Background: Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells. Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erkuclear factor-kappa B (NF-κB) pathway. Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.

Background: Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells. Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erkuclear factor-kappa B (NF-κB) pathway. Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.

Background: Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells. Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erkuclear factor-kappa B (NF-κB) pathway. Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.

Background: Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells. Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erkuclear factor-kappa B (NF-κB) pathway. Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.

In this study, lipopolysaccharide(LPS), ovalbumin(OVA), and compound 48/80(C48/80) were administered to establish non-infectious pneumonia models under simulated clinical conditions, and the correlation between their pathological characteristics and traditional Chinese medicine(TCM) syndromes was compared, providing the basis for the selection of appropriate animal models for TCM efficacy evaluation. An acute pneumonia model was established by nasal instillation of LPS combined with intraperitoneal injection for intensive stimulation. Three doses of OVA mixed with aluminum hydroxide adjuvant were injected intraperitoneally on days one, three, and five and OVA was administered via endotracheal drip for excitation on days 14-18 to establish an OVA-induced allergic pneumonia model. A single intravenous injection of three doses of C48/80 was adopted to establish a C48/80-induced pneumonia model. By detecting the changes in peripheral blood leukocyte classification, lung tissue and plasma cytokines, immunoglobulins(Ig), histamine levels, and arachidonic acid metabolites, the multi-dimensional analysis was carried out based on pathological evaluation. The results showed that the three models could cause pulmonary edema, increased wet weight in the lung, and obvious exudative inflammation in lung tissue pathology, especially for LPS. A number of pyrogenic cytokines, inclading interleukin(IL)-6, interferon(IFN)-γ, IL-1β, and IL-4 were significantly elevated in the LPS pneumonia model. Significantly increased levels of prostacyclin analogs such as prostaglandin E2(PGE2) and PGD2, which cause increased vascular permeability, and neutrophils in peripheral blood were significantly elevated. The model could partly reflect the clinical characteristics of phlegm heat accumulating in the lung or dampness toxin obstructing the lung. The OVA model showed that the sensitization mediators IgE and leukotriene E4(LTE4) were increased, and the anti-inflammatory prostacyclin 6-keto-PGF2α was decreased. Immune cells(lymphocytes and monocytes) were decreased, and inflammatory cells(neutrophils and basophils) were increased, reflecting the characteristics of "deficiency", "phlegm", or "dampness". Lymphocytes, monocytes, and basophils were significantly increased in the C48/80 model. The phenotype of the model was that the content of histamine, a large number of prostacyclins(6-keto-PGE1, PGF2α, 15-keto-PGF2α, 6-keto-PGF1α, 13,14-D-15-keto-PGE2, PGD2, PGE2, and PGH2), LTE4, and 5-hydroxyeicosatetraenoic acid(5S-HETE) was significantly increased, and these indicators were associated with vascular expansion and increased vascular permeability. The pyrogenic inflammatory cytokines were not increased. The C48/80 model reflected the characteristics of cold and damp accumulation. In the study, three non-infectious pneumonia models were constructed. The LPS model exhibited neutrophil infiltration and elevated inflammatory factors, which was suitable for the efficacy study of TCM for clearing heat, detoxifying, removing dampness, and eliminating phlegm. The OVA model, which took allergic inflammation as an index, was suitable for the efficacy study of Yiqi Gubiao formulas. The C48/80 model exhibited increased vasoactive substances(histamine, PGs, and LTE4), which was suitable for the efficacy study and evaluation of TCM for warming the lung, dispersing cold, drying dampness, and resolving phlegm. The study provides a theoretical basis for model selection for the efficacy evaluation of TCM in the treatment of pneumonia.
Animals ; Disease Models, Animal ; Mice ; Pneumonia/genetics* ; Medicine, Chinese Traditional ; Male ; Humans ; Cytokines/immunology* ; Female ; Lipopolysaccharides/adverse effects* ; Lung/drug effects* ; Drugs, Chinese Herbal ; Ovalbumin ; Mice, Inbred BALB C

OBJECTIVE: To summarize the early clinical results and safety of Stand-alone OLIF application of lumbar lesions, and explored its surgical indications. METHODS: Total of 92 cases of lumbar spine lesions treated with Stand-alone OLIF at two medical centers from October 2014 to December 2018 were retrospectively analyzed, including 30 males and 62 females with an average age of (61.20±12.94) years old ranged from 32 to 83 years old. There were 20 cases of lumbar spinal stenosis, 15 cases of lumbar disc degeneration, 11 cases of lumbar degenerative spondylolisthesis, 6 cases of discogenic low back pain, 7 cases of giant lumbar disc herniation, 13 cases of primary lumbar discitis, 6 cases of adjacent vertebral disease after lumbar internal fixation surgery, and 14 cases of degenerative lumbar scoliosis. Pre-operative dual energy X-ray bone density examination 31 cases' T-values ranged from -1 to -2.4, 8 cases' T-values ranged from -2.5 to -3.5, and the rest had normal bone density. The number of fusion segments: 68 cases of single segment, 9 cases of two segment, 12 cases of three segment , and 3 cases of four segment. Fusion site:L_1,2 1 case, L_2,3 4 cases, L_3,4 10 cases, L_4,5 53 cases, L_2,3-L_3,4 3 cases, L_3,4-L_4,5 6 cases, L_1,2L_2,3L_3,4 1 case, L_1,2L_3,4L_4,5 1 case, L_2,3L_3,4L_4,5 10 cases, L_1,2L_2,3L_3,4L_4,5 3 cases. The clinical results and imaging results of this group of cases were observed, as well as the complications. RESULTS: The surgical time ranged from 40 to 140 minutes with an average of (60.92±27.40) minutes. The intraoperative bleeding volume was 20 to 720 ml with an average of (68.22±141.60) ml. The patients had a follow-up period of 6 to 84 months with an average of (38.50±12.75) months. The height of the intervertebral space recovered from (9.23±1.94) mm in preoperative to (12.68±2.01) mm in postoperative, and (9.11±1.72) mm at the last follow-up, there was a statistically significant difference(F=6.641, P=0.008);there was also a statistically significant difference between the postoperative and preoperative height of the intervertebral space(t=9.27, P<0.000 1);and there was also a statistically significant difference (t=10.06, P<0.000 1) between the last follow-up and postoperative height of the intervertebral space. At the last follow-up, cage subsidence grading was as follows:level 0 in 69 cases (76 segments), levelⅠin 17 cases (43 segments), level Ⅱin 5 cases (14 segments), and level Ⅲ in 1 case (1 segment);according to the number of segments, normal subsidence accounts for 56.72%, abnormal subsidence accounts for 43.28%. Bone mineral desity of normal subsidence groups was -0.50±0.07 whinch was better than that the abnormal subsidence groups -2.10±0.43, and the difference was statistically significant(χ²=2.275, P=0.014). As well as there was a statistically significant difference in the patient's VAS of backache from (6.28±2.11) in preoperative to (1.48±0.59) in last follow-up(t=8.56, P<0.05). The ODI recovered from (36.30±7.52)% before surgery to (10.20±2.50)% at the last follow-up, with a statistically significant difference (t=7.79, P<0.000 1). Complications involved 4 cases of intraoperative vascular injury, 21 cases of endplate injury, and 4 cases of combined vertebral fractures. The incision skin has no necrosis or infection. There were 4 cases of left sympathetic chain injury, 4 cases of transient left hip flexion weakness, 2 cases of left thigh anterolateral numbness with quadriceps femoris weakness, and 1 case of incomplete intestinal obstruction;8 cases were treated with posterior pedicle screw fixation due to fusion cage settlement accompanied by stubborn lower back pain, and 6 cases were treated with fusion cage settlement and lateral displacement. According to the actual number of cases, there were 38 complications, with an incidence rate of 41.3%. CONCLUSION The application of Stand alone OLIF in lumbar spine disease fusion has achieved good early results, with obvious clinical advantages, but also there are high probability of complications. It is recommended to choose carefully. It is necessary to continuously summarize and gradually clarify and complete the surgical indications and specific case selection criteria.
Humans ; Male ; Female ; Middle Aged ; Spinal Fusion/methods* ; Lumbar Vertebrae/injuries* ; Aged ; Adult ; Retrospective Studies ; Aged, 80 and over

The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms. Testosterone, as one of the most critical sex hormones, is essential for the development of the reproductive system, maintenance of reproductive function, and the overall health of males. The secretion of testosterone in mammals is characterized by distinct circadian rhythms and is closely associated with the regulation of circadian clock genes. Here we review the central and peripheral regulatory mechanisms underlying the influence of circadian clock genes upon testosterone synthesis. We also examined the specific effects of these genes on the occurrence, development, and treatment of common male diseases, including late-onset hypogonadism, erectile dysfunction, male infertility, and prostate cancer.
Testosterone/metabolism* ; Humans ; Male ; Circadian Clocks/genetics* ; Circadian Rhythm Signaling Peptides and Proteins/metabolism* ; Circadian Rhythm/physiology* ; Hypogonadism/metabolism* ; Erectile Dysfunction/metabolism* ; Infertility, Male/metabolism* ; Prostatic Neoplasms/metabolism* ; Men's Health

OBJECTIVES: To investigate the clinical features of children with STAT gene mutations, and to explore corresponding immunotherapy strategies. METHODS: A retrospective analysis was performed for the clinical data of 10 children with STAT gene mutations who were admitted to the Department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University, from October 2015 to October 2024. Exploratory immunotherapy was implemented in some refractory cases, and the changes in symptoms, imaging manifestations, and cytokine levels were assessed after treatment. RESULTS: For the 10 children, the main clinical manifestations were recurrent rash since birth (7/10), cough (8/10), wheezing (5/10), expectoration (4/10), and purulent nasal discharge (4/10). Genotyping results showed that there was one child with heterozygous loss-of-function (LOF) mutation in the STAT1 gene, four children with heterozygous LOF mutation in the STAT3 gene, and five children with heterozygous gain-of-function (GOF) mutation in the STAT3 gene. Two children with LOF mutation in the STAT3 gene showed decreased interleukin-6 levels and improved clinical symptoms and imaging findings after omalizumab treatment. Three children with GOF mutation in the STAT3 gene achieved effective disease control after treatment with methylprednisolone (0.5 mg/kg per day). Two children with GOF mutation in the STAT3 gene received treatment with JAK inhibitor and then showed some improvement in symptoms. CONCLUSIONS STAT gene mutation screening should be considered for children with recurrent rash and purulent respiratory tract infections. Targeted immunotherapy may improve prognosis in patients with no response to conventional treatment.
Humans ; Male ; Immunotherapy ; Female ; Child, Preschool ; Child ; Gain of Function Mutation ; Retrospective Studies ; Infant ; Loss of Function Mutation ; STAT Transcription Factors/genetics*

OBJECTIVE: To comprehensively evaluate the effect of icariin in alleviating reproductive function damage (RFD) in male mice via in vitro and in vivo experiments. METHODS: We isolated Leydig cells from 60 KM male mice in vitro, and examined the toxic effect of icariin on the Leydig cells using Cell Counting Kit-8 (CCK-8). We equally randomized the mice into six groups: normal control, RFD model control (made by intraperitoneal injection of busulfan at 10 mg/kg combined with cyclophosphamide (CP) at 120 mg/kg), positive control, and low-, medium- and high-dose icariin. After modeling, we treated the mice in the positive control group with Wuziyanzong Pills and those in the low-, medium- and high-dose icariin groups by intragastrical administration of icariin at 20, 40 and 80 mg/kg-1, respectively, for 30 successive days. Then we obtained the weight and visceral coefficients of the reproductive organs, calculated the sperm count, observed the pathological changes in the testis tissue by HE staining, measured the serum testosterone (T) level by ELISA, determined the indexes of testicular oxidative stress and nitric oxide (NO) signaling pathway by colorimetric assay, and detected the expression levels of the pro-apoptotic genes Fas and Bax by qRT-PCR. RESULTS: CCK-8 assay confirmed that icariin had no toxic effect on the isolated Leydig cells of the mice, and could effectively reduce busulfan- and CP-induced cytotoxicity and promote the secretion of serum T. Icariin at 80 mg/kg significantly increased the visceral coefficient of the testis and promoted spermatogenesis (P<0.05), but had little effect on the visceral coefficient of the epididymis in the RFD model mice. Testicular histomorphometric observation revealed significantly improved testis structure, intact boundary membrane of seminiferous tubules and increased numbers of various types of spermatogenic cells of the model mice after treated with icariin. Compared with the mice in the model control group, those treated with high-dose icariin showed a significantly reduced content of malondialdehyde (MDA) (by 35.3%, P<0.01), elevated total antioxidant capacity (TAOC) and superoxide dismutase (T-SOD) activity (P<0.05), and decreased NO content and nitric oxide synthase (NOS) activity in the testis tissue (P<0.01). In addition, icariin exhibited an evident inhibitory effect on the expressions of the pro-apoptotic genes Bax and Fas. CONCLUSION Icariin can ameliorate oxidative stress-induced damage to the testicular function and protect spermatogenesis of male mice by elevating TAOC, decreasing NOS activity, inhibiting the NO level in the testis, and suppressing busulfan- and CP-induced apoptosis of testicular cells.
Animals ; Male ; Cyclophosphamide/adverse effects* ; Mice ; Busulfan/adverse effects* ; Flavonoids/pharmacology* ; Leydig Cells/drug effects* ; Oxidative Stress/drug effects* ; Testis/drug effects* ; Apoptosis/drug effects* ; Testosterone/blood*