Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

OBJECTIVE To explore the risk factors for serum COVID-19 antibodies in the population of Fuzhou to provide scientific basis for prevention and control strategies.METHODS The prospective study and the multi-stage stratified random sampling method were performed to select at least 200 subjects from each of the 12 counties(cit-ies)in Fuzhou.Questionnaires follow-ups and serum collections were conducted in Mar,Jun,Sep,and Dec.2024,respectively.The antibody levels in Dec.were divided into a high protective antibody group(IgG antibody≥50 AU/ml)and a low protective antibody group(IgG antibody≤20 AU/ml).The influencing factors of serum anti-body levels were analyzed by multivariate logistic regression model.RESULTS A total of 2816 subjects were en-rolled.In Mar,1454 subjects with high-protective antibodies were identified.After nine months of follow-up,of the 1454 subjects,344 had high protective antibodies and 369 had low protective antibodies in Dec..There were statistically significant differences in age,presence of typical symptoms after infection,underlying diseases,surgi-cal history,healing time,smoking and drinking histories between the high and low antibody groups(P<0.05).Multivariate logistic regression model showed that older age,underlying diseases,history of surgery,smoking and drinking were risk factors which could reduce antibody levels(P<0.05),while typical symptoms after infec-tion and longer recovery time were protective factors which could increase antibody levels(P<0.05).After the COVID-19 infection in spring of 2024,the serum antibody levels in Fuzhou residents showed the downward trend,especially after Sep.2024,with a more pronounced downward trend.CONCLUSIONS According to the risk factors of COVID-19 antibody levels,prevention and control efforts should be focused on the key population.It is necessa-ry to strengthen health education and carry out vaccination to maintain the levels of immunity to protect population from COVID-19 infection.

BACKGROUND:The pathogenesis of diabetic peripheral neuropathy has not yet been clarified,and TAM(Tyro3,Axl,and MerTK)receptor tyrosine kinases can control apoptotic cells and suppress inflammatory responses in the central nervous system. OBJECTIVE:To investigate the difference of Mer receptor tyrosine kinase(MerTK)levels in plasma and sciatic nerve tissue of Sprague-Dawley rats with type 2 diabetes and diabetic peripheral neuropathy,and to study the correlation between MerTK and diabetic peripheral neuropathy. METHODS:Forty male Sprague-Dawley were randomly divided into control group with 15 rats,type 2 diabetes group with 10 rats,and diabetic peripheral neuropathy group with 15 rats.The control group was fed with ordinary diet,while the experimental groups were fed with high-fat and high-sugar diet.After 6 weeks,intraperitoneal injection of streptozotocin at the minimum dose of 35 mg/kg was administered in the two experimental groups.After 14 days,tail vein blood was collected to detect blood glucose.If blood glucose≥16.7 mmol/L,the model of type 2 diabetes was successfully established.Rats in the diabetic peripheral neuropathy group continued to be fed with a high-sugar and high-fat diet for 8 weeks.The sciatic nerve conduction velocity of rats was detected through live isolation under anesthesia.Blood samples were collected from the abdominal aorta,and the sciatic nerve tissue was collected.Histological changes of nerve fibers in each group were observed under a light microscope to confirm the success of diabetic peripheral neuropathy modeling.ELISA was used to detect peripheral blood glucose,blood lipids and serum MerTK levels in rats;hematoxylin-eosin staining was used to observe the histological changes in the sciatic nerve;immunofluorescence,immunohistochemistry and western blot were used to detect the expression of MerTK in the sciatic nerve tissue. RESULTS AND CONCLUSION:The Sprague-Dawley rat models of type 2 diabetes and type 2 diabetes peripheral neuropathy were successfully constructed,and the modeling rate of diabetic peripheral neuropathy was 80%.Compared with the control group,the blood glucose levels of rats in the type 2 diabetes and diabetic peripheral neuropathy groups were significantly higher(P<0.000 1),while the blood glucose level in the diabetic peripheral neuropathy group was higher than that in the type 2 diabetes group;and the sciatic nerve conduction velocity was significantly decreased(P<0.05),which was lower in the diabetic peripheral neuropathy group than the type 2 diabetes group.Histological examination:Compared with the control group,the sciatic nerve nuclei were reduced in the type 2 diabetes group,with some vacuolar degeneration and phagocytosis;in the diabetic peripheral neuropathy group,the cell body was swollen,the nuclear spacing was increased,vacuolar degeneration was observed,and the myelin sheath was partitioned and unsmooth,and lattice-like axons appeared.Serum MerTK levels were significantly higher in the diabetic peripheral neuropathy group than the control group.Expression of MerTK in the sciatic nerve tissue was significantly upregulated in the diabetic peripheral neuropathy group compared with the control group(P<0.05).To conclude,elevated levels of MerTK in plasma and sciatic nerve tissue of rats with diabetic peripheral neuropathy are presumably related to its anti-inflammatory and immunomodulatory effects.

Objective:To investigate changes of choroid plexus volume in patients with essential hypertension using deep learning-based segmentation technique.Methods:According to the inclusion criteria,19 patients with essential hypertension who visited The 900th Hospital of People's Liberation Army Joint Service Support Force from December 2022 to May 2024 were divided into hypertension group.Additionally,19 healthy individuals,matched with the hypertension group in terms of gender,age,and years of education,were recruited as the healthy control group during the same period.All participants underwent data acquisition of three-dimensional T1(T1-3D)brain structural images using a Siemens 3.0T Trio magnetic resonance(MR)scanner.A pre-trained deep learning model,which based on the 3D U-Net architecture and generated by fully convolutional neural network,was employed for choroid plexus segmentation,and the total brain volume and lateral ventricle volume were calculated using the United Imaging Artificial Intelligence(AI)platform.Statistical analysis of the choroid plexus volume and other data for both groups were performed using SPSS27.0.Results:Compared with the healthy control group(1 866 mm3),the hypertensive group(2 047 mm3)showed an abnormal increase in choroid plexus volume(x2=3.900,P<0.05).Moreover,the choroid plexus volume was positively correlated with lateral ventricle volume and systolic blood pressure(r=0.849,P<0.05),and was negatively correlated with digit span(forward)in the hypertensive group(r=-0.374,P<0.05).Conclusion:The choroid plexus volume in patients with essential hypertension abnormally increased,which might be a factor promoting to changes in brain structure,it can affect further the cognitive function of patients with hypertension.

OBJECTIVE To observe the effect of acupuncture combined with a modified Zhengan Xifeng Decoction on the early clinical symptoms and oxidative stress status of patients with hypertensive intracerebral hemorrhage(HICH)of liver-kidney yin defi-ciency syndrome.METHODS A total of 60 patients with hypertensive intracerebral hemorrhage(liver-kidney yin deficiency syn-drome)who successfully received 24-hour acute-phase treatment at the Department of Neurosurgery,Acupuncture and Rehabilitation Department,and wards of Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine(Kunshan Traditional Chinese Medi-cine Hospital)from July 2021 to January 2023 were recruited.A randomization table generated by SPSS 22.0 software was used to di-vide the patients into a control group and an observation group,with 30 patients in each group.The control group received symptomatic treatment,conventional rehabilitation training,and modified Zhengan Xifeng Decoction,while the observation group received additional acupuncture treatment on the basis of the control group.The treatment course was 1 month for both groups.Clinical effective rate,TCM syndrome scores,motor and neurological function scores[Activity of Daily Living(ADL)scale,National Institutes of Health Stroke Scale(NIHSS),Modified Ashworth Scale(MAS),Simplified Fugl-Meyer Assessment(FMA)scale],improvement in hematoma lesions,Fraction anisotropy(FA)ratio(rFA),and serum levels of antioxidant stress response factors Kelch-like ECH-associated protein 1(Keap1)and nuclear factor-E2-related factor 2(Nrf2)were observed before and after treatment in both groups.RESULTS After treat-ment,the clinical effective rate in the observation group was significantly higher than that in the control group(P<0.05);the TCM syn-drome scores in both groups decreased significantly(P<0.05),with the observation group showing better results than the control group(P<0.05);the ADL and FMA scores in both groups reduced significantly(P<0.05,P<0.01),while the NIHSS and Ashworth Scale scores increased significantly(P<0.05,P<0.01),with the observation group showing better improvement than the control group(P<0.05);serum Keap1 levels decreased significantly in both groups(P<0.01),while Nrf2 levels enhanced significantly(P<0.05,P<0.01),with the observation group showing better improvement than the control group(P<0.05);imaging studies showed that after treat-ment,the residual hematoma volume decreased significantly in both groups(P<0.05,P<0.01),and the rFA value increased signifi-cantly(P<0.05,P<0.01),with the observation group showing better results than the control group(P<0.01).CONCLUSION On the basis of standard treatment for the acute phase,acupuncture combined with Zhengan Xifeng Decoction can significantly improve the early clinical symptoms of HICH patients with liver-kidney yin deficiency,reduce oxidative stress levels,and promote the recovery of nerve and motor functions.

OBJECTIVE To observe the effect of acupuncture combined with a modified Zhengan Xifeng Decoction on the early clinical symptoms and oxidative stress status of patients with hypertensive intracerebral hemorrhage(HICH)of liver-kidney yin defi-ciency syndrome.METHODS A total of 60 patients with hypertensive intracerebral hemorrhage(liver-kidney yin deficiency syn-drome)who successfully received 24-hour acute-phase treatment at the Department of Neurosurgery,Acupuncture and Rehabilitation Department,and wards of Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine(Kunshan Traditional Chinese Medi-cine Hospital)from July 2021 to January 2023 were recruited.A randomization table generated by SPSS 22.0 software was used to di-vide the patients into a control group and an observation group,with 30 patients in each group.The control group received symptomatic treatment,conventional rehabilitation training,and modified Zhengan Xifeng Decoction,while the observation group received additional acupuncture treatment on the basis of the control group.The treatment course was 1 month for both groups.Clinical effective rate,TCM syndrome scores,motor and neurological function scores[Activity of Daily Living(ADL)scale,National Institutes of Health Stroke Scale(NIHSS),Modified Ashworth Scale(MAS),Simplified Fugl-Meyer Assessment(FMA)scale],improvement in hematoma lesions,Fraction anisotropy(FA)ratio(rFA),and serum levels of antioxidant stress response factors Kelch-like ECH-associated protein 1(Keap1)and nuclear factor-E2-related factor 2(Nrf2)were observed before and after treatment in both groups.RESULTS After treat-ment,the clinical effective rate in the observation group was significantly higher than that in the control group(P<0.05);the TCM syn-drome scores in both groups decreased significantly(P<0.05),with the observation group showing better results than the control group(P<0.05);the ADL and FMA scores in both groups reduced significantly(P<0.05,P<0.01),while the NIHSS and Ashworth Scale scores increased significantly(P<0.05,P<0.01),with the observation group showing better improvement than the control group(P<0.05);serum Keap1 levels decreased significantly in both groups(P<0.01),while Nrf2 levels enhanced significantly(P<0.05,P<0.01),with the observation group showing better improvement than the control group(P<0.05);imaging studies showed that after treat-ment,the residual hematoma volume decreased significantly in both groups(P<0.05,P<0.01),and the rFA value increased signifi-cantly(P<0.05,P<0.01),with the observation group showing better results than the control group(P<0.01).CONCLUSION On the basis of standard treatment for the acute phase,acupuncture combined with Zhengan Xifeng Decoction can significantly improve the early clinical symptoms of HICH patients with liver-kidney yin deficiency,reduce oxidative stress levels,and promote the recovery of nerve and motor functions.

OBJECTIVE To explore the risk factors for serum COVID-19 antibodies in the population of Fuzhou to provide scientific basis for prevention and control strategies.METHODS The prospective study and the multi-stage stratified random sampling method were performed to select at least 200 subjects from each of the 12 counties(cit-ies)in Fuzhou.Questionnaires follow-ups and serum collections were conducted in Mar,Jun,Sep,and Dec.2024,respectively.The antibody levels in Dec.were divided into a high protective antibody group(IgG antibody≥50 AU/ml)and a low protective antibody group(IgG antibody≤20 AU/ml).The influencing factors of serum anti-body levels were analyzed by multivariate logistic regression model.RESULTS A total of 2816 subjects were en-rolled.In Mar,1454 subjects with high-protective antibodies were identified.After nine months of follow-up,of the 1454 subjects,344 had high protective antibodies and 369 had low protective antibodies in Dec..There were statistically significant differences in age,presence of typical symptoms after infection,underlying diseases,surgi-cal history,healing time,smoking and drinking histories between the high and low antibody groups(P<0.05).Multivariate logistic regression model showed that older age,underlying diseases,history of surgery,smoking and drinking were risk factors which could reduce antibody levels(P<0.05),while typical symptoms after infec-tion and longer recovery time were protective factors which could increase antibody levels(P<0.05).After the COVID-19 infection in spring of 2024,the serum antibody levels in Fuzhou residents showed the downward trend,especially after Sep.2024,with a more pronounced downward trend.CONCLUSIONS According to the risk factors of COVID-19 antibody levels,prevention and control efforts should be focused on the key population.It is necessa-ry to strengthen health education and carry out vaccination to maintain the levels of immunity to protect population from COVID-19 infection.

Objective:To investigate changes of choroid plexus volume in patients with essential hypertension using deep learning-based segmentation technique.Methods:According to the inclusion criteria,19 patients with essential hypertension who visited The 900th Hospital of People's Liberation Army Joint Service Support Force from December 2022 to May 2024 were divided into hypertension group.Additionally,19 healthy individuals,matched with the hypertension group in terms of gender,age,and years of education,were recruited as the healthy control group during the same period.All participants underwent data acquisition of three-dimensional T1(T1-3D)brain structural images using a Siemens 3.0T Trio magnetic resonance(MR)scanner.A pre-trained deep learning model,which based on the 3D U-Net architecture and generated by fully convolutional neural network,was employed for choroid plexus segmentation,and the total brain volume and lateral ventricle volume were calculated using the United Imaging Artificial Intelligence(AI)platform.Statistical analysis of the choroid plexus volume and other data for both groups were performed using SPSS27.0.Results:Compared with the healthy control group(1 866 mm3),the hypertensive group(2 047 mm3)showed an abnormal increase in choroid plexus volume(x2=3.900,P<0.05).Moreover,the choroid plexus volume was positively correlated with lateral ventricle volume and systolic blood pressure(r=0.849,P<0.05),and was negatively correlated with digit span(forward)in the hypertensive group(r=-0.374,P<0.05).Conclusion:The choroid plexus volume in patients with essential hypertension abnormally increased,which might be a factor promoting to changes in brain structure,it can affect further the cognitive function of patients with hypertension.

Objective:To investigate the relationship between serum soluble CD155 (sCD155), soluble CD163 (sCD163) and chemotherapy efficacy and prognosis in patients with diffuse large B-cell lymphoma (DLBCL).Methods:A total of 126 patients with DLBCL admitted to Handan Central Hospital from May 2018 to May 2020 (DLBCL group) and 126 healthy subjects (control group) were prospectively selected to compare serum sCD155 and sCD163 levels. According to the chemotherapy effect of DLBCL patients, they were divided into effective group and ineffective group, and the serum sCD155 and sCD163 levels were compared before and after treatment. The effective rate of chemotherapy in patients with different serum sCD155 and sCD163 levels was compared. Kaplan-Meier method was used to analyze the relationship between serum sCD155 and sCD163 levels and 3-year overall survival (OS) and progression-free survival (PFS) of DLBCL patients. Cox proportional risk regression model was used to analyze the prognostic factors of DLBCL patients.Results:The serum levels of sCD155 and sCD163 in DLBCL group were higher than those in control group before treatment (all P<0.05). The effective rate of chemotherapy in 126 DLBCL patients in this group was 69.8%(88/126). Compared with the effective group, the serum levels of sCD155 and sCD163 were higher in the ineffective group before and after treatment (all P<0.05). Compared with before treatment, serum sCD155 and sCD163 levels in the effective group were decreased after treatment (all P<0.05). The effective rate of DLBCL patients in sCD155 and sCD163 high level groups was lower than that in sCD155 and sCD163 low level groups (all P<0.05). Kaplan-Meier analysis showed that the 3-year OS and PFS of DLBCL patients in the low level group of sCD155 and sCD163 were higher than those in the high level group (all P<0.05). The high level of sCD155 and sCD163 were independent risk factors for 3-year PFS and OS in DLBCL patients (all P<0.05). Conclusions:Abnormal levels of serum sCD155 and sCD163 in DLBCL patients may reduce the efficacy of chemotherapy and lead to poor prognosis.

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2(ALDH2)alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.Methods Thirty 8-week-old C57 BL/6 mice were randomized into control,hypoxia,and hypoxia+Alda-1(an ALDH2 activator)group(n=10),and the mice in the latter two groups,along with 10 ALDH2 knockout(ALDH2-/-)mice,were exposed to hypoxia(10%O2,90%N2)with or without daily intraperitoneal injection of Alda-1 for 4 weeks.The changes in right ventricular function and pressure(RVSP)of the mice were evaluated by echocardiography and right ventricular catheter test,and pulmonary artery pressure was estimated based on RVSP.Pulmonary vascular remodeling,right ventricular injury,myocardial α-SMA expression,distal pulmonary arteriole muscle normalization,right ventricular cross-sectional area,myocardial cell hypertrophy,and right cardiac hypertrophy index were assessed with HE staining,immunofluorescence staining and WGA staining,and the expressions of ALDH2,SIRT1,PGC-1α,P16INK4A and P21CIP1 were detected.In pulmonary artery smooth muscle cells with hypoxic exposure,the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.Results The wild-type mice with hypoxic exposure showed significantly increased RVSP,right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1,which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/-mice.In cultured pulmonary artery smooth muscle cells,hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1,which were all lowered by treatment with Alda-1,but its effect was obviously attenuated by EX527 treatment.Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.