induction of senescence with limited toxicity.