Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

[This corrects the article DOI: 10.1016/j.apsb.2021.08.008.].

Objective:To analyze the cognitive changes and alterations in the topological properties of functional and structural brain networks in elderly women with mild cognitive impairment (MCI), and explore the relationship between brain network and cognitive function, and find the neuroimaging mechanism of cognitive decline in female patients with MCI.Methods:A cross-sectional study was conducted, collecting clinical data from 38 elderly women with MCI, aged 60-79, recruited between October 1, 2019 and May 31, 2021, through community visits, online advertisements, free consultations by experts at the First Hospital of China Medical University and outpatient promotions. A matched control group of 37 healthy women of similar age was also recruited. Both groups underwent comprehensive neuropsychological assessments and MRI data collection, Brain functional and structural networks were constructed, and the corresponding global and nodal topological metrics were calculated. Differences in general demographic data, cognitive function scores, and network topology attribute indexes were compared. Pearson correlation analysis was used to explore the relationship between the altered topological properties of brain networks and cognitive function differences.Results:Cognitive function assessments showed that compared to the healthy control group, elderly women with MCI scored lower on the Rey Auditory Verbal Learning Test-N5 (AVLT-N5), Digit Span Test (DST), Clock Drawing Test (CDT), and Verbal Fluency Test (VFT) (1.95±1.02 vs 6.42±1.63, t=14.85; 7.14±1.58 vs 8.08±1.29, t=2.93; 3.30±1.12 vs 3.73±0.55, t=2.20; 15.49±3.87 vs 18.53±3.80, t=3.60; all P<0.05). The results of brain functional and structural network nodal topological properties indicated that the left inferior parietal angular gyri, left supramarginal gyrus, right orbital inferior frontal gyrus, and right insula showed incomplete white matter network structure or reduced efficiency in brain network functional transmission ( P<0.05). Conversely, regions such as the left cuneus, left superior frontal gyrus orbital part, left middle occipital gyrus, left precuneus, right superior parietal gyrus, and left paracentral lobule showed enhanced structural integrity of white matter network or increased efficiency in brain network functional transmission ( P<0.05). Correlation analysis suggested that abnormal nodal topological attributes were associated with language function (VFT), short-term memory (AVLT-N5), and visuospatial ability (CDT) in patients with MCI(All P<0.05). Conclusion:Elderly women with MCI exhibit declines in short-term memory, linguistic function, attention, and visuospatial abilities. Changes in the topological properties of brain function and structural networks occur in regions such as the orbital superior frontal gyrus, middle occipital gyrus, and cuneus in the elderly women.

Objective:To analyze the cognitive changes and alterations in the topological properties of functional and structural brain networks in elderly women with mild cognitive impairment (MCI), and explore the relationship between brain network and cognitive function, and find the neuroimaging mechanism of cognitive decline in female patients with MCI.Methods:A cross-sectional study was conducted, collecting clinical data from 38 elderly women with MCI, aged 60-79, recruited between October 1, 2019 and May 31, 2021, through community visits, online advertisements, free consultations by experts at the First Hospital of China Medical University and outpatient promotions. A matched control group of 37 healthy women of similar age was also recruited. Both groups underwent comprehensive neuropsychological assessments and MRI data collection, Brain functional and structural networks were constructed, and the corresponding global and nodal topological metrics were calculated. Differences in general demographic data, cognitive function scores, and network topology attribute indexes were compared. Pearson correlation analysis was used to explore the relationship between the altered topological properties of brain networks and cognitive function differences.Results:Cognitive function assessments showed that compared to the healthy control group, elderly women with MCI scored lower on the Rey Auditory Verbal Learning Test-N5 (AVLT-N5), Digit Span Test (DST), Clock Drawing Test (CDT), and Verbal Fluency Test (VFT) (1.95±1.02 vs 6.42±1.63, t=14.85; 7.14±1.58 vs 8.08±1.29, t=2.93; 3.30±1.12 vs 3.73±0.55, t=2.20; 15.49±3.87 vs 18.53±3.80, t=3.60; all P<0.05). The results of brain functional and structural network nodal topological properties indicated that the left inferior parietal angular gyri, left supramarginal gyrus, right orbital inferior frontal gyrus, and right insula showed incomplete white matter network structure or reduced efficiency in brain network functional transmission ( P<0.05). Conversely, regions such as the left cuneus, left superior frontal gyrus orbital part, left middle occipital gyrus, left precuneus, right superior parietal gyrus, and left paracentral lobule showed enhanced structural integrity of white matter network or increased efficiency in brain network functional transmission ( P<0.05). Correlation analysis suggested that abnormal nodal topological attributes were associated with language function (VFT), short-term memory (AVLT-N5), and visuospatial ability (CDT) in patients with MCI(All P<0.05). Conclusion:Elderly women with MCI exhibit declines in short-term memory, linguistic function, attention, and visuospatial abilities. Changes in the topological properties of brain function and structural networks occur in regions such as the orbital superior frontal gyrus, middle occipital gyrus, and cuneus in the elderly women.

Substantial progress in the use of chemo-photodynamic nano-drug delivery systems (nano-DDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here, we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative (pheophorbide-diphenylalanine peptide, PPA-DA) with a hypoxia-activated camptothecin (CPT) prodrug [(4-nitrophenyl) formate camptothecin, N-CPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser, PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.

OBJECTIVE: To explore the clinical feature, diagnosis and phenotype of Majeed syndrome. METHODS: Clinical manifestation, diagnostic process, imaging feature and genetic testing of an ethnic Han Chinese patient with Majeed syndrome were reviewed. RESULTS: The patient, a 3-year-9-month-old boy, had featured psychomotor retardation and developed bone pain from 8 month on. The child had tenderness of the lower limbs and presented with repeatedly joint swelling and pain accompanied by fever. Physical signs included limb muscle weakening, slightly decreased muscle tone, reduced muscle volume and positive Gower sign. High-throughput sequencing revealed that the child has carried compound heterozygous variants of the LPIN2 gene, including c.1966A>G and c.2534delG. MRI showed multiple lesions in bilateral knee joints and distal middle tibia presenting as patchy SPAIR high signals with unclear edge, in addition with edema of soft tissue surrounding the right distal femur. CONCLUSION Majeed syndrome is characterized by chronic and recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and growth retardation. Surrounding muscle tissue of osteomyelitis may also be involved. The syndrome may also affect the central nervous system, resulting in delayed language and motor development. Discovery of multiple pathological variants of the LPIN2 gene suggested that the clinical phenotype of this syndrome may vary between patients to some extent.
Anemia, Dyserythropoietic, Congenital/genetics* ; Child ; Genetic Testing ; Humans ; Immunologic Deficiency Syndromes/genetics* ; Infant ; Male ; Osteomyelitis/genetics*

Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.