Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium.

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg-1·wk-1), and the second group was injected with 7.5 mg·kg-1·wk-1 as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD2, PGE2, and 6-keto-PG2α) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169+ metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169+ cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.

Influences of AMY1 gene copy number and protein expression on salivary alpha-amylase activity before and after citric acid stimulation in splenic asthenia children.

OBJECTIVE: To compare the correlations between salivary alpha-amylase (sAA) activity and amylase, alpha 1 (salivary) gene (AMYl) copy number or its gene expression between splenic asthenia and healthy children, and investigate the reasons of attenuated sAA activity ratio before and after citric acid stimulation in splenic asthenia children. METHODS: Saliva samples from 20 splenic asthenia children and 29 healthy children were collected before and after citric acid stimulation. AMYl copy number, sAA activity, and total sAA and glycosylated sAA contents were determined, and their correlations were analyzed. RESULTS: Although splenic asthenia and healthy children had no differences in AMY1 copy number, splenic asthenia children had positive correlations between AMY1 copy number and sAA activity before or after citric acid stimulation. Splenic asthenia children had a higher sAA glycosylated proportion ratio and glycosylated sAA content ratio, while their total sAA content ratio and sAA activity ratio were lower compared with healthy children. The glycosylated sAA content ratio was higher than the total sAA content ratio in both groups. Splenic asthenia and healthy children had positive correlations between total sAA or glycosylated sAA content and sAA activity. However, the role played by glycosylated sAA content in sAA activity in healthy children increased after citric acid stimulation, while it decreased in splenic asthenia children. CONCLUSION: Genetic factors like AMY1 copy number variations, and more importantly, sAA glycosylation abnormalities leading to attenuated sAA activity after citric acid stimulation, which were the main reasons of the attenuated sAA activity ratio in splenic asthenia children compared with healthy children.

[Study on interference effect of Sijunzi decoction on brain-gut CaM/CaMK II of spleen Qi deficiency syndrome rats].

OBJECTIVE: To observe the dynamic time-phase expressions of key genes of brain-gut CaM signal pathway of spleen Qi deficiency rats and the intervention effect of Sijunzi decoction. METHOD: Male Wistar rats were randomly divided into the normal control group, model 14 d, 21 d, 28 d groups, and Sijunzi decoction 14 d, 21 d, 28 d groups. Except for the normal control group, the remaining groups were included into the spleen Qi deficiency model with the bitter cold breaking Qi method (ig 7.5 g · kg⁻¹ · d⁻¹ of Rheum officinale, Fructus aurantii immaturus, Magnolia officinalis preparation) and the exhaustive swimming method. On the 7th day after the modeling, the Sijunzi decoction groups were orally administered with Sijunzi decoction 20 g · kg⁻¹ · d⁻¹. The expressions of key genes CaM/CaMK II of CaM signaling pathway in hippocampus and intestine at different time points by immunohistochemical method and Western blot. At the same time, the intervention effect of Sijunzi decoction on spleen Qi deficiency rats and its mechanism were analyzed. RESULT: Spleen Qi deficiency rats showed higher intestinal CaM/CaMK II expression and lower hippocampus CaM/CaMK II expression than normal rats (P < 0.05, P < 0.01). After the treatment of Sijunzi decoction, spleen Qi deficiency rats showed reduction in intestinal CaM/CaMK II expression and increase in hippocampus CaM/CaMK II expression (P < 0.05, P < 0.01). CONCLUSION: The formation of spleen Qi deficiency syndrome may be related to the high expression of CaM/CaMK II in small intestine tissues and its low expression in hippocampus tissues. Sijunzi decoction may achieve the therapeutic effect in spleen Qi deficiency syndrome by reducing the CaM/CaMK II expression in intestinal tissues and increasing it in hippocampus tissues.

Terminal deoxynucleotidyl transferase-positive cells in spleen, appendix and branchial cleft cysts in pediatric patients.

We evaluated spleens (n = 26), appendices (n = 10) and branchial cleft cysts (n = 6) for TdT-positive cells in pediatric patients. In spleen, appendix and branchial cleft cysts the range of TdT-positivity was 0-13, 0-96 and 0-6 TdT+ cells/hpf, respectively. In spleens, scattered TdT+ cells were seen most frequently in periarteriolar lymphoid sheath regions.

Inflammatory pseudotumor of lymph node and spleen: an entity biologically distinct from inflammatory myofibroblastic tumor.

Inflammatory pseudotumors (IPTs) of the lymph node and spleen are an uncommon, benign cause of lymphadenopathy and/or splenomegaly that often bear striking clinicopathologic similarities to the inflammatory myofibroblastic tumors (IMTs) found in soft tissues. These tumors have classically been grouped together under the umbrella category of "inflammatory pseudotumor." Recent evidence shows that IMTs are in fact neoplastic processes that often harbor balanced chromosomal translocations involving the ALK kinase gene. These translocations result in expression of ALK kinase in IMTs as assessed by immunohistochemical studies. However, the relationship between IMT and IPT of the lymph node and spleen is uncertain. To determine if ALK tyrosine kinase expression is also present in IPT, 13 cases of IPT (9 involving lymph nodes, 4 splenic lesions) were examined for the presence of ALK tyrosine kinase by immunohistochemical staining on paraffin-embedded tissue. In addition, in situ hybridization studies for Epstein-Barr virus--encoded RNAs (EBER) and immunoperoxidase studies for human herpesvirus-8 (HHV8)--specific proteins were performed. All cases had clinical, morphologic, and immunophenotypic findings typical of IPT and had varying proportions of fibroblastic and inflammatory components. Age ranged from 11 to 75 (median, 40) years; 8 subjects were male, and 5 were female. None of the cases (0 of 13) had positive staining for ALK kinase or HHV8, and in 1 a lymph node (1 of 13) was focally positive for EBV (EBER) by in situ hybridization. The absence of ALK kinase as detected by immunohistochemical studies in IPT of the lymph node and spleen suggests that this entity is biologically distinct from the histologically similar IMT.

Nodular sarcoidosis of the liver and spleen: analysis of 32 cases.

PURPOSE: To describe the computed tomographic (CT) appearance of nodular hepatosplenic sarcoidosis and its association with stage with chest radiography and clinical status. MATERIALS AND METHODS: Thirty-two patients (21 women, 11 men; aged 25-68 years) with nodular hepatosplenic sarcoidosis were evaluated. CT findings were described along with chest radiographic stage, clinical status, and level of angiotensin-converting enzyme (ACE). RESULTS: Nodules were small, multiple, and of low attenuation. Organomegaly was common. Abdominal adenopathy was present in 76% of the patients. Chest radiographs were normal in 25%; 61% had stage 1 or 2 radiographs. Abdominal or systemic symptoms were present in 66%. ACE level was elevated in 10 (91%) of 11 patients tested. No change in chest radiographic stage was noted in 74% of patients with follow-up radiographs. CONCLUSION: Nodular hepatosplenic sarcoidosis is associated with organomegaly, adenopathy, and symptoms. Nodules were not associated with advanced lung disease and did not herald a change in chest radiographic stage. An elevated ACE level may be helpful in diagnosis.

[Preliminary study on pathophysiology of liver-qi deficiency syndrome].

The authors advocate a program for diagnosing Liver-Qi Deficiency Syndrome (LQDS) based on the TCM theory and clinical practice. Through investigation, LQDS was found to be widely existed as latent period or as external manifestation, which occupied 18.85% in Qi Deficiency Syndrome. The subjects were divided into four groups including normal group, Spleen-Qi Deficiency Syndrome (SQDS) group, LQDS with Liver diseases (LD) and LQDS with non-Liver diseases (NLD) group. In order to explore the essence, the simultaneous determinations were done on lactate dehydrogenase (LDH) and its isoenzyme, dopamine beta-hydroxylase (D beta H), trace element Zn and Cu, and other serological indexes such as GPT, TP, Alb, A/G, etc. The results were, the content of LDH and trace element Zn in both LQDS-NLD and SQDS were significantly lower than that of normal group. D beta H reflecting sympathetic nerve function in LQDS-NLD was significantly higher than that of both normal and SQDS group; comparing LQDS-LD and LQDS-NLD group, the content of GPT, LDH, LDH5 and trace element Cu in former was significantly higher than that of the latter, but the content of TP, Alb, A/G, D beta H and Zn in former was remarkably lower than that of the latter. In order to avoid confusion, in studying this syndrome, one should distinguish LD and NLD.

Serum trypsin in hepatosplenic schistosomiasis in the Sudan.

Serum trypsin was measured by radioimmunoassay in 30 patients with hepatosplenic schistosomiasis and 30 healthy controls. Patients with hepatosplenic schistosomiasis had a significantly lower serum trypsin 164.3 +/- 43.3 ng/ml than controls 241.3 +/- 74.0 ng/ml (P less than 0.001). It is concluded that the exocrine pancreatic function is impaired with regard to serum trypsin in hepatosplenic schistosomiasis.

Enzyme activities and protein concentrations in serum of patients with hepatosplenic schistosomiasis.

The hepatosplenic form of Schistosoma mansoni infection contributes considerably to morbidity and mortality in endemic areas. The present study investigated serum protein concentrations and serum enzyme activities of 58 Sudanese patients with hepatosplenic schistosomiasis. All of them had a history of infection with S. mansoni and one or several episodes of oesophageal bleeding due to portal hypertension. Diagnosis was based on clinical (n = 24), ultrasonographical (n = 18) and histological (n = 16) grounds. The control group consisted of 40 Sudanese healthy blood donors. Serum albumin was found to be significantly lower in patients with hepatosplenic schistosomiasis (median = 37 g/l) than in controls (median = 47 g/l). Serum enzyme analysis revealed only minimal alterations of cellular enzyme activities, but a marked decrease of cholinesterase activity. Serum albumin concentration correlated significantly with cholinesterase activity. We conclude that liver function in patients with schistosomiasis and portal hypertension is partially disturbed. Low serum albumin and low cholinesterase activity reflected an impaired protein synthesis of the liver. Destruction of parenchymal liver cells was mild or absent.

An immunoelectron microscopic study of glucocerebrosidase in type 1 Gaucher's disease spleen.

An immunogold labeling procedure was applied to ultrathin cryosections and used to study the subcellular localization of glucocerebrosidase in lipid-laden "Gaucher cells" in spleen from a patient with type 1 Gaucher's disease. Glucocerebrosidase protein was associated with the characteristic stored lipid material in large, irregularly shaped vacuoles. As shown by double labeling, the storage vacuoles contained not only glucocerebrosidase protein but also other lysosomal enzymes. Thus the storage vacuoles can be considered to be secondary lysosomes. The findings indicate that although glucocerebrosidase was present in secondary lysosomes in this patient, the activity of the mutant enzyme was insufficient to prevent storage of glucocerebroside in the spleen.

Serum enzyme tests in hepatosplenic schistosomiasis.

The serum activities of monoamine oxidase (MAO), gamma-glutamyl transferase (GGT) and glutamic dehydrogenase (GDH) enzymes were measured in 25 patients with Schistosoma mansoni infection (Group I), 26 patients with schistosomal hepatosplenomegaly and ascites (Group II) and 21 normal controls. The activities of these enzymes were compared with those of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP). The mean levels of MAO, GGT and GDH of Group I were not significantly different from controls. The mean levels of MAO and GGT in Group II, however, were significantly different from corresponding mean levels of Group I and the controls at P less than .001. Changes in the mean level of GDH and ALT were not significant. By contrast, the levels of AST and ALP in both groups showed significant elevation over control levels at P less than .001. These results indicate that estimation of the two enzymes MAO and GGT may aid in the biochemical differentiation of the stages of schistosomiasis and their associated hepatic complications.

Changes in the activity of aspartate and alanine aminotransferase caused by aseptic inflammatory reaction and ionizing radiation in the liver, kidney and spleen of mice.

The activity of aspartate aminotransferase and alanine aminotransferase and the content of soluble proteins were determined in mice irradiated with single dose of 100 R or injected with turpentine and in mice subjected to both these stress factors. The aim of this study was determination of changes in the activity of both these enzymes in the liver, kidney and spleen within 48 hours). It was found that the action of both these stress factors caused significant changes in the activity of AspAT and A1AT in the first phase of the response of the organism to stress and caused statistically significant changes of this activity on the second day of the experiment.

Studies on certain serum enzymatic activities in hepatosplenic bilharziasis.

Determination of serum enzymatic activities in hepatosplenic bilharziasis (H.S.B.) were conducted in 100 bilharzial patients, in different stages and 30 controls SGot, SGPT, ALK pH, ALD and SLDH with its both fractions heat stable and labile.). Early elevation of serum enzymatic activities of SGOT, SGPT and SALK. pH, may be considered as a sensitive parameter for functional changes in H.S.B. rather than other conventional liver function tests. The elevated enzymic activity of total LDH in this study was associated with elevation in its both fractions. In particular, the changes in the total activity was in parallel with that of its heat labile fraction. The latter may be considered as a confirmatory test for marked deterioration of liver functions in H.S.B. The changes in the heat stable fraction was inconstant and may be attributed to extrahepatic bilharzial dissimilation. Significantly high serum enzymatic activity of SALD was found in cases of H.S.B. particularly those showing striking muscle wasting.