Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies.

Alzheimer's disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate and diverse, stemming from a combination of factors such as aging, genetics, and environment. Our current understanding of AD pathologies involves various hypotheses, such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Nonetheless, unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and validation. In the past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available drugs primarily offer symptomatic relief and often accompanied by undesirable side effects. However, recent approvals of aducanumab (1) and lecanemab (2) by the Food and Drug Administration (FDA) present the potential in disrease-modifying effects. Nevertheless, the long-term efficacy and safety of these drugs need further validation. Consequently, the quest for safer and more effective AD drugs persists as a formidable and pressing task. This review discusses the current understanding of AD pathogenesis, advances in diagnostic biomarkers, the latest updates of clinical trials, and emerging technologies for AD drug development. We highlight recent progress in the discovery of selective inhibitors, dual-target inhibitors, allosteric modulators, covalent inhibitors, proteolysis-targeting chimeras (PROTACs), and protein-protein interaction (PPI) modulators. Our goal is to provide insights into the prospective development and clinical application of novel AD drugs.

A randomized controlled trial on hair follicular-derived microtissue for promoting wound healing and alleviating postoperative complications after hair transplantation.

BACKGROUND: Hair transplantation, particularly through follicular unit extraction (FUE), can lead to postoperative complications, such as numbness, itching, and pain in donor areas, primarily because of delayed wound healing. Efficient management of donor-site healing is crucial to mitigate these complications and improve overall patient outcomes. OBJECTIVE: This study aimed to assess the efficacy of hair follicular-derived microtissue (HFMT) in promoting wound healing and alleviating postoperative complications in donor areas after FUE hair transplantation. METHODS: Perifollicular tissue obtained during the trimming phase of hair transplantation was processed into HFMT and analyzed for its properties using histological and molecular techniques. In a single-blind, split-scalp study involving 98 participants, Group A received HFMT or mupirocin, whereas Group B received HFMT or no treatment. Dermatoscopic images were captured postoperatively, and visual analog scale scores were used to evaluate pain, itching, and numbness. RESULTS: HFMT-treated donor sites in Group A demonstrated a significantly higher wound closure ratio on postoperative day 3 than mupirocin-treated sites. Pain scores for HFMT-treated sites were consistently lower on postoperative days 3, 5, and 7. Similar trends were observed for itching scores. Group B exhibited outcomes comparable with Group A. CONCLUSION: The application of HFMT homogenates effectively accelerated wound healing and alleviated donor-site complications after FUE hair transplantation.

Hyperandrogenism Decreases Seizure Threshold in a Rat Model of Polycystic Ovary Syndrome.

INTRODUCTION: In women of childbearing age with epilepsy, 30% experience the comorbidity of polycystic ovary syndrome (PCOS), which is marked by a higher prevalence of hyperandrogenism. Our recent clinical observations indicate the potential contribution of hyperandrogenism-induced PCOS to epilepsy susceptibility, and this study aimed to unravel the underlying factors that increase the susceptibility of females to epilepsy. METHODS: A letrozole-induced PCOS rat model was employed to simulate endogenous hyperandrogenism. The threshold of seizure was assessed through seizure kindling rates using pentetrazol and electroencephalogram recordings. Additionally, the role of androgens in epilepsy was verified through interventions using Diane-35. RESULTS: This study revealed that letrozole-induced elevated testosterone levels and PCOS-related changes in female rats. PCOS rats, through pentetrazol-kindling, exhibited a reduced seizure threshold compared with controls. Elevated testosterone levels were observed in both the hippocampal and frontal brain tissues, accompanied by changes in circulation. Two weeks of Diane-35 intervention showed a tendency to alleviate these changes, modifying testosterone levels in both the plasma and brain tissue. Western blotting and immunohistochemistry revealed increased expression of GABA-A receptor in the hippocampus and decreased AMPA receptor expression in the frontal cortex, correlating with antiepileptic status in PCOS rats. CONCLUSION: This study delves into the impact of elevated androgen levels on seizure threshold, providing crucial insights into the underpinnings of the comorbidity between PCOS and epilepsy. These findings significantly contribute to the evolving field of epilepsy research, emphasizing the imperative consideration of hormonal influences for the development of targeted therapeutic interventions in individuals with epilepsy and PCOS.

Research and application of the wavelet high-frequency coefficient direct mapping algorithm in the micro-defect target detection system of an infrared objective lens.

Various lens detection techniques for military sighting telescopes have been the focus of military production. However, most of the micro-defect detection of lenses is detected manually, which cannot guarantee the measurement precision and quality. In order to solve these problems, the wavelet high-frequency coefficients direct mapping algorithm is applied to the automatic detection system of a micro-defect target in an infrared objective lens, thus obtaining a new method of detection. The detection method utilizes the correlation feature between wavelet coefficient scales to process the acquired images to suppress the background signals. Then the noise is further filtered by the pipelined filtering method to finally realize the detection of micro-targets. The experimental results show that a relatively high signal-to-noise ratio can be obtained, and the method can detect the small and dim target whose signal-to-noise ratio is more than 2.5 times. The measurement range is ≥3p i x e l s and the error precision is 4±1 pixels.

Risk Factors and Hazards of Recipient-Area Perifollicular Erythema After Hair Transplantation: A Multicenter Retrospective Cohort Study.

BACKGROUND: Recipient-area perifollicular erythema (RPE) may delay graft growth after hair transplantation. However, there is currently a lack of observational clinical studies of RPE. OBJECTIVE: To study the clinical features and risk factors associated with RPE while analyzing its correlation with graft growth. METHODS: We conducted a multicenter retrospective cohort study between June 2020 and January 2023. RESULTS: A total of 1090 participants were included, 178 (16.33%) showed mild RPE, 56 (5.14%) showed moderate RPE, and 10 (0.92%) showed severe RPE. Patients with RPE had severe hair shaft shedding (P < 0.001) and a lower survival rate (P < 0.001) of grafts. Logistic regression analysis showed that folliculitis is a significant risk factor for mild RPE (OR 6.061, 95% CI 3.343-10.991, P < 0.001) and moderate RPE (OR 3.397, 95% CI 1.299-8.882, P = 0.013). Besides, untimely first postoperative hair washing was associated with the development of moderate RPE (OR 0.724, 95% CI 0.553-0.947, P = 0.018) and severe RPE (OR 1.553, 95% CI 1.156-2.086, P = 0.003). CONCLUSION: RPE is a postoperative complication closely related to high hair shaft shedding proportion and low graft survival rate. Both postoperative folliculitis and untimely first postoperative hair washing may induce the occurrence of RPE. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Retinoic acid drives hair follicle stem cell activation via Wnt/ß-catenin signalling in androgenetic alopecia.

BACKGROUND: Depletion or permanent quiescence of the hair follicle stem cell (HFSC) pool underlies pathogenesis in androgenetic alopecia (AGA). Reactivation of quiescent HFSCs is considered an efficient treatment strategy for hair loss. The retinoic acid (RA) is critical to ensure stem cell homeostasis and function. However, little is known about whether RA regulates HFSC homeostasis. We aimed to investigate the impact of RA on HFSC homeostasis and the underlying mechanisms, in order to provide new potential targets for medical therapies of AGA. METHODS: Microdissected hair follicles from the occipital and frontal scalp in AGA were obtained for RNA sequencing analysis and test. The C57BL/6 mice model in telogen was established to investigate the effect of exogenous RA. Miniaturized hair follicles from frontal scalp were incubated with or without RA in hair follicle organ culture to test the effects on hair shaft elongation, hair cycling and HFSC activities. A strategy to characterize the effect of RA on HFSC in primary culture was developed to identify novel mechanisms that control HFSC activation. A clinical study was performed to test the efficacy of RA treatment in AGA patients. RESULTS: RA signalling was inhibited in the course of AGA pathogenesis along with HFSC dysfunction. Hair regeneration was retarded in AGA miniaturized hair follicles with RA deficiency, but they tended to recover after treatment with RA. In addition, RA treatment during the telogen phase facilitated HFSC anagen entry and accelerated hair growth. Mechanistically, RA promoted hair growth by stimulating stem cells via Wnt/ß-catenin signalling and accelerating the transition from a dormant to an activated state. Furthermore, a clinical study suggested that RA has obvious advantages in the early intervention of AGA by reactivating HFSCs. CONCLUSIONS: Our study provides insights into the reactivation of HFSCs in AGA and provides potential targets for medical therapies.

Association between per- and polyfluoroalkyl substances exposure and prevalence of chronic obstructive pulmonary disease: The mediating role of serum albumin.

BACKGROUND: No study has examined the association between per- and polyfluoroalkyl substances (PFAS) exposure and chronic obstructive pulmonary disease (COPD) risk. This study aims to explore this relationship. METHODS: This study enrolled 4541 individuals who had available data on PFAS, COPD, and covariates from NHANES 2007-2018. Serum PFAS including perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) were analyzed, because of high detective rates. Considering the skew distribution of PFAS levels, the natural logarithm-transformed PFAS (Ln-PFAS) was used. Logistic regression analysis, restricted cubic spline (RCS), and weighted quantile sum (WQS) regression were performed to explore the single, nonlinear, and mixed effects. A mediating analysis was used to evaluate the mediated effects of albumin. RESULTS: Individuals with COPD had higher levels of PFHxS, PFNA, PFOA, and PFOS compared to those without COPD. Ln-PFNA (OR males: 1.92, 95 % CI:1.31 to 2.80, P: <0.001; OR females: 1.07, 95 % CI: 0.81 to 1.40, P: 0.636) and ln-PFOA (OR males: 2.17, 95 % CI:1.38 to 3.41, P: <0.001; OR females: 1.49, 95 % CI: 1.08 to 2.05, P: 0.016) were associated with COPD risk especially in males. The interaction between PFNA exposure and sex on COPD risk was significant (P interaction: <0.001). The RCS curve demonstrated the nonlinear relationship between the ln-PFOA (P nonlinear:0.001), ln-PFNA (P nonlinear:0.045), and COPD risk in males. WQS analysis showed mixed PFAS exposure was correlated with COPD risk in males (OR: 1.44, 95 % CI:1.18 to 1.75, P: <0.001). Albumin mediated the relationship between PFOA and COPD (mediated proportion: -17.94 %). CONCLUSION: This study concludes PFOA and PFNA are linked to a higher COPD risk in males, and serum albumin plays a mediating role in the relationship between PFOA and COPD. Thess findings are beneficial for the prevention of COPD. Further studies are required to explore potential mechanisms.

Integrating serum pharmacochemistry and network pharmacology to reveal the mechanism of chickpea in improving insulin resistance.

Although chickpea have great potential in the treatment of obesity and diabetes, the bioactive components and therapeutic targets of chickpea to prevent insulin resistance (IR) are still unclear. The purpose of this study was to investigate the chemical and pharmacological characteristics of chickpea on IR through serum pharmacochemistry and network pharmacology. The results revealed that compared with other polar fractions, the ethyl acetate extract of chickpea (CE) had the definitive performance on enhancing the capacities of glucose consumption and glycogen synthesis. In addition, we analyzed the components of CE in vivo and in vitro based on UPLC-Q-Orbitrap HRMS technology. There were 28 kinds of in vitro chemical components, among which the isoflavones included biochanin A, formononetin, ononin, sissotrin, and astragalin, etc. Concerningly, the chief prototype components of CE absorbed into the blood were biochanin A, formononetin, loliolide, and lenticin, etc. Furthermore, a total of 209 common targets between IR and active components of CE were screened out by network pharmacology, among which the key targets involved PI3K p85, NF-κB p65 and estrogen receptor 1, etc. Specifically, KEGG pathway analysis indicated that PI3K-AKT signaling pathway, HIF-1 signaling pathway, and AGE-RAGE signaling pathway may play critical roles in the IR remission by CE. Finally, the in vitro validation experiments disclosed that CE significantly balanced the oxidative stress state of IR-HepG2 cells and inhibited expressions of inflammatory cytokines. In conclusion, the present study will be an important reference for clarifying the pharmacodynamic substance basis and underlying mechanism of chickpea to alleviate IR.

Hair follicle extraction combined with an expanded scalp flap for facial organ reconstruction.

BACKGROUND: Use of scalp skin for facial organ reconstruction represents a mainstream procedure for organ reconstruction. In most cases, adequate amounts of skin can be obtained by using tissue expanders, but harvesting sufficient scalp tissue in patients with low hairlines is challenging. Hair follicular unit extraction (FUE) is one approach to resolve this problem. With FUE, hair follicles are removed from the scalp skin, which can then be prepared as a donor site to obtain sufficient amounts of hairless skin. OBJECTIVES: To evaluate the safety and efficacy of FUE when combined with an expanded scalp flap for facial organ reconstruction. MATERIAL AND METHODS: Patients with low hairlines requiring facial organ reconstruction were selected for this study. The area of skin extension and hair removal were determined prior to surgery, a process which was performed in three stages. Stage I consisted of hair follicle removal using the FUE technique at the donor site. Stage II involved expander implantation using water injections. In Stage III facial organ reconstruction was completed. RESULTS: With the use of the FUE technique, hair follicles from the donor scalp were thoroughly removed and the donor scalp tissue was successfully expanded. Postoperatively, no evident scar formation at the reconstruction site or contracture of the expanded flap was observed. All patients were satisfied with the outcome of their reconstruction procedure. CONCLUSION: FUE provides a means for hair follicle removal from the donor site and can be employed to achieve a safe and effective procedure for facial reconstruction in patients with low hairlines.

Characterization and Risk Factors of Folliculitis after Hair Transplantation: A Multicenter Retrospective Study.

BACKGROUND: Postoperative folliculitis is a common complication of hair transplantation (HT) requiring effective preventive interventions. This study characterized postoperative folliculitis and determined risk factors in patients underwent HT. METHODS: We retrospectively reviewed 1317 patients who underwent HT and completed 9-month follow-up between January 2018 and June 2021 at four medical centers. The incidence of postoperative folliculitis and patient demographics were assessed. Logistic regression analysis was used to identify risk factors, and the characteristics of different types of folliculitis were compared. RESULTS: The overall incidence of postoperative folliculitis was 12.11%, and clinical characteristics varied among the different types of folliculitis. Surgery in summer (odds ratio [OR], 1.772, 95% confidence interval [CI]: 1.05-2.992), number of transplant grafts ≥4000 (OR: 4.818, 95% CI: 1.45-16.014), transplant density >45 grafts per/cm 2 (OR: 2.152, 95% CI: 1.376-3.367), and first nursing time >3 days (OR: 1.555, 95% CI: 1.088-2.223) were the main risk factors for postoperative folliculitis. CONCLUSIONS: Postoperative folliculitis after HT presents different characteristics. Surgical factors and postoperative nursing were demonstrated to be related to folliculitis. Therefore, we propose a preventive folliculitis model based on preoperative, intraoperative, and postoperative factors.

A clinical trial of treating androgenic alopecia with mesenchymal stem cell suspension derived from autologous hair follicle.

BACKGROUND: Androgenic alopecia (AGA) is characterized by progressive hair follicle miniaturization, and novel treatments are needed to intervene in the miniaturization process. We aimed to evaluate the efficacy, safety, effectiveness, and effective population of autologous hair follicle mesenchymal stem cell therapy for the treatment of advanced AGA in Chinese people. METHODS: 50 patients ranging from 25 to 45 years old, with an average age of 32 ± 1.24 years were included. None of them had ever used minoxidil, finasteride, or other drugs to promote hair growth. Healthy hair follicles were extracted from the occipital area and treated to obtain hair follicle mesenchymal stem cells suspensions. The recipient sites were divided into two groups. Nine points were injected in a 1 cm 2 area, and 100 µl of solution containing either 1 × 10 5 cells or normal saline was injected at each point. The follow-up duration was 9 months. Observers were blinded to patient groupings and measurements. RESULTS: An increased proportion of terminal hair and hair shaft diameter was observed in the experimental group at 1 month; the effect lasted until 3 months. The hair thickening effect of advanced miniaturized hair follicles with hair shaft diameter less than 60 µm was more notable than that above 60 µm. None of the patients experienced any obvious side effects. CONCLUSIONS: Hair follicle mesenchymal stem cells were effective in the treatment of Chinese advanced AGA, and a hair shaft diameter of 60µm can be used as a key index to predict the effectiveness of the therapy.

Pharmacological modulation of autophagy for epilepsy therapy: Opportunities and obstacles.

Epilepsy (EP) is a long-term neurological disorder characterized by neuroinflammatory responses, neuronal apoptosis, imbalance between excitatory and inhibitory neurotransmitters, and oxidative stress in the brain. Autophagy is a process of cellular self-regulation to maintain normal physiological functions. Emerging evidence suggests that dysfunctional autophagy pathways in neurons are a potential mechanism underlying EP pathogenesis. In this review, we discuss current evidence and molecular mechanisms of autophagy dysregulation in EP and the probable function of autophagy in epileptogenesis. Moreover, we review the autophagy modulators reported for the treatment of EP models, and discuss the obstacles to, and opportunities for, the potential therapeutic applications of novel autophagy modulators as EP therapies.

Evaluation of a Novel Graft-Holding Solution in Hair Transplantation: A Randomized Controlled Clinical Study.

BACKGROUND: Hair transplantation has become a popular choice for alopecia treatment; however, postsurgical hair shedding still annoys both patients and surgeons. OBJECTIVE: To explore the impact of graft-holding solution on postsurgical hair shedding and testify the protective efficacy of histidine-tryptophan-ketoglutarate solution with adenosine triphosphate and deferoxamine (HTK-AD). METHODS: There were 240 patients enrolled in the study, and the follicles were placed into either HTK-AD or Ringer solution (RS). Masson staining and live/dead staining were performed to evaluate graft morphology and apoptosis levels, respectively. The between-group comparison of postsurgical graft shedding, survival rate, complications, and patient satisfaction was performed. RESULTS: Grafts in HTK-AD maintained organized dense collagen construction and higher cell viability, but those preserved in RS became soft, which hindered implantation. Histidine-tryptophan-ketoglutarate solution with adenosine triphosphate and deferoxamine significantly reduced the incidence of postsurgical hair shedding (73.81% vs 95%), delayed shedding onset, and diminished shedding amount versus RS ( p < .05) when ≥3,000 grafts were transplanted. The shedding duration was shortened, and hair regrowth started earlier in HTK-AD versus RS ( p < .05); thus, satisfaction was increased. The final survival rate showed no difference between 2 groups. CONCLUSION: Histidine-tryptophan-ketoglutarate solution with adenosine triphosphate and deferoxamine is superior to RS for hair graft preservation because it improves graft viability and alleviates postsurgical shedding.

Live Lactobacillus acidophilus alleviates ulcerative colitis via the SCFAs/mitophagy/NLRP3 inflammasome axis.

As a disease caused by an impaired intestinal epithelial barrier, imbalanced flora, immune imbalance and genetic susceptibility, ulcerative colitis (UC) is becoming a health threat for all ages. Lactobacillus acidophilus (L. acidophilus), an attracting probiotic, has already been confirmed to improve immune dysfunction, stabilize intestinal microflora, and combat gut disorders. However, no studies have focused on the effects of different forms of L. acidophilus on UC, and its mechanism involved in the mitophagy/NLRP3 inflammasome pathway has not been reported. In this study, we found that compared with the heat-killed L. acidophilus and the culture supernatant of L. acidophilus, the live L. acidophilus (La) has the optimal therapeutic effect on UC rats. Furthermore, La evidently increased the contents of SCFAs, inhibited NLRP3 inflammasome and facilitated autophagy. SCFAs regulated by La balanced inflammation homeostasis and improved intestinal barrier dysfunctions in vitro and in vivo, which was achieved by activating the mitophagy/NLRP3 inflammasome pathway. Moreover, PCR analysis indicated that the aforementioned effects of SCFAs regulated by La may be due to the activation of G protein-coupled receptors. These findings provided guidance for the application of L. acidophilus in daily life and provided a new molecular target for interactions among L. acidophilus, its metabolites and host immunity.

Effects of sex and estrous cycle on the brain and plasma arginine metabolic profile in rats.

L-arginine is a versatile amino acid with a number of bioactive metabolites. Increasing evidence implicates altered arginine metabolism in the aging and neurodegenerative processes. The present study, for the first time, determined the effects of sex and estrous cycle on the brain and blood (plasma) arginine metabolic profile in naïve rats. Female rats displayed significantly lower levels of L-arginine in the frontal cortex and three sub-regions of the hippocampus when compared to male rats. Moreover, female rats had significantly higher levels of L-arginine and γ-aminobutyric acid, but lower levels of L-ornithine, agmatine and putrescine, in plasma relative to male rats. The observed sex difference in brain L-arginine appeared to be independent of the enzymes involved in its metabolism, de novo synthesis and blood-to-brain transport (cationic acid transporter 1 protein expression at least), as well as circulating L-arginine. While the estrous cycle did not affect L-arginine and its metabolites in the brain, there were estrous cycle phase-dependent changes in plasma L-arginine. These findings demonstrate the sex difference in brain L-arginine in the estrous cycle-independent manner. Since peripheral blood has been increasingly used to identify biomarkers of brain pathology, the influences of sex and estrous cycle on blood arginine metabolic profile need attention when experimental research involves female rodents.

Chickpea Extract Ameliorates Metabolic Syndrome Symptoms via Restoring Intestinal Ecology and Metabolic Profile in Type 2 Diabetic Rats.

SCOPE: Chickpeas have been recognized as a natural Uyghur medicine in Xinjiang (China) for 2500 years. Although the phenotypic effect on obesity or diabetes was authenticated, the mechanism was unclear. This work aims to study the effect of chickpea extract (CE) on metabolic syndrome induced by type 2 diabetes and to reveal its related mechanisms, focusing on intestinal flora and metabolomics. METHODS AND RESULTS: Diabetic rats are induced by a high-fat diet and intraperitoneal injection of streptozotocin. CE supplementation (3 g kg-1 ) for 4 weeks improved the hyperglycemia, inflammatory state, and organ functions of diabetic rats. The metabolic profile trajectories of urine and faeces obtained by NMR have good separations among all groups, and CE significantly increases the contents of SCFAs in the cecum. Moreover, CE relieves intestinal dysbiosis by increasing the abundance of SCFAs-producing bacteria (e.g., Enterococcaceae) but reduces conditional pathogenic bacteria (e.g., Corynebacterium). PICRUSt predicts the functions of gut microbiome from the 16S rRNA gene sequences and metagenome, and finds that CE restored amino acids degradation, bile acids metabolism, and carbohydrate metabolism. CONCLUSION: This study elucidates the role of CE from the perspective of metabolomics and the microbiota, which provides evidence for chickpea as a prebiotic to prevent diabetes.

Black Phosphorus Nanosheets Induced Oxidative Stress In Vitro and Targeted Photo-thermal Antitumor Therapy.

Black phosphorus (BP) nanosheets with excellent features have been broadly employed for cancer therapy. BPs in blood were known to form BP nanomaterial-corona complexes, yet not explored their biological effects. In this study, BPs as delivery vehicles loaded with doxorubicin (DOX) (BP-DOX) by electrostatic interaction had been successfully prepared for photo-thermal/chemotherapy with a tumor inhibition rate of 81.47% more than the rates of BPs (69.50%) and free DOX (51.91%) in the Hela-bearing mice model by a pH/photo-responsive controlled drug release property. Then, in vivo experiments demonstrated that the treatment of healthy mice with BPs led to mild inflammation in the body and oxidative stress in the liver and lung which caused cell apoptosis. In vitro studies further showed that oxidative stress and metabolic disorders could be induced by BPs in A549, HepG2, Beas-2B, and LO2 cells. Lastly, the RGD peptide-conjugated red blood cell (RBC) membrane-coated BPs (RGD-RBC@BP) was prepared by lipid insertion and co-ultrasound methods for efficient photo-thermal therapy (PTT) cancer via a tumor-targeted strategy. RGD-RBC@BP showed positive biocompatibility, photo-thermal properties, and increased cellular uptake by Hela cells benefited by the long circulation property of RBC and RGD peptides. Pharmacokinetics and bio-distribution study of RGD-RBC@BP were found to prolong circulation time and tended to accumulate in the tumors, which overexpression of ανß3 integrin rather than livers after intravenous injection 24 h in vivo. After 808 nm laser irradiation, RGD-RBC@BP nanoparticles exhibited a better PTT than PEGylated BPs (BP-PEG). The active-targeting strategy of biomimetic nanomaterials based on the tumor microenvironment have been proved to have favorable biological prospects in cancer PTT.

Ligand-Modified Erythrocyte Membrane-Cloaked Metal-Organic Framework Nanoparticles for Targeted Antitumor Therapy.

Systemic chemotherapy for treating tumors often leads to serious systemic side effects and affects patient compliance. Although the emerging technology of drug delivery systems (DDSs) can deliver the required cargo to tumor sites, DDSs are limited due to insufficient targeting ability or deficient pharmacokinetics. Herein, we assembled a novel targeting DDS for precision tumor therapy by applying a tumor-targeting polypeptide cyclic RGD (cRGD)-modified erythrocyte membrane (eM-cRGD) cloaked on zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) with encapsulated doxorubicin (DOX). For a mass ratio of ZIF-8:DOX = 1:1, the loading capacity was up to 49%. The nanoscale-sized targeting DDS promoted NP accumulation in tumor tissues via enhanced permeability and retention (EPR) effects, and the NPs actively targeted ligands and were then transferred to endosomes. The pH-sensitive carriers released higher DOX levels under the low pH mimicking that of a tumor microenvironment and tumor intracellular organelles, allowing enhanced inhibition of cancer cell growth. The cumulative release rate of DOX from DOX@ZIF-8 NPs reached 82.8% at 48 h in acidic conditions of pH = 5.0, while the cumulative release rate of DOX from the DOX@ZIF-8 NPs reached only 24.92% at pH = 7.4. The internalization of the DDS was approximately 44.35% that of the unmodified DDS by immune cells, as confirmed by flow cytometry. In vivo studies verified that the RGD-modified DDS had the ability to prolong blood circulation (t1/2 = 6.81 h), enhancing the tumor-specific accumulation of NPs by means of the integrin αvß3 receptor-mediated pathway, which was further valuated in mice bearing human cervical cancer (HeLa) cells, and yielding a significant antitumor effect; the tumor inhibition rate was as high as 85.46%. Under the same conditions, the blood circulation half-life of the unmodified DDS was only 3.22 h, and the tumor inhibition rate of free DOX was 81.34%. Moreover, the RGD modified with a carrier could achieve a satisfactory chemotherapeutic effect while minimizing side effects. In summary, our novel targeting DDS could contribute to the development of intelligent DDSs for tumor precision therapy.

Maternal immune activation altered microglial immunoreactivity in the brain of postnatal day 2 rat offspring.

Microglia, the resident immune cells of the central nervous system, play critical roles in neurodevelopment, synaptic pruning, and neuronal wiring. Early in development, microglia migrate via the tangential and radial migration pathways to their final destinations and mature gradually, a process that includes morphological changes. Recent research has implicated microglial abnormality in the etiology of schizophrenia. Since prenatal exposure to viral or bacterial infections due to maternal immune activation (MIA) leads to increased risk of schizophrenia in the offspring during adulthood, the present study systematically investigated how MIA induced by polyinosinic:polycytidylic acid (a mimic of viral double-stranded RNA) affected microglial immunoreactivity along the migration and maturation trajectories in the brains of male and female rat offspring on postnatal day (PND) 2. The immunohistochemistry revealed significant changes in the density of IBA-1 immunoreactive cells in the corpus callosum, somatosensory cortex, striatum, and the subregions of the hippocampus of the MIA offspring. The male and female MIA offspring displayed markedly altered microglial immunoreactivity in both the tangential and radial migration, as well as maturation, pathways when compared to their sex- and age-matched controls as evidenced by morphology-based cell counting. Given the important roles of microglia in synaptic pruning and neuronal wiring and survival, these changes may lead to structural and functional neurodevelopmental abnormalities, and so contribute to the functional deficits observed in juvenile and adult MIA offspring. Future research is required to systematically determine how MIA affects microglial migration and maturation in rat offspring.