OBJECTIVE: To evaluate the efficacy and safety of glyceryl phenylbutyrate (GPB) therapy for patients with Ornithine transcarbamylase deficiency (OTCD). METHODS: Two children with OTCD were selected as the study subjects, and their clinical manifestations, blood ammonia, liver enzymes, growth and development information following the treatment with GPB were retrospectively analyzed. A literature review was also carried out by searching the PubMed database for studies on the GPB treatment for urea cycle disorders. RESULTS: With the GPB treatment, the blood ammonia and liver enzyme level in both patients have decreased to the normal range within 3 months. Motor development in child 2 has improved. No adverse reaction was noted, except for transient palmar greasy smell and loss of appetite in child 1. Analysis of the literature showed that patients had lower ammonia exposure, lower annual incidence of hyperammonemic crisis, more actual protein intake and fewer adverse events during GPB treatment. CONCLUSION GPB is safe and effective for the treatment of OTCD.
Child ; Humans ; Ornithine Carbamoyltransferase Deficiency Disease/drug therapy* ; Phenylbutyrates/therapeutic use* ; Ammonia ; Retrospective Studies

Objective: To analyze the utilization of adult vaccination among people aged 18 and above in Shandong Province from 2018 to 2022. Methods: Data on vaccination units in 2022 and individual cases of vaccination information for people aged 18 and above were extracted from the Shandong Immunization Information System. A descriptive analysis was conducted on the distribution of adult vaccination units and adult vaccination varieties. The total vaccination amount and vaccination rate were calculated. Results: By the end of 2022, there were 3 948 vaccination units providing adult vaccination in Shandong Province, with 0.36 adult vaccination clinics per 10 000 people. Adult vaccination including RabV(rabies vaccine for human use), InfV(influenza vaccine), HPV(human papillomavirus), HepB(hepatitis B vaccine), PPV23(23-valent pneumococcal polysaccharide vaccine), MenACYW135(meningococcal polysaccharide vaccine group ACYW135), MMR(measles, mumps and rubella combined attenuated live vaccine), HEV(hepatitise E vaccine), RZV(recombinant zoster vaccine), TV(tetanus vaccine) and HF(haemorrhagic fever with renal syndrome vaccine) vaccines were administered, with a cumulative dose of 40.056 9 million and an average of 0.1 doses per person per year from 2018 to 2022. The top three vaccines were RabV, InfV and HPV, accounting for 31.48%, 22.57%, and 15.93% of the total vaccination amount, respectively. The annual vaccination dose for adults increased from 3.477 3 million in 2018 to 13.308 6 million in 2022, with an average annual growth rate of 56.55%. The cumulative 5-year doses of RabV and TV were 15.90 doses per 100 people and 0.21 doses per 100 people. The average annual vaccination rate of InfV was 2.28%. The cumulative full vaccination rates of HPV, HepB, PPV23 and RZV were 12.44%, 1.61%, 0.52% and 0.17%, respectively. The cumulative 5-year doses of RabV and TV were 29.19 doses per 100 people and 0.43 doses per 100 people in the age group of 20 to<30 years old. The vaccination rates of InfV and PPV23 were 9.08% and 1.27% in the age group of 70 to<80 years old. The vaccination rate of RZV was 0.11% in the age group of 50 to<60 years old. The HPV vaccination rate was 18.09% in the age group of 20 to<30 years old, and the HepB, MenACYW135, MMR and HEV vaccination rates were 6.21%, 9.55%, 2.65%, and 2.83% in the 18-19 age group, respectively. Conclusion: There are relatively few types of adult vaccination in Shandong Province, with narrow coverage and low vaccination rates.
Adult ; Humans ; Young Adult ; Aged ; Middle Aged ; Adolescent ; Aged, 80 and over ; Papillomavirus Infections ; Vaccination ; Phenylbutyrates ; Influenza Vaccines

Objective: To analyze the utilization of adult vaccination among people aged 18 and above in Shandong Province from 2018 to 2022. Methods: Data on vaccination units in 2022 and individual cases of vaccination information for people aged 18 and above were extracted from the Shandong Immunization Information System. A descriptive analysis was conducted on the distribution of adult vaccination units and adult vaccination varieties. The total vaccination amount and vaccination rate were calculated. Results: By the end of 2022, there were 3 948 vaccination units providing adult vaccination in Shandong Province, with 0.36 adult vaccination clinics per 10 000 people. Adult vaccination including RabV(rabies vaccine for human use), InfV(influenza vaccine), HPV(human papillomavirus), HepB(hepatitis B vaccine), PPV23(23-valent pneumococcal polysaccharide vaccine), MenACYW135(meningococcal polysaccharide vaccine group ACYW135), MMR(measles, mumps and rubella combined attenuated live vaccine), HEV(hepatitise E vaccine), RZV(recombinant zoster vaccine), TV(tetanus vaccine) and HF(haemorrhagic fever with renal syndrome vaccine) vaccines were administered, with a cumulative dose of 40.056 9 million and an average of 0.1 doses per person per year from 2018 to 2022. The top three vaccines were RabV, InfV and HPV, accounting for 31.48%, 22.57%, and 15.93% of the total vaccination amount, respectively. The annual vaccination dose for adults increased from 3.477 3 million in 2018 to 13.308 6 million in 2022, with an average annual growth rate of 56.55%. The cumulative 5-year doses of RabV and TV were 15.90 doses per 100 people and 0.21 doses per 100 people. The average annual vaccination rate of InfV was 2.28%. The cumulative full vaccination rates of HPV, HepB, PPV23 and RZV were 12.44%, 1.61%, 0.52% and 0.17%, respectively. The cumulative 5-year doses of RabV and TV were 29.19 doses per 100 people and 0.43 doses per 100 people in the age group of 20 to<30 years old. The vaccination rates of InfV and PPV23 were 9.08% and 1.27% in the age group of 70 to<80 years old. The vaccination rate of RZV was 0.11% in the age group of 50 to<60 years old. The HPV vaccination rate was 18.09% in the age group of 20 to<30 years old, and the HepB, MenACYW135, MMR and HEV vaccination rates were 6.21%, 9.55%, 2.65%, and 2.83% in the 18-19 age group, respectively. Conclusion: There are relatively few types of adult vaccination in Shandong Province, with narrow coverage and low vaccination rates.
Adult ; Humans ; Young Adult ; Aged ; Middle Aged ; Adolescent ; Aged, 80 and over ; Papillomavirus Infections ; Vaccination ; Phenylbutyrates ; Influenza Vaccines

Objective: To compare the efficacy and safety between indobufen and aspirin in the prevention of restenosis of bridge vessels at 1 year after off-pump coronary artery bypass grafting. Methods: This study was a prospective cohort study. We selected 152 patients who received coronary artery bypass grafting in Beijing Anzhen Hospital from December 2016 to December 2018. Patients were divided into the indobufen group and the aspirin group. Patients in the aspirin group were treated with aspirin and clopidogrel, and patients in the indobufen group were treated with indobufen and clopidogrel. During the 1-year follow-up, the rate of restenosis of saphenous vein bridge and internal mammary artery bridge, the rate of adverse cardiac events and adverse reactions were compared between the two groups. The levels of fibrinogen (FIB), D-dimer (D-D), thrombomodulin (TM) and thrombin-activatable fibrinolysis inhibitor (TAFI) were compared before and after antiplatelet therapy. Results: There were 76 cases in the indobufen group, including 57 males (75.0%), aged (60.3±6.6) years. There were 76 cases in the aspirin group, including 62 males (81.6%), aged (59.7±7.2) years. Baseline data were comparable between the two groups (P>0.05). During the follow-up, 3 cases were lost to follow up. Follow-up was completed in 74 patients in the indobufen group and 75 in the aspirin group. A total of 268 bridging vessels were grafted in the indobufen group and 272 in the aspirin group. One year after surgery, the patency rates of great saphenous vein bridge and internal mammary artery bridge were 94.5% (189/200) and 97.1% (66/68) in the indobuphen group, and 91.3% (189/207) and 96.9% (63/65) in the aspirin group, respectively. There was no significant difference in patency rate of great saphenous vein bridge and internal mammary artery bridge between the two groups (χ²=0.282, 0.345, P>0.05). The total incidence of adverse cardiac events was 5.4% (4/74) in the indobufen group and 6.7% (5/75) in the aspirin group (χ²=0.126, P>0.05). The overall incidence of gastrointestinal adverse reactions was significantly lower in the indobufen group than in the aspirin group (4.1% (3/74) vs. 13.3% (10/75), χ²=4.547, P<0.05). The levels of FIB, D-D, TM and TAFI in the two groups were lower than those before surgery (P<0.05), and there was no statistical significance between the two groups at baseline and post-operation (P>0.05). Conclusion: The efficacy of indobufen combined with clopidogrel in the prevention of 1-year restenosis after coronary artery bypass graft is similar to that of aspirin combined with clopidogrel, but the incidence of adverse reactions is lower, and the safety is higher in patients treated with indobufen combined with clopidogrel compared to aspirin combined with clopidogrel strategy.
Aspirin/therapeutic use* ; Clopidogrel/therapeutic use* ; Coronary Artery Bypass/adverse effects* ; Drug Therapy, Combination ; Humans ; Isoindoles ; Male ; Phenylbutyrates ; Platelet Aggregation Inhibitors/therapeutic use* ; Prospective Studies ; Treatment Outcome

OBJECTIVE: To investigate the role of endoplasmic reticulum stress (ERS) in rats with acute respiratory distress syndrome (ARDS) related right ventricular dysfunction and the protective effect of sodium 4-phenylbutyrate (4-PBA) on right ventricle. METHODS: Sixty male Spragne-Dawley (SD) rats were randomly divided into control group (CON group), lipopolysaccharide (LPS) model group, 4-PBA prevention group and 4-PBA treatment group, with 15 rats in each group. ARDS rat model was established by intratracheal instillation of LPS 10 mg/kg after tracheotomy; CON group was given the same amount of saline. 4-PBA prevention group and 4-PBA treatment group were given 4-PBA 500 mg/kg intragastric administration 2 hours before and after LPS respectively. Echocardiography was performed 12 hours after treatment to evaluate the right ventricular function. Then, the rats were sacrificed by bloodletting, and the serum and right ventricular tissue were harvested. The histopathological changes of myocardial were observed by hematoxylin-eosin (HE) staining, the levels of tumor necrosis factor-α (TNF-α), interleukins (IL-1β and IL-6) in serum and myocardial were detected by enzyme linked immunosorbent assay (ELISA), and Western Blot was used to detect the expression of the marker proteins of ERS in myocardial, including glucose regulatory protein 78 (GRP78), C/EBP cyclic adenosine phosphate reaction primitive binding transcription factor homologous protein (CHOP), caspase-12 and caspase-3. RESULTS: Compared with the CON group, the echocardiography showed pulmonary artery maximum pressure gradient (PAmaxPG), pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE) in LPS model group were significantly decreased, and right ventricular end-diastolic excursion (RVDd) was significantly increased, and the levels of TNF-α, IL-1β and IL-6 in serum and myocardial, as well as the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly increased. Compared with LPS model group, TAPSE of 4-PBA preventive and treatment groups were significantly increased (mm: 3.08±0.65, 2.96±0.61 vs. 2.48±0.45), RVDd were significantly decreased (mm: 3.67±0.58, 3.60±0.61 vs. 4.18±0.71), the levels of TNF-α, IL-1β and IL-6 in serum and myocardial were significantly decreased [TNF-α (ng/L): 187.98±18.98, 176.08±17.98 vs. 332.00±19.90 in serum, 135.06±19.00, 132.78±17.00 vs. 155.00±20.00 in myocardial; IL-1β(ng/L): 12.07±2.98, 11.05±2.41 vs. 24.06±4.01 in serum, 19.89±2.80, 21.06±2.80 vs. 26.00±2.60 in myocardial; IL-6 (ng/L): 42.98±7.90, 34.05±6.09 vs. 89.80±10.07 in serum, 129.45±25.00, 127.08±26.06 vs. 145.77±23.00 in myocardial]; the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly decreased (GRP78/GAPDH: 0.090±0.070, 0.103±0.060 vs. 0.167±0.090, CHOP/GAPDH: 0.109±0.090, 0.090±0.080 vs. 0.186±0.090, caspase-12/GAPDH: 0.769±0.230, 0.799±0.210 vs. 1.040±0.350, caspase-3/GAPDH: 0.391±0.060, 0.401±0.054 vs. 0.603±0.340), with statistically significant differences (all P < 0.05). There were no significant differences in each indexes between 4-PBA prevention group and 4-PBA treatment group (all P > 0.05). CONCLUSIONS ERS is involved in ARDS-related right ventricular dysfunction. 4-PBA can protect the right ventricular function of ARDS rats by inhibiting ERS and alleviating inflammation, and the preventive and therapeutic effects of 4-PBA are similar.
Animals ; Antineoplastic Agents/therapeutic use* ; Endoplasmic Reticulum Stress ; Male ; Phenylbutyrates/therapeutic use* ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome ; Tumor Necrosis Factor-alpha ; Ventricular Dysfunction, Right

OBJECTIVE: To determine the mitigating effects of sodium 4-phenylbutyrate (4-PBA) on high-fat diet (HFD)-induced spermatogenesis dysfunction. METHODS: Male rats (n = 30) were randomly divided into three groups: control, HFD, and 4-PBA (HFD +4-PBA). After 13 weeks, rats were euthanized. Testes and epididymis were harvested for further analysis. Sex hormones were detected, and hematoxylin and eosin staining was performed to examine the histological changes in the testes. Semen samples were collected to evaluate sperm quality. Spermatogenic cell apoptosis was detected by TUNEL assay. RESULTS: Compared with the control group, the final body weight and body weight gain were significantly higher in HFD-fed rats, while the testicle/body weight ratios were lower (P < 0.05). In HFD-fed rats, obvious pathological changes in the testicular tissue were observed. Treatment with 4-PBA attenuated HFD-induced histological damage, ameliorated the HFD-induced decrease in serum testosterone (T), and reduced the rate of testicular cell apoptosis (P < 0.05) in obese male rats. Finally, 4-PBA significantly improved semen parameters in HFD rats (P < 0.05). CONCLUSION HFD exposure induced detrimental effects on spermatogenesis, semen quality, serum T level, and testicular cell apoptosis in rats. Treatment with 4-PBA ameliorated HFD？induced impaired spermatogenesis via inhibition of apop-tosis in rats. 4-PBA may have therapeutic value in the treatment of obesity？related impairment of spermatogenesis.
Animals ; Diet, High-Fat ; adverse effects ; Male ; Phenylbutyrates ; pharmacology ; Rats, Sprague-Dawley ; Semen Analysis ; Spermatogenesis ; drug effects ; Testis ; drug effects ; pathology ; Testosterone ; blood

The purpose of the present study was to investigate the effect of advanced glycated albumin (AGE-alb) on the activation of caspase-12, a key molecule in endoplasmic reticulum stress (ERS)-associated apoptotic pathway, and to elucidate the underlying molecular mechanisms of macrophage apoptosis. RAW264.7 macrophages were treated with AGE-alb (2, 4 and 6 g/L), control albumin (C-alb, 4 g/L), tunicamycin (TM, 4 mg/L), or pretreated with 4-phenylbutyric acid (PBA, 5 mmol/L) for 1 h and then treated with AGE-alb (4 g/L). After incubation for 24 h, the cell viability and apoptosis were determined by using MTT assay and TUNEL detection kit, respectively. Lactate dehydrogenase (LDH) activity in media was determined by using an assay kit. The protein levels of caspase-12 were examined by Western blot analysis. The results showed that like TM (an ERS inducer), incubation with AGE-alb led to significant decrease in viability and increase in LDH activity in media and apoptotic rate in a dose-dependent manner. In addition, AGE-alb induced activation of caspase-12 especially at the concentration of 4 and 6 g/L (P < 0.01), which was similar to TM. However, PBA (an ERS inhibitor) protected RAW264.7 macrophages from AGE-alb-induced decrease in viability and increases in LDH activity and apoptosis. Moreover, PBA also inhibited the caspase-12 activation induced by AGE-alb (P < 0.05). These results suggest that AGE-alb may induce apoptosis in RAW 264.7 macrophages, and the mechanism may be related to the activation of ERS-associated apoptotic pathway mediated by caspase-12.
Animals ; Apoptosis ; Caspase 12 ; Cell Line, Tumor ; Cell Survival ; Endoplasmic Reticulum Stress ; Macrophages ; Mice ; Phenylbutyrates ; Serum Albumin ; Tunicamycin

Hyperhomocysteinemia (HHcy) accelerates atherosclerosis by increasing proliferation and stimulating cytokine secretion in T cells. However, whether homocysteine (Hcy)-mediated T cell activation is associated with metabolic reprogramming is unclear. Here, our in vivo and in vitro studies showed that Hcy-stimulated splenic T-cell activation in mice was accompanied by increased levels of mitochondrial reactive oxygen species (ROS) and calcium, mitochondrial mass and respiration. Inhibiting mitochondrial ROS production and calcium signals or blocking mitochondrial respiration largely blunted Hcy-induced T-cell interferon γ (IFN-γ) secretion and proliferation. Hcy also enhanced endoplasmic reticulum (ER) stress in T cells, and inhibition of ER stress with 4-phenylbutyric acid blocked Hcy-induced T-cell activation. Mechanistically, Hcy increased ER-mitochondria coupling, and uncoupling ER-mitochondria by the microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial reprogramming, IFN-γ secretion and proliferation in T cells, suggesting that juxtaposition of ER and mitochondria is required for Hcy-promoted mitochondrial function and T-cell activation. In conclusion, Hcy promotes T-cell activation by increasing ER-mitochondria coupling and regulating metabolic reprogramming.
Animals ; Calcium ; metabolism ; Cell Proliferation ; drug effects ; Cells, Cultured ; Endoplasmic Reticulum ; metabolism ; Endoplasmic Reticulum Stress ; drug effects ; Endoribonucleases ; metabolism ; Female ; Homocysteine ; toxicity ; Interferon-gamma ; analysis ; Metabolic Engineering ; Mice ; Mice, Inbred C57BL ; Mitochondria ; drug effects ; metabolism ; Nocodazole ; pharmacology ; Phenylbutyrates ; pharmacology ; Protein-Serine-Threonine Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Reactive Oxygen Species ; metabolism ; T-Lymphocytes ; cytology ; drug effects ; metabolism ; eIF-2 Kinase ; metabolism

OBJECTIVETo explore the effects and the molecular mechanisms of 4-phenylbutyric acid (PBA) on carbon tetraehloride (CCl4)-induced acute liver injury in mice.

METHODSSixty adult, healthy, male ICR mice were divided equally into the control group, PBA group, CCl4 12 h group, CCl4 24 h group, CCl4 48 h group, CCl4 72 h group, PBA+CCl4 12 h group, PBA+CCl4 24 h group, PBA+CCl4 48 h group, and PBA+CCl4 72 h group. The CCl4 groups and the PBA+CCl4 groups were intraperitoneally (i.p.) injected with CCl4 (300 mL/kg). In the PBA+CCl4 groups, the mice were i.p. injected with PBA (400 mg/kg). All mice were sacrificed to collect blood and liver specimens at different time points after the CCl4 treatment. Serum alanine aminotransferase (ALT) was detected. Histological examination was performed using hematoxylin-eosin staining and light microscopy, and apoptosis was detected using terminal transferase dUTP nick end labeling. The hepatic distribution of proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry. The hepatic protein expression of glucose-regulated protein (GRP78), C/EBP homologousprotein (CHOP), phosphorylated c-Jun N-terminal kinases (p-JNK), phosphorylated eukaryotic initiation factor 2a subunit (p-eIF2a), phosphorylated serine threonine kinase (p-akt), and nuclear factor-kappa B p65 (NF-kappa Bp65) were determined by western blot.

RESULTSThe serum ALT level in the PBA+CCl4 groups was reduced as compared with that in the CCl4 groups at the various time points examined.The liver-to-body weight ratio of two groups showed a significant difference only at the 48 h time point (P<0.01). PBA reduced the degree of hepatic necrosis and apoptosis caused by CCl4, and reduced the expression of hepatic GRP78 and other endoplasmic reticulum stress-related proteins (P<0.01). The protein levels of p-akt, NF-kappa Bp65 and PCNA was significantly decreased in the PBA+CCl4 groups (P<0.01).

CONCLUSIONThe endoplasmic reticulum stress inhibitor PBA alleviated acute hepatic necrosis and apoptosis but restrained hepatic proliferation.

Alanine Transaminase ; Animals ; Apoptosis ; Carbon Tetrachloride ; Chemical and Drug Induced Liver Injury ; Endoplasmic Reticulum Stress ; HSP70 Heat-Shock Proteins ; Male ; Membrane Proteins ; Mice ; Mice, Inbred ICR ; NF-kappa B ; Phenylbutyrates ; Phosphorylation

OBJECTIVETo observe the the expression of endoplasmic reticulum stress (ERS) related factors in deep tissue injury (DTI) at pressure ulcer rat and to investigate the ERS mechanism of DTI in muscle tissue and protective effect of 4-phenylbutyric acid (4-PBA) in local tissue.

METHODSFifty male SD rats were randomly devided into control group, model group, experimental group NS group and PBA group, the experimental groups were divided into 4 d, 7 d, 14 d and 21 d group according to the observation time (n = 5). Rats in the PBA group were administrated with gastric perfusion of 4-PBA after the modeling; the NS group was given normal saline of the same quantity. Using HE staining to observe morphologic character. The expression of glucose regulated protein 78 (GRP78), CHOP, Caspase 12 were detected by immunohistochernical staining. Cell apoptosis was detected by TUNEL assay.

RESULTSHE staining results showed that each group demonstrated compression injury compared with control group: cellular swelling, ompaction of nuclear, and apoptosis in muscle tissue. The new muscle fiber in 4-PBA group fused faster than those in NS group. The number of TUNEL positive cells peaked at 4 day after compression, then got decreased on day 7 in muscle tissue, apoptosis positive cells were diminished after 4-PBA treatment. The immunohistochemical staining results showed that the expression of protein GRP78, CHOP, Caspase 12 peakd 4 d after modeling and decreased gradually. The GRP78, CHOP, Caspase 12 protein expression were significantly higher than those of PBA group at all time points (P < 0.05).

CONCLUSIONCell apoptosis induced by endoplasmic reticulum stress took part in deep tissue injury resulting of pressure ulcer, which mechanism might be related to reducing apoptosis mediated by CHOP, Caspase 12.

Animals ; Apoptosis ; Caspase 12 ; metabolism ; Endoplasmic Reticulum Stress ; Heat-Shock Proteins ; metabolism ; Male ; Muscle, Skeletal ; pathology ; Phenylbutyrates ; pharmacology ; Pressure Ulcer ; physiopathology ; Proteomics ; Rats ; Rats, Sprague-Dawley ; Transcription Factor CHOP ; metabolism