The Inter-α-Trypsin Inhibitor Family: Versatile Molecules in Biology and Pathology.

Inter-α-trypsin inhibitor (IαI) family members are ancient and unique molecules that have evolved over several hundred million years of vertebrate evolution. IαI is a complex containing the proteoglycan bikunin to which heavy chain proteins are covalently attached to the chondroitin sulfate chain. Besides its matrix protective activity through protease inhibitory action, IαI family members interact with extracellular matrix molecules and most notably hyaluronan, inhibit complement, and provide cell regulatory functions. Recent evidence for the diverse roles of the IαI family in both biology and pathology is reviewed and gives insight into their pivotal roles in tissue homeostasis. In addition, the clinical uses of these molecules are explored, such as in the treatment of inflammatory conditions including sepsis and Kawasaki disease, which has recently been associated with severe acute respiratory syndrome coronavirus 2 infection in children.

Determination of Psychological Stress, Serum Immune Parameters, and Cortisol Levels in Patients With Human Papilloma Virus.

PURPOSE: Because the results of studies investigating the relation between human papilloma virus (HPV) infection and the effects of psychological stress are inconsistent, this study was conducted to expand on previous research by analyzing patient stress levels, serum immune parameters, and cortisol levels in patients with clinical HPV manifestations. It also looked for differences in clinical manifestations of HPV depending on patient level of experienced stress. METHODS: This cross-sectional study included 213 subjects (94 women and 119 men aged ≥18 years; average age, 41 years) with clinical manifestations of HPV infection (165 subjects with extragenital manifestations and 48 with genital manifestations) who were treated at the Department of Dermatovenerology, Karlovac General Hospital, from January 1, 2012, to December 31, 2015. Psychological, neurohormonal and immune parameters (serum values of leukocytes, alpha2-globulins, beta-globulins, albumins, and proteins), and serum cortisol levels were analyzed. Questionnaires were used to determine patients' perception of stress: the Recent Life Changes Questionnaire, the Perceived Stress Scale, and the Brief Cope Test. One group of subjects had confirmed stressful experiences, defined by the Recent Life Changes Questionnaire as a period of 1 year with at least 500 life change units; the control group included patients with no significant stressful experiences. FINDINGS: Patients with confirmed significant stress experience had a statistically significant higher degree of perception of stress. There were no statistically significant differences in terms of the impact of stress on clinical HPV manifestations (genital and extragenital), sex, lesional duration, or recurrence. In patients with significant stress experience, significantly higher values of leukocytes (6.68 × 109/L), alpha2-globulins (6.85 g/L), and beta-globulins (7.33 g/L) were observed. Adaptive coping and a lower perception of stress significantly reduced the chances of having extragenital manifestations by 2.63 times. A higher perception of stress significantly increased the likelihood of genital manifestations. IMPLICATIONS: Although this study found that stress increased the values of leukocytes, alpha2-globulins, and beta-globulins, no evidence was found that it affected clinical manifestations of HPV infection. The redundancy of the immune system could account for this finding. This study is among the first to investigate the correlation between psychological, neurohormonal, and immune indicators of stress.

Serum Alpha1-Globulin as a Novel Prognostic Factor in Metastatic Renal Cell Carcinoma Treated with Tyrosine Kinase Inhibitors.

BACKGROUND: Serum protein fraction (SPF) is a common parameter reflecting the nutritional and inflammatory status of the human body. However, its role in patients with cancer, particularly those treated with targeted agents, is unknown. OBJECTIVE: We conducted this study to explore the prognostic value of SPF in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors and its association with clinical characteristics. METHODS: Patients with mRCC (n = 213) who initiated first-line sunitinib or sorafenib systemic therapy for metastatic disease between March 2007 and June 2017 at Zhongshan Hospital, Fudan University, were retrospectively included in our analysis. Clinical and pathological data were collected. SPF was measured by capillary electrophoresis. Prognostic factors of overall survival (OS) and progression-free survival (PFS) were analyzed using the Cox proportional hazards model. Correlation was estimated with Spearman's correlation coefficient. RESULTS: Among all SPF components, high α1-globulin was an independent prognostic factor for OS and PFS (dichotomized by median, hazard ratio [HR] 2.356; 95% confidence interval [CI] 1.399-3.966, p = 0.001; and HR 1.994; 95% CI 1.360-2.923, p < 0.001, respectively). In our cohort, α1-globulin showed better predictive value for OS than the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model (C-index 0.682 vs. 0.597; p = 0.005). Moreover, serum α1-globulin was positively correlated with International Society of Urological Pathology (ISUP) grade (r = 0.237; p < 0.001), tumor size (r = 0.242; p < 0.001), initial tumor/node/metastasis (TNM) stage (r = 0.185; p = 0.007), and IMDC risk group (r = 0.485; p < 0.001). CONCLUSIONS: High serum α1-globulin correlates with high tumor load. Serum α1-globulin is an independent prognostic factor of OS and PFS in mRCC and demonstrates better predictive value for OS than does the IMDC model.

P-Nitrobenzoic acid alpha2u nephropathy in 13-week studies is not associated with renal carcinogenesis in 2-year feed studies.

The objective of this study was to characterize the renal toxicity and carcinogenicity of p-nitrobenzoic acid in F344 rats. Dose levels in 13-week and 2-year studies ranged from 630-10,000 ppm and 1,250-5,000 ppm, respectively. At 13 weeks, renal lesions included minimal to mild hyaline droplet accumulation in male rats and karyomegaly in male and female rats. At 2 years, renal lesions included proximal tubule epithelial cell hyperplasia in male rats and oncocytic hyperplasia in high-dose male and female rats, and a decreased severity of nephropathy in males and females. The hvaline droplets in renal tubular epithelial cells of male rats at 13 weeks were morphologically similar to those described in alpha2u-globulin nephropathy. Using immunohistochemical methods, alpha2u-globulin accumulation was associated with the hyaline droplets. In addition, at 13 weeks, cell proliferation as detected by PCNA immunohistochemistry was significantly increased in males exposed to 5,000 and 10,000 ppm when compared to controls. Cytotoxicity associated with alpha2U-globulin nephropathy such as single-cell necrosis of the P2 segment epithelium or accumulation of granular casts in the outer medulla did not occur in the 13-week study. In addition, chronic treatment related nephrotoxic lesions attributed to accumulation of alpha2u-globulin such as linear foci of mineralization within the renal papilla, hyperplasia of the renal pelvis urothelium and kidney tumors were not observed. Although there was histologic evidence of alpha2u-globulin accumulation in male rats at 13 weeks, the minimal severity of nephropathy suggests that the degree of cytotoxicity was below the threshold, which would contribute to the development of renal tumors at 2 years.

Long-term oral administration of ginseng extract decreases serum gamma-globulin and IgG1 isotype in mice.

Effects of long-term oral administration of ginseng extract on serum protein profile and immunoglobulin (Ig) isotypes were studied in mice. Ginseng extract was orally administered to healthy female mice for 52 days at doses of 30 and 150 mg/kg per day and serum protein electrophoretograms and Ig isotypes levels were evaluated. Serum level of gamma-globulin was decreased dose dependently to 82% (P < 0.05) and 56% (P < 0.01) of control values at the doses of 30 and 150 mg/kg per day, respectively. Levels of total protein, albumin, alpha2- and beta-globulin fractions, as well as the ratio of albumin to globulin (A/G) did not change significantly. However, the alpha1-globulin level increased by 24% (P < 0.05) at the doses of 30 and 150 mg/kg per day. Among the Ig isotypes, including IgG1, IgG2a, IgG2b, IgG3, IgM and IgA, serum IgG1 was dose dependently decreased to 68% (P < 0.05) of control values at the dose of 150 mg/kg per day without significant changes in other Ig isotypes. As IgG1 isotype is rarely cytotoxic and can act as a blocking antibody, it is suggested that the selective decrease in serum IgG1 induced by ginseng extract without changes in the cytotoxic antibodies such as IgG2a may be helpful for the prevention and inhibition of cancer.

Effects of lead on the kidney: roles of high-affinity lead-binding proteins.

Lead-induced nephropathy produces both tubular and interstitial manifestations of cell injury, but the pathophysiology of these lesions is not completely understood. Delineation of the molecular factors underlying renal handling of lead is one of central importance in understanding the mechanisms of renal cell injury from this agent. Recent studies from this laboratory have identified several distinct high-affinity lead-binding proteins (PbBP) from rat kidney and brain that appear to play critical roles in the intracellular bioavailability of lead to several essential cellular processes in these target tissues at low dose levels. The PbBP from rat kidney has been shown to be a specific cleavage product of alpha 2-microglobulin, which is a member of the retinol-binding protein superfamily. Recent preliminary Western blot and immunohistochemical studies have shown that a polyclonal antibody to the renal PbBP does not recognize the brain PbBP, which appears to be a chemically similar, but distinct molecule. These studies have also shown that the renal PbBP is selectively localized in only certain nephrons and only specific segments of the renal proximal tubule. The striking nephror and cell-type specificity of the localization reaction could result from physiological differences in nephron functional activity or selective molecular uptake mechanisms/metabolism differences that act to define target cell populations in the kidney. In addition, other preliminary studies have shown that short-term, high-dose lead exposure produces increased excretion of this protein into the urine with concomitant decreases in renal concentrations.

Hydrocarbon-induced hyaline droplet nephropathy in male rats during senescence.

Male rats administered unleaded gasoline rapidly develop nephropathy characterized by accumulation of hyaline droplets in cells of the proximal convoluted tubules (PCT). This acute response is implicated in development of renal carcinoma in male rats exposed chronically to wholly volatilized gasoline. A major constituent of hyaline droplets is alpha 2 mu-globulin, a protein of hepatic origin for which the rate of synthesis declines during aging. Little information, however, is presently available on possible age-dependent susceptibility of male rats to hydrocarbon-induced nephropathy. In kidneys of untreated male Fischer 344 rats the number of constitutive hyaline droplets declined progressively with increasing age. Electrophoresis of renal cortical homogenates revealed a protein with Mr about 18 X 10(3), probably alpha 2 mu-globulin, in young (3.5 months old) male rats and total absence of this protein in aged (26 months old) males. RIA confirmed that constitutive levels of renal and hepatic alpha 2 mu-globulin in old rats were less than 1.5% of those in young adults. Unleaded gasoline (0.4 ml/kg/day, po, 5 days) caused accumulation of hyaline droplets in renal PCT of 3.5-month-old males accompanied by a marked increase (about twofold) in the renal content of alpha 2 mu-globulin, whereas the same treatment was without effect in 26-month-old rats. Finally, in the renal cortex of young rats the activities of the lysosomal proteases cathepsin B and D were increased following gasoline administration, presumably in response to protein accumulation. However, in 26-month-old rats cathepsin B activity was unaffected, while cathepsin D was increased by gasoline administration. Thus, we conclude that animal age is an important determinant in the development of hydrocarbon-induced nephropathy and only rats which produce large amounts of alpha 2 mu-globulin are susceptible to development of this pathology.

Effects of electroacupuncture on leukocytes and plasma protein in the X-irradiated rats.

The effects of electroacupuncture on leukocytes and plasma protein on the X ray-irradiated rats were investigated in the present study. The results showed that X-irradiation had an evident inhibitory effect on the counts of total leukocytes, lymphocytes and neutrocytes, and the concentration of the total plasma protein, plasma albumin, globulin and alpha- and beta-globulin in X-irradiated rats. The electroacupuncture was able to help the X-irradiated rats to recover the counts of the total leukocyte, lymphocyte and neutrocyte. The electroacupuncture had a helpful tendency to recover the concentration of the total plasma protein, albumin, globulin, and alpha- and beta-globulin in the irradiated rats.

Characterization of alpha 1-microglobulin in human colostrum and milk.

The mean concentration of alpha 1-microglobulin in human colostrum and milk, estimated by electroimmunoassay, was found to be about 0.4-0.6 mg/l and 0.1-0.2 mg/l, respectively. Both liquids contained alpha 1-microglobulin in mono- and dimeric forms, while the presence of higher polymeric forms, as characterized in plasma, could not be demonstrated.

Serological investigations in 15 cases of bird fanciers disease.

Serological studies in 15 patients with bird fanciers disease are reported. Quantitative analysis of serum proteins showed elevation of IgG in almost every case. High IgE was observed in three patients with isolated asthmatic reactions. In four patients alpha1-antitrypsin was transiently diminished. Two of these had heterozygous deficiency of this protein (genotype MS and MZ). Precipitins against avian sera and avian droppings were found in all patients, but also in some exposed and nonexposed controls. Cross-reactions to avian antigens from different species were observed quite regularly in patients but not in controls. One case is presented suggesting that these cross-reactions may be of clinical importance. Precipitins against other inhaled antigens such as Aspergillus fumigatus, cereals or Micropolyspora faeni were observed significantly more frequently in patients than in controls. These precipitins showed no cross-reactions with those against avian antigens.

Serum vitamin B12-binding proteins in a case of eosinophilic leukemia.

A patient with subacute eosinophilic leukemia is presented, with full recognition of the controversy surrounding that entity. Serum vitamin B12 and B12-binding protein studies and simultaneous complete blood counts were done before and during 6 months of high-dose, intermittent combination chemotherapy. The patient presented with extremely high levels of serum vitamin B12, unsaturated B12-binding capacity, and transcobalamin I, all of which resembled the highest values seen in chronic myelogenous leukemia. Serial studies, during and after remission induction, showed a precipitous fall of serum vitamin B12 and unsaturated B12-binding capacity to normal levels. The data show that transcobalamin I levels, which eventually reached low-normal range, correlate best with the level of circulating and bone marrow eosinophils. Transcobalamin II and serum third binder appeared to be normal throughout the patient's course. The B12-binding protein abnormalities are not considered diagnostic of eosinophilic leukemia.

[Age changes in the composition of immunoglobulins in cattle]. / Vikovi zminy skadu imunohlobuliniv u velykoï rohatoï khudoby

The electrophoretic and immunochemical methods as well as gelfiltration through Sephadex G-200 showed that there are no immunoglobulins in blood serum of fetuses and new-born calves. Specific proteins in a zone of gamma-globulins electrophoretic mobility which correspond to Ig M and Ig A are found in the serum of calves 3 hrs after their feeding on colostrum. The content of these proteins reaches the maximum on the third day of life but at the age of three months it lowers up to minimum. On the third month after birth in the blood serum of calves there appears a new protein in a zone of gamma2-globulins mobility which correspond to Im G-main immunoglobulin of adult animals. An assumption is advanced that the protective functions of calves of the early age are found chiefly with immunoglobulins Ig M and Ig A.