Objective:To explore the alterations in gray matter morphology and contributing factors in patients with post-infectious olfactory dysfunction (PIOD) using voxel-based morphometry (VBM) and surface-based morphometry (SBM), thereby providing scientific insights into the neuropathological mechanisms underlying PIOD.Methods:A total of 46 PIOD patients (PIOD group) and 46 normosmic volunteers (control group) were recruited from the Smell and Taste Disorders Clinic of Beijing Anzhen Hospital, Capital Medical University, between January 2020 and December 2024. All participants underwent olfactory psychophysical tests (Sniffin′ Sticks) and olfactory event-related potential (oERP) examination. High-resolution T1-weighted 3D MRI structural images were obtained for both groups. VBM was employed to analyze inter-group differences in gray matter volume, while SBM was used to assess cortical thickness and folding index. Correlations between gray matter volume in significant difference brain regions and disease duration, Sniffin′ Sticks scores, oERP parameters were analyzed. A two-tailed P<0.05 was considered statistically significant. Results:No significant differences were observed in age, sex, education level, or Mini-Mental State Examination (MMSE) scores ( t=1.80, χ2=0.41, t=0.17, t=1.77, all P>0.05). Compared with controls, the PIOD group showed significantly lower Sniffin′ Sticks scores ( t=28.70, P<0.001), prolonged oERP latencies and reduced amplitudes (all P<0.001). VBM revealed significantly reduced gray matter volume in the right orbitofrontal cortex (OFC) in the PIOD group ( t=5.38, P<0.001). SBM demonstrated decreased cortical thickness in the right OFC ( t=5.27, P<0.001), with no significant differences in folding index. The gray matter volume in the right OFC was negatively correlated with disease duration ( r=-0.61, P<0.001), but no significant correlations were found with Sniffin′ Sticks scores or oERP parameters. Conclusion:Patients with PIOD show atrophy in the right OFC, which correlates with disease duration, suggesting that persistent olfactory dysfunction may be associated with neurodegenerative changes.

OBJECTIVE To prepare Arg-Gly-Asp（RGD）-modified doxorubicin （DOX）-loaded “core-shell” nanoparticles （RGD@DOX-LPNs）， characterize the nanoparticles， and investigate their antitumor effects. METHODS RGD@DOX-LPNs were prepared using the nanoprecipitation method. Their morphology was examined by visual inspection and electron microscopy. Particle size， polydispersity index （PDI）， and Zeta potential were determined， and differential scanning calorimetry （DSC） and X-ray diffraction （XRD） were employed. Encapsulation efficiency （EE）， drug loading （DL）， and stability were evaluated. The in vitro release kinetics， mucus diffusion， and tumor cell uptake [tracked using coumarin 6 （COU）] were investigated. The in vivo tissue distribution and gastrointestinal retention [labeled with 11-chloro-1， 1′-dipropyl-3， 3， 3′， 3′-tetramethyl-10， 12- trimethyleneindotricarbocyanine iodide （IR780）] were investigated. Using 4T1 tumor-bearing mice as the experimental subjects， the effects of the prepared formulation on tumor volume， tumor weight， and cell apoptosis rate were evaluated. RESULTS RGD@DOX-LPNs presented as orange transparent liquid with uniform and near-spherical particles. The particle size was （159.67± 8.02） nm， PDI was 0.15±0.06， and Zeta potential was （－19.70±0.79） mV. After modification with RGD， the thermal absorption peak and crystalline diffraction peak of DOX disappeared. EE and DL of RGD@DOX-LPNs were （72.65±4.37）% and （4.62± 0.38）% ， respectively. No obvious changes in appearance， particle size， or EE were observed after storage at 4 ℃ and 25 ℃ for 7 days. The cumulative drug release at 4 h was approximately 73%， which was lower than that of free DOX（almost completely released within 1 h）. The amount of COU in the first segmental mucus layer of COU-LPNs was significantly lower than that in the corresponding segment of RGD@COU- LPNs， whereas it was significantly higher in the 2nd to 5th segmental mucus layers compared to RGD@COU-LPNs （P＜0.01）. Cellular uptake of RGD@COU-LPNs was significantly higher than that of COU-LPNs（P＜0.05）. The isolated tissue fluorescence intensity of RGD@IR780-LPNs was stronger than that of IR780-LPNs， indicating better small intestinal retention. Compared with free DOX and unmodified nanoparticles （DOX-LPNs）， RGD@DOX-LPNs exhibited a higher tumor inhibition rate of 65.74%， significantly reduced tumor volume and weight， and increased apoptosis rate（P＜0.01）. CONCLUSIONS RGD@DOX-LPNs are successfully prepared with sustained release properties， which can improve gastrointestinal mucus retention， enhance cellular uptake of DOX， and have potent antitumor activity against breast cancer.

Objective:To explore the alterations in gray matter morphology and contributing factors in patients with post-infectious olfactory dysfunction (PIOD) using voxel-based morphometry (VBM) and surface-based morphometry (SBM), thereby providing scientific insights into the neuropathological mechanisms underlying PIOD.Methods:A total of 46 PIOD patients (PIOD group) and 46 normosmic volunteers (control group) were recruited from the Smell and Taste Disorders Clinic of Beijing Anzhen Hospital, Capital Medical University, between January 2020 and December 2024. All participants underwent olfactory psychophysical tests (Sniffin′ Sticks) and olfactory event-related potential (oERP) examination. High-resolution T1-weighted 3D MRI structural images were obtained for both groups. VBM was employed to analyze inter-group differences in gray matter volume, while SBM was used to assess cortical thickness and folding index. Correlations between gray matter volume in significant difference brain regions and disease duration, Sniffin′ Sticks scores, oERP parameters were analyzed. A two-tailed P<0.05 was considered statistically significant. Results:No significant differences were observed in age, sex, education level, or Mini-Mental State Examination (MMSE) scores ( t=1.80, χ2=0.41, t=0.17, t=1.77, all P>0.05). Compared with controls, the PIOD group showed significantly lower Sniffin′ Sticks scores ( t=28.70, P<0.001), prolonged oERP latencies and reduced amplitudes (all P<0.001). VBM revealed significantly reduced gray matter volume in the right orbitofrontal cortex (OFC) in the PIOD group ( t=5.38, P<0.001). SBM demonstrated decreased cortical thickness in the right OFC ( t=5.27, P<0.001), with no significant differences in folding index. The gray matter volume in the right OFC was negatively correlated with disease duration ( r=-0.61, P<0.001), but no significant correlations were found with Sniffin′ Sticks scores or oERP parameters. Conclusion:Patients with PIOD show atrophy in the right OFC, which correlates with disease duration, suggesting that persistent olfactory dysfunction may be associated with neurodegenerative changes.

Objectives:To explore the dynamic changes of right ventricular global longitudinal strain (RVGLS) on echocardiography during the process of right ventricular fibrosis with right ventricular pressure overload.Methods:Animal models with RV pressure overload (n=5) were established by main pulmonary artery (PA) banding in piglets.The ratio of RV pressure to left ventricular (LV) pressure was greater than 60％ as assessed by the pressure measuring needle during the operation.Pre-and post-operative echocardiography were performed.Histopathological examination of RV tissues was performed at the end of the experiment.Results:During the establishment of the animal models,2 piglets died due to hemorrhagic shock,while 3 piglets survived and were included in the analysis.Systolic RV pressure,systolic PA pressure and mean PA pressure(measured at the proximal end of the constriction) were significantly increased immediately after PA banding,mean RV pressure and mean PA pressure were significantly inreased at 14 weeks postopseratively (all P<0.05).Tricuspid annulus plane systolic excursion and peak early diastolic velocity of tricuspid annulus (TV e') decreased immediately after operation (all P<0.05).They returned to the pre-operative level in the following three weeks.The absolute values of RVGLS were reduced after PA banding (all P>0.05).The RVGLS of the inner membrane layer began to recover after 3 weeks,and the RVGLS of the middle and outer membrane layers began to recover after 7 weeks.However,the time to peak RVGLS was significantly prolonged and could not be restored even untill the end of the experiment (14 weeks after surgery)(all P<0.05).At the end of the experiment,pathological examination revealed fibrous tissue hyperplasia in both the myocardial interstitium and endocardium.Conclusions:The measurement of intracardiac pressure and pathological results confirmed the success of the establishment of the animal model of increased right ventricular afterload.Both stress and strain cannot truly represent the intrinsic characteristics of the myocardium under pressure overload.The prolonged time to peak of longitudinal strain might indirectly reflect the progression of myocardial injury more persistently during the process of increased right ventricular afterload and myocardial injury.

Objectives:To explore the dynamic changes of right ventricular global longitudinal strain (RVGLS) on echocardiography during the process of right ventricular fibrosis with right ventricular pressure overload.Methods:Animal models with RV pressure overload (n=5) were established by main pulmonary artery (PA) banding in piglets.The ratio of RV pressure to left ventricular (LV) pressure was greater than 60％ as assessed by the pressure measuring needle during the operation.Pre-and post-operative echocardiography were performed.Histopathological examination of RV tissues was performed at the end of the experiment.Results:During the establishment of the animal models,2 piglets died due to hemorrhagic shock,while 3 piglets survived and were included in the analysis.Systolic RV pressure,systolic PA pressure and mean PA pressure(measured at the proximal end of the constriction) were significantly increased immediately after PA banding,mean RV pressure and mean PA pressure were significantly inreased at 14 weeks postopseratively (all P<0.05).Tricuspid annulus plane systolic excursion and peak early diastolic velocity of tricuspid annulus (TV e') decreased immediately after operation (all P<0.05).They returned to the pre-operative level in the following three weeks.The absolute values of RVGLS were reduced after PA banding (all P>0.05).The RVGLS of the inner membrane layer began to recover after 3 weeks,and the RVGLS of the middle and outer membrane layers began to recover after 7 weeks.However,the time to peak RVGLS was significantly prolonged and could not be restored even untill the end of the experiment (14 weeks after surgery)(all P<0.05).At the end of the experiment,pathological examination revealed fibrous tissue hyperplasia in both the myocardial interstitium and endocardium.Conclusions:The measurement of intracardiac pressure and pathological results confirmed the success of the establishment of the animal model of increased right ventricular afterload.Both stress and strain cannot truly represent the intrinsic characteristics of the myocardium under pressure overload.The prolonged time to peak of longitudinal strain might indirectly reflect the progression of myocardial injury more persistently during the process of increased right ventricular afterload and myocardial injury.

Objective : To investigate the effect and mechanism of exosome ( Exo) transported miR⁃223 on brain tissue injury and microglial activation in rats with traumatic brain injury ( TBI) . Methods : The miR⁃NC plasmid and miR⁃223 mimic plasmid were transfected into HEK293 cells by liposome method , and the expression level of miR⁃223 in the cells was determined by quantitative real⁃time PCR . Exo was extracted from transfected HEK293 cells and identified by transmission electron microscopy , nanoparticle tracking analysis and Western blot , the expression level of miR⁃223 in Exo was determined by quantitative real⁃time PCR . Forty SD rats were randomly divided into sham group , model group , NC⁃Exo group and miR⁃223 ⁃Exo group , with 10 rats in each group , TBI model was prepared by modified Feeney free fall method in all groups except sham group , rats in NC⁃Exo group and miR⁃223 ⁃Exo group were injected with cell⁃derived Exo transfected with miR⁃NC plasmid and cell⁃derived Exo transfected with miR⁃223 mimic plasmid via tail vein , respectively . Two weeks later , hematoxylin⁃eosin (HE) staining was used to observe the pathological changes of brain tissue in each group , Nissl staining was used to detect the changes and distribution of Nissl bodies in each group , enzyme⁃linked immunosorbent assay (ELISA) was used to measure the serum levels of tumor necrosis factor⁃α (TNF⁃α ) , interleukin⁃1β (IL⁃1β) and interleukin⁃6(IL⁃6) , immunofluorescence double staining was used to observe the expression of nod⁃like receptor family pyrin domain containing 3(NLRP3) and ionized calcium binding adaptor molecule 1 (Iba⁃1) , Western blot was used to detect the protein expression of NLRP3 , apoptosis⁃associated speck⁃like protein containing( ASC) and Caspase⁃1 . Results: After transfection , compared with control group and miR⁃NC group , the relative expression of miR⁃223 in miR⁃223 group significantly increased (P < 0. 05) . The isolated particles had typical Exo morphology , the peak particle size was about 120 nm , the Exo marker proteins CD9 , CD63 and CD81 were significantly overexpressed , and the relative expression of miR⁃223 significantly non of brain tissue in the miR⁃223 ⁃Exo group was improved , the morphology and number of Nissl bodies were re⁃increased (P < 0. 05) . Compared with the model group , the damage phenome stored , the levels of TNF⁃α , IL⁃1β and IL⁃6 in serum decreased ( P < 0. 05) , the intensity of NLRP3 and Iba⁃1 fluorescence staining in brain tissue decreased (P < 0. 05) , the relative protein expressions of NLRP3 , ASC and Caspase⁃1 in brain tissue were down⁃regulated (P < 0. 05) . Conclusion Exo operation of miR⁃223 can significant ly improve brain tissue injury and inhibit microglial activation in TBI rats , which may be related to the inhibition of NLRP3 .

In clinical application, a microneedle system that continuously delivers drugs is of great value for the delivery of some vaccines and hormone drugs. In this study, a controlled-release chitosan-based microneedle array (PVA/CS-MN) was designed, combining microneedle patches with drugs for controlled-release of drugs. Here we report the optimization of the preparation process of PVA/CS-MN. The appearance, morphology, mechanical properties, dissolution and swelling properties, and in vitro penetration properties of the MN arrays were characterized. The PVA/CS-MN prepared by the optimal process showed good morphology and mechanical properties. PVA/CS-MN can smoothly open microchannels on the skin and achieve controllable dissolution and swelling functions. Ascorbic acid (l-ascorbic acid) was used as a model drug to prepare a Vc-PVA/CS-MN. In vitro transdermal diffusion experiments showed that the Vc-PVA/CS-MN released about 57% of the drug within 1 h. About 66.7% of the drug was slowly released within 12 h, and a total of 92% of the drug was released after 7 days. The controllable sustained-release properties and excellent drug delivery efficiency of PVA/CS-MN provide a new option for sustained transdermal drug delivery.
Ascorbic Acid ; Chitosan ; Delayed-Action Preparations ; Drug Delivery Systems ; Hormones ; Vaccines

The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth

Objective To explore the activition and polarization of microglia in the epileptic rats induced by lithium chloride-pilocarpine. Methods One hundred male SD rats were randomly divided into five groups: control group and different time points model groups including 1d,3d,7d and 14d. Epilepsy models were established by lithium chloride-pilocarpine intraperitoneal injection. The control group was given the same dosage of normal saline. The morphology change was detected by immunofluorescence,and the expressions of iNOS and Arg-1 were determined by IHC at respective time points. Results Compared the model groups with control group,microglia was activated,synapsis was shorten,volume got bigger,most of them seemed as amoebocyte,the expression of iNOS increased and Arg-1 decreased,especially at 3d.ConclusionThe results from this study indicated that microglia was activated and polarized in epileptic rats induced by pilocarpine.

Chronic constipation is a common gastrointestinal disease severely affecting the patient׳s quality of life. The traditional treatment of constipation is the use of laxatives. Recently, several new drugs including lubiprostone, linaclotide and prucalopride have been approved for treatment of chronic constipation. However, a significant unmet medical need still remains, particularly among those patients achieving poor results by current therapies. The 5-HT4 receptor modulators velusetrag and naronapride, the guanylate cyclase C agonist plecanatide and the ileal bile acid transporter inhibitor elobixibat are recognized as the most promising drugs under investigation. Herein, we give a comprehensive review on the pharmacological therapeutics for the treatment of chronic constipation, with the purpose of reflecting the drug development trends in this field.