Enhancing oocyte in vitro maturation and quality by melatonin/bilirubin cationic nanoparticles: A promising strategy for assisted reproduction techniques.

In assisted reproduction techniques, oocytes encounter elevated levels of reactive oxygen species (ROS) during in vitro maturation (IVM). Oxidative stress adversely affects oocyte quality, hampering their maturation, growth, and subsequent development. Thus, mitigating excessive ROS to safeguard less viable oocytes during IVM stands as a viable strategy. Numerous antioxidants have been explored for oocyte IVM, yielding considerable effects; however, several aspects, including solubility, stability, and safety, demand attention and resolution. In this study, we developed nanoparticles by self-assembling endogenous bilirubin and melatonin hormone coated with bilirubin-conjugated glycol chitosan (MB@GBn) to alleviate oxidative stress and enhance oocyte maturation. The optimized MB@GBn exhibited a uniform spherical shape, measuring 128 nm in particle size, with a PDI value of 0.1807 and a surface potential of +11.35 mV. The positively charged potential facilitated nanoparticle adherence to the oocyte surface through electrostatic interaction, allowing for functional action. In vitro studies demonstrated that MB@GB significantly enhanced the maturation of compromised oocytes. Further investigation revealed MB@GB's effectiveness in scavenging ROS, reducing intracellular calcium levels, and suppressing mitochondrial polarization. This study not only offers a novel perspective on nano drug delivery systems for biomedical applications but also presents an innovative strategy for enhancing oocyte IVM.

Supramolecular self-sensitized dual-drug nanoassemblies potentiating chemo-photodynamic therapy for effective cancer treatment.

Chemo-photodynamic synergistic therapy (CPST) holds tremendous promise for treating cancers. Unfortunately, existing CPST applications suffer from complex synthetic procedures, low drug co-loading efficiency, and carrier-related toxicity. To address these issues, we have developed a supramolecular carrier-free self-sensitized nanoassemblies by co-assembling podophyllotoxin (PTOX) and chlorin e6 (Ce6) to enhance CPST efficiency against tumors. The nanoassemblies show stable co-assembly performance in simulative vivo neural environment (∼150 nm), with high co-loading ability for PTOX (72.2 wt%) and Ce6 (27.8 wt%). In vivo, the nanoassemblies demonstrate a remarkable ability to accumulate at tumor sites by leveraging the enhanced permeability and retention (EPR) effect. The disintegration of nanoassemblies following photosensitizer bioactivation triggered by the acidic tumor environment effectively resolves the challenge of aggregation-caused quenching (ACQ) effect. Upon exposure to external light stimulation, the disintegrated nanoassemblies not only illuminate cancer cells synergistically but also exert a more potent antitumor effect when compared with PTOX and Ce6 administered alone. This self-sensitized strategy represents a significant step forward in CPST, offering a unique co-delivery paradigm for clinic cancer treatment.

Design of berberine hydrochloride sustained-release cold sol using hydroxypropyl methyl cellulose K100M to achieve superior drug dissolution and transdermal absorption.

In this study, berberine hydrochloride (Ber) was used as model drug to prepare a sustained-release cold sol using hydroxypropyl methyl cellulose (HPMC) to achieve superior drug dissolution and transdermal absorption effects. For comparison, a Ber cold sol without HPMC was also prepared using the same method. The preparation process was optimized based on the in vitro release and transdermal permeability of the drug. The results indicated that 1.67 wt% Carbomer 940 and 1.33 wt% HPMC K100M were selected as matrix components with the best sustained-release effect, and drug dissolution of cold sol prepared by combination of these two matrices was significantly slower than the cold sol without HPMC. In addition, transdermal absorption result demonstrated that 0.67 wt% glycerin and 1.33 wt% peppermint oil were the best osmotic enhancers for the optimization of Ber sustained-release cold sol. Herein, HPMC K100M performed important functions in the external application of Ber.

Counter-intuitive discovery in the formulation of poorly water-soluble drugs: Amorphous small-molecule gels.

Amorphous strategies have been extensively used in improving the dissolution of insoluble drugs for decades due to their high free energy. However, the formation of amorphous small-molecule gels (ASMGs) presents a counter-intuitive discovery that significantly limits their practical application. Recently, ASMGs have garnered attention because of their noncovalent structures, excellent biodegradability, and significant potential in various drug delivery systems in the pharmaceutical field. Hence, a comprehensive review is necessary to contribute to a better understanding of recent advances in ASMGs. This review aimed to introduce the main formation mechanisms, summarize possible influencing factors, generalize unique properties, outline elimination strategies, and discuss clinical application potential with preclinical cases of ASMGs. Moreover, few ASMGs are advanced to clinical stages. Intensive clinical research is needed for further development. We hope that this review can provide more efficient and rational guidance for exploring further clinical applications of ASMGs.

Cholesterol sulfate-mediated ion-pairing facilitates the self-nanoassembly of hydrophilic cationic mitoxantrone.

HYPOTHESIS: Hydrophilic cationic drugs such as mitoxantrone hydrochloride (MTO) pose a significant delivery challenge to the development of nanodrug systems. Herein, we report the use of a hydrophobic ion-pairing strategy to enhance the nano-assembly of MTO. EXPERIMENTS: We employed biocompatible sodium cholesteryl sulfate (SCS) as a modification module to form stable ion pairs with MTO, which balanced the intermolecular forces and facilitated nano-assembly. PEGylated MTO-SCS nanoassemblies (pMS NAs) were prepared via nanoprecipitation. We systematically evaluated the effect of the ratio of the drug module (MTO) to the modification module (SCS) on the nanoassemblies. FINDINGS: The increased lipophilicity of MTO-SCS ion pair could significantly improve the encapsulation efficiency (∼97 %) and cellular uptake efficiency of MTO. The pMS NAs showed prolonged blood circulation, maintained the same level of tumor antiproliferative activity, and exhibited reduced toxicity compared with the free MTO solution. It is noteworthy that the stability, cellular uptake, cytotoxicity, and in vivo pharmacokinetic behavior of the pMS NAs increased in proportion to the molar ratio of SCS to MTO. This study presents a self-assembly strategy mediated by ion pairing to overcome the challenges commonly associated with the poor assembly ability of hydrophilic cationic drugs.

Emerging Chemodynamic Nanotherapeutics for Cancer Treatment.

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species -mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals. Its notable advantages in cancer treatment are demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine are devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment.

Association between amino acids and recent osteoporotic fracture: a matched incident case-control study.

Context: Osteoporotic fracture is a major public health issue globally. Human research on the association between amino acids (AAs) and fracture is still lacking. Objective: To examine the association between AAs and recent osteoporotic fractures. Methods: This age and sex matched incident case-control study identified 44 recent x-ray confirmed fracture cases in the Second Hospital of Jilin University and 88 community-based healthy controls aged 50+ years. Plasma AAs were measured by high performance liquid chromatography coupled with mass spectrometry. After adjusting for covariates (i.e., body mass index, milk intake >1 time/week, falls and physical activity), we conducted conditional logistical regression models to test the association between AAs and fracture. Results: Among cases there were 23 (52.3%) hip fractures and 21 (47.7%) non-hip fractures. Total, essential, and non-essential AAs were significantly lower in cases than in controls. In the multivariable conditional logistic regression models, after adjusting for covariates, each standard deviation increase in the total (odds ratio [OR]: 0.304; 95% confidence interval [CI]: 0.117-0.794), essential (OR: 0.408; 95% CI: 0.181-0.923) and non-essential AAs (OR: 0.290; 95%CI: 0.107-0.782) was negatively associated with recent fracture. These inverse associations were mainly found for hip fracture, rather than non-hip fractures. Among these AAs, lysine, alanine, arginine, glutamine, histidine and piperamide showed the significantly negative associations with fracture. Conclusion: There was a negative relationship between AAs and recent osteoporotic fracture; such relationship appeared to be more obvious for hip fracture.

Associations of global biomarkers of oxidative stress with osteoporosis, bone microstructure and bone turnover: Evidence from human and animal studies.

PURPOSE: Human evidence on the association between oxidative stress and osteoporosis is inconsistent. Fluorescent Oxidation Products (FlOPs) are global biomarkers of oxidative stress. We examined the associations of FlOPs (excitation/emission wavelengths 320/420 nm for FlOP_320, 360/420 nm for FlOP_360, and 400/475 nm for FlOP_400) with osteoporosis, bone microstructure, and bone turnover markers in humans and rats. METHODS: In humans, we conducted a 1:2 age, sex, hospital, and specimen-matched case-control study to test the association between FlOPs and osteoporosis diagnosed from dual-energy X-ray absorptiometry. In eight-week-old male Wistar rats, we administrated D-galactose and 0.9 % saline for 90 days in treatment and control groups (n = 8/group); micro-CT was used to determine bone microstructure. RESULTS: In humans, higher levels of FlOP_320 (OR for per 1 SD increase = 1.49, 95 % CI: 1.01-2.20) and FlOP_360 (OR for per 1 SD increase = 1.59, 95 % CI: 1.07-2.37) were associated with increased odds of osteoporosis. FlOP_400 were not associated with osteoporosis. D-galactose treated rats, as compared with control rats, showed higher levels of FlOP_320 and MDA, and lower P1NP levels during 90 days of experiment (all P < 0.05). The D-galactose group had lower trabecular bone volume fraction (0.07 ± 0.03 vs. 0.13 ± 0.05; P = 0.008) and volumetric BMD (225.4 ± 13.8 vs. 279.1 ± 33.2 mg HA/cm3; P = 0.001) than the control group. CONCLUSION: In conclusion, higher FlOP_320 levels were associated with increased odds of osteoporosis, impaired bone microstructure and decreased bone formation.

Small molecules modified mesoporous silica nanoparticles orally deliver indomethacin with synergistic effect.

Molecularly functional drug delivery systems possessed huge potentials to realize novel drug administration. To explore small molecules modified drug delivery, a series of small molecules modified mesoporous silica nanoparticles (L-Mal-MSNs, D-Mal-MSNs) were established by grafting small molecules. Poorly water-soluble indomethacin (IMC) was chosen to load into these small molecules modified carriers as well as corresponding control carrier, and further to study characteristics and delivery effects of drug loaded carriers. The results indicated that all these small molecules modified carriers formed hydrogen bonds with drugs and can successfully convert drug crystal phase to amorphous state so as to enhance drug dissolution compared to raw drug. In vivo rat intestinal perfusion demonstrated that IMC loaded L-Mal-MSNs performed the fastest drug absorption while analgesic and anti-inflammatory effects of IMC loaded D-Mal-MSNs turned out to be the best, giving hints that D-malic acid exhibited best synergic functions for IMC. The herein small molecules modified delivery system is an effective solution strategy for the current application of analgesia and anti-inflammatory drugs with outstanding significance.

Cylindrical granules in the development of mesalazine solid formulations (â ¡): The contribution of high aspect ratio to favorable tabletability.

Recently, cylindrical granules have been applied in pharmaceutical fields and their aspect ratio (AR) is considered an important factor in the manufacturing process. However, the relationships between AR and the tableting process were seldom reported. This study aims to clarify the role of AR in the tableting process of cylindrical granules. First, mesalazine cylindrical granules with different AR were extruded, and their physical attributes were then comprehensively characterized. Subsequently, their compression behaviors and tableting performances were systematically assessed. Notably, it was found that the cylindrical granules with high AR possessed good anti-deformation capacity and favorable tabletability. Finally, the dissolution test suggested that tablets compressed from cylindrical granules with higher AR showed lower dissolution rates. Collectively, findings in this study identified that the AR of cylindrical granules was a critical factor in the tableting process and provided valuable guidance for the application of these granules in oral solid formulations.

Minor Changes in Response Modules Leading to a "U-Shaped" Conversion Rate of Docetaxel Prodrug Nanoassemblies.

The prodrug-based nanoassemblies offer an alternative to settle the deficiencies of traditional chemotherapy drugs. In this nanosystem, prodrugs typically comprise drug modules, modification modules, and response modules. The response modules are crucial for facilitating the accurate conversion of prodrugs at specific sites. In this work, we opted for differentiated disulfide bonds as response modules to construct docetaxel (DTX) prodrug nanoassemblies. Interestingly, a subtle change in response modules leads to a "U-shaped" conversion rate of DTX-prodrug nanoassemblies. Prodrug nanoassemblies with the least carbon numbers between the disulfide bond and ester bond (PDONα) offered the fastest conversion rate, resulting in powerful treatment outcomes with some unavoidable toxic effects. PDONß, with more carbon numbers, possessed a slow conversion rate and poor antitumor efficacy but good tolerance. With most carbon numbers in PDONγ, it demonstrated a moderate conversion rate and antitumor effect but induced a risk of lethality. Our study explored the function of response modules and highlighted their importance in prodrug development.

Small molecule-engineered nanoassembly for lipid peroxidation-amplified photodynamic therapy.

Photodynamic therapy (PDT), extensively explored as a non-invasive and spatio-temporal therapeutic modality for cancer treatment, encounters challenges related to the brief half-life and limited diffusion range of singlet oxygen. Lipid peroxides, formed through the oxidation of polyunsaturated fatty acids by singlet oxygen, exhibit prolonged half-life and potent cytotoxicity. Herein, we employed small molecule co-assembly technology to create nanoassemblies of pyropheophorbide a (PPa) and docosahexaenoic acid (DHA) to bolster PDT. DHA, an essential polyunsaturated fatty acid, co-assembled with PPa to generate nanoparticles (PPa@DHA NPs) without the need for additional excipients. To enhance the stability of these nanoassemblies, we introduced 20% DSPE-PEG2k as a stabilizing agent, leading to the formation of PPa@DHA PEG2k NPs. Upon laser irradiation, PPa-produced singlet oxygen swiftly oxidized DHA, resulting in the generation of cytotoxic lipid peroxides. This process significantly augmented the therapeutic efficiency of PDT. Consequently, tumor growth was markedly suppressed, attributed to the sensitizing and amplifying impact of DHA on PDT in a 4T1 tumor-bearing mouse model. In summary, this molecule-engineered nanoassembly introduces an innovative co-delivery approach to enhance PDT with polyunsaturated fatty acids.

Emerging nanotherapeutic strategies targeting gut-X axis against diseases.

Gut microbiota can coordinate with different tissues and organs to maintain human health, which derives the concept of the gut-X axis. Conversely, the dysbiosis of gut microbiota leads to the occurrence and development of various diseases, such as neurological diseases, liver diseases, and even cancers. Therefore, the modulation of gut microbiota offers new opportunities in the field of medicines. Antibiotics, probiotics or other treatments might restore unbalanced gut microbiota, which effects do not match what people have expected. Recently, nanomedicines with the high targeting ability and reduced toxicity make them an appreciative choice for relieving disease through targeting gut-X axis. Considering this paradigm-setting trend, the current review summarizes the advancements in gut microbiota and its related nanomedicines. Specifically, this article introduces the immunological effects of gut microbiota, summarizes the gut-X axis-associated diseases, and highlights the nanotherapeutics-mediated treatment via remolding the gut-X axis. Moreover, this review also discusses the challenges in studies related to nanomedicines targeting the gut microbiota and offers the future perspective, thereby aiming at charting a course toward clinic.

Nitric oxide-driven nanotherapeutics for cancer treatment.

Nitric oxide (NO) is a gaseous molecule endowed with diverse biological functions, offering vast potential in the realm of cancer treatment. Considerable efforts have been dedicated to NO-based cancer therapy owing to its good biosafety and high antitumor activity, as well as its efficient synergistic therapy with other antitumor modalities. However, delivering this gaseous molecule effectively into tumor tissues poses a significant challenge. To this end, nano drug delivery systems (nano-DDSs) have emerged as promising platforms for in vivo efficient NO delivery, with remarkable achievements in recent years. This review aims to provide a summary of the emerging NO-driven antitumor nanotherapeutics. Firstly, the antitumor mechanism and related clinical trials of NO therapy are detailed. Secondly, the latest research developments in the stimulation of endogenous NO synthesis are presented, including the regulation of nitric oxide synthases (NOS) and activation of endogenous NO precursors. Moreover, the emerging nanotherapeutics that rely on tumor-specific delivery of NO donors are outlined. Additionally, NO-driven combined nanotherapeutics for multimodal cancer theranostics are discussed. Finally, the future directions, application prospects, and challenges of NO-driven nanotherapeutics in clinical translation are highlighted.

Curcumin amorphous solid dispersions benefit from hydroxypropyl methylcellulose E50 to perform enhanced anti-inflammatory effects.

The solubility and permeability enhancement of curcumin (Cur) is crucial for its manufacture and application in medical field. Herein, Cur amorphous solid dispersions (ASDs) with enhanced drug solubility and permeability was formulated by Eudragit EPO (EuD) and biological macromolecules of hydroxypropyl methylcellulose E50 (HPMC), and significant functions of HPMC for Cur ASDs were mainly studied. The results showed that the mean particle size of Cur decreased from more than 300 nm to less than 200 nm with the addition of HPMC in excipient aqueous solution evidenced by dynamic light scattering result, confirming that HPMC had the ability to inhibit crystallization by lowering drug-rich droplets in the initial mixing process. Innovatively for molecular dynamic modeling study, crystalline Cur molecules in EuD medium trended to aggregate while not for EuD/HPMC 1:1 and EuD/HPMC 3:1 medium. HPMC functioned as surfactant converted the arrangement of phospholipid bilayers to un-ordered, and un-ordered state of phospholipids lead to the enhancement of Cur transmembrane using HPMC as auxiliary excipient. Cur-EuD/HPMC 3:1 contributed greatly to the Cur permeability, leading to obtain superior relative oral bioavailability and anti-inflammatory effect. Cur ASDs with proper amount of HPMC can be rendered as outstanding therapeutic strategy for medical application.

Cedrol-loaded dissolvable microneedles based on flexible backing for promoting hair growth.

OBJECTIVES: The dissolvable microneedles loaded with cedrol based on flexible backing were developed to deliver cedrol directly and continuously to the dermis, where the drug concentration in the hair follicle can be increased locally. METHODS: The tip-layer matrix solution was prepared by mixing cedrol and polyvinylpyrrolidone K25 (PVP K25), and the pedestal matrix solution was prepared with aqueous hyaluronic acid. The cedrol-loaded dissolvable microneedles (cedrol-DMNs) were prepared under vacuum conditions. The mechanical properties, pig skin penetration efficiency, in vitro cutaneous permeation test, and the amount of drug in the skin and receptor chamber were evaluated. Pharmacodynamical studies were performed with C57BL/6 mice. RESULTS: The mechanical properties of cedrol-DMNs were good. In vitro cutaneous permeation tests and pharmacodynamical studies demonstrated that cedrol-DMN could efficiently deliver the drug to the deep dermis and effectively promote hair growth. CONCLUSIONS: The cedrol-DMNs offer a promising strategy for treating patients suffering from hair loss.

Global biomarkers of oxidative stress and fractures: a matched case-control study.

Background: Evidence for a relationship between oxidative stress and osteoporotic fractures in humans is limited. Fluorescent oxidation products (FlOPs, excitation/emission wavelengths 320/420nm denoted FlOP_320; 360/420nm [FlOP_360]; and 400/475nm [FlOP_400]) are global biomarkers of oxidative stress, and reflect oxidative damage to proteins, phospholipids, and nucleic acids. We investigated the association between FlOPs and a recent osteoporotic fracture. Methods: We conducted a case-control study in a Chinese population aged 50 years or older. A recent osteoporotic fracture in the cases was confirmed by x-ray. Cases were matched with community-based non-fracture controls (1:2 ratio) for age (± 4 years) and sex. In addition, we conducted a sensitivity unmatched case-control study which included all fracture cases and all eligible non-fracture controls prior to matching. Plasma FlOPs were measured with a fluorescent microplate reader. We used unconditional logistic regression to analyze the association between FlOPs (per 1-SD increase in logarithmic scale) and fracture; odds ratios (OR) and 95% confidence intervals (95% CI) were reported. Results: Forty-four cases and 88 matched controls (mean age: 68.2 years) were included. After covariate adjustment (i.e., body mass index, physical activity, and smoking), higher FlOP_360 (OR = 1.85; 95% CI = 1.03 - 3.34) and FlOP_400 (OR = 13.29; 95% CI = 3.48 - 50.69) levels, but not FlOP_320 (OR = 0.56; 95% CI = 0.27 - 1.15), were associated with increased fracture risk. Subgroup analyses by fracture site and unmatched case-control study found comparable associations of FlOP_360 and FlOP_400 with hip and non-hip fractures. Conclusions: Higher FlOP_360 and FlOP_400 levels were associated with increased risk of fracture, and this association was comparable for hip and non-hip fractures. Prospective studies are warranted to confirm this finding.

Role of KLF4/NDRG1/DRP1 axis in hypoxia-induced pulmonary hypertension.

N-myc downstream regulated gene 1 (NDRG1) has recently drawn increasing attention because of its involvement in angiogenesis, cell proliferation, and differentiation. We used in vitro [human pulmonary artery smooth muscle cells (hPASMCs)] and in vivo (rat) models under hypoxic conditions and found a vital role of NDRG1 in reducing apoptosis and increasing proliferation and migration by overexpressing and knocking down NDRG1. We also proved that hypoxia induced the protein expression of dynamin-related protein 1 (DRP1) and stimulated The phosphatidylinositol-3-kinase (PI3K)/ Protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathways, and these effects were reversed by NDRG1 knockdown. The relationship between NDRG1 and DRP1 and the PI3K/Akt/mTOR pathway was further evaluated by adding mdivi-1 (DRP1 inhibitor) or LY294002 (PI3K inhibitor). NDRG1 was found to regulate the proliferation, apoptosis, and migration of hypoxia-treated hPASMCs via DRP1 and PI3K/Akt/mTOR signaling pathways. We explored the upstream regulators of NDRG1 using in vivo and in vitro hypoxia models. Hypoxia was found to upregulate and downregulate KLF transcription factor 4 (KLF4) protein expression in the cytoplasm and nucleus, respectively. Further, we showed that KLF4 regulated the proliferation and migration of hypoxia-treated hPASMCs via NDRG1. These results indicated a link between KLF4, NDRG1, and DRP1 for the first time, providing new ideas for treating hypoxic pulmonary hypertension.

Self-assembled short peptides: Recent advances and strategies for potential pharmaceutical applications.

Self-assembled short peptides have intrigued scientists due to the convenience of synthesis, good biocompatibility, low toxicity, inherent biodegradability and fast response to change in the physiological environment. Therefore, it is necessary to present a comprehensive summary of the recent advances in the last decade regarding the construction, route of administration and application of self-assembled short peptides based on the knowledge on their unique and specific ability of self-assembly. Herein, we firstly explored the molecular mechanisms of self-assembly of short peptides, such as non-modified amino acids, as well as Fmoc-modified, N-functionalized, and C-functionalized peptides. Next, cell penetration, fusion, and peptide targeting in peptide-based drug delivery were characterized. Then, the common administration routes and the potential pharmaceutical applications (drug delivery, antibacterial activity, stabilizers, imaging agents, and applications in bioengineering) of peptide drugs were respectively summarized. Last but not least, some general conclusions and future perspectives in the relevant fields were briefly listed. Although with certain challenges, great opportunities are offered by self-assembled short peptides to the fascinating area of drug development.