THE ALTERNATIVE PATHWAY OF HUMAN T CELL ACTIVATION BY MONOCLONAL ANTIBODIES(A COMPARATIVE STUDY BETWEEN NORMAL INDIVIDUALS AND CANCER PATIENTS)

This paper described T cell proliferative response by an alternative pathway in normal subjects and In patients with malignant diseases. Two McAbs, Anti-CCTl and Lo-CD2-act recognizing two distinct epitopes on E-receptor (CD2) were used to costimulate PBMC. Proliferative responsiveness was measured by 3H-thymidine incorporation. It was found that 82% of 72 nonnal subjects gave proliferative response whereas only 23% of the 93 patients did. The average cpm±SD in patients with bladder cancer (118±2314), kidney cancer (1619±2719) or lymphoma (2518±4057) was significantly lower than that in normal subjects (4935±2314), (P<0.001). These results indicate that T cell proliferation through the alternative pathway was significantly depressed in patients with cancer, and this can be used as a new parameter to monitor the immune status of cancer patients.

Comparison of the Effects of H_2O_2 and Salicylic Acid on Alternative Respiratory Pathway in Aged Potato Tuber Slices

The influences of exogenous H 2O 2 and salicylic acid (SA) treatments on the alternative respiratory pathway (ARP) in aged potato (Solanum tuberosum L.) tuber slices were compared. The results showed that both H 2O 2(5.0 mmol/L) and SA (0.1 mmol/L) treatments had a significant inducing effect on ARP capacity (V alt ) and its ratio to total respiration (V alt /V t) in potato slices aged for 24 h. With a monoclonal antibody against the alternative oxidase (AOX), Western blotting results showed that both H 2O 2 and SA treatments increased the AOX expression levels in aged potato tuber slices. However, the results of oxygen isotope discrimination experiments showed that H 2O 2 had no influence on the in vivo ARP activity (ρV alt ) and its contribution to V t(expressed as ρV alt /V t) in potato slices aged for 24 h, but SA had a significant influence on the ρV alt and ρV alt /V t values of the aged potato tuber slices. These results indicate that there are differences between the effects of H 2O 2 and SA on ARP in plant tissues. Both of them possess the ability to induce ARP capacity through inducing AOX expression. However, SA can simultaneously stimulate the operation of ARP, but H 2O 2 can not.

Effects of Photoperiod on Alternative Respiration Pathway in Nectarine Flower Buds During Dormancy Induction

Characteristics of dormancy induction and alternative respiration pathway （also known as cyanide-resistant respiration） of nectarine flower buds in different photoperiods were studied to determine the function of photoperiod and alternative respiration pathway in dormancy induction. Oxygen-electrode system and respiratory inhibitors were used to measure total respiratory rates and rates of alternative respiration pathway. The results showed that total respiration rate （Vt） in flower buds showed to be double hump-shaped curves. Short day raised, brought the first-hump of Vt forward and delayed the second-hump, while long day delayed the whole curve. The capacity （Vast） and activity （pValt） of SD and LD changed synchronously and both showed to be double hump-shaped curves. Short day made the first climax of Vast and pValt existed much earlier, while long day increased their rates significantly. The length of day had little effects on the later period climax. Long day also increased the contributions of altemative respiration pathway in total respiration rate （pValt/Vt）. The changes in alternative respiration pathway were correlated with the induction of dormancy and adjusted by photoperiod. Short day promoted dormancy induction of nectarine trees, while long day delayed it.

Relation Between Endodormancy Induction and Changes in Two Main Electron Transport Pathways of Nectarine Buds

Operation regulations of two main electron transport pathways in nectarine （Prunus persica var. nectariana cv. Shuguang） buds during endodormancy induction were studied to understand possible roles which two main electron transport pathways played in the buds of deciduous fruit trees during endodormancy induction. Respiratory inhibitors （KCN and SHAM） were used to investigate total respiration rate （Vt）, the development and operation of the alternative pathway and partitioning of electrons between the cytochrome and alternative pathways in nectarine buds during endodormancy induction. Results indicated that changes of Vt in flower and leaf buds showed single and double hump-shaped curves, respectively. In endodormancy induction, the capacity （Valt,） and activity （ρValt） of the alternative pathway rapidly increased, but changes of them had different patterns during the entire measuration. At the same time, changes of engagements of the alternative （ρValt/Vt） and cytochrome pathway （ρ′Vcyt/Vt） were opposite, and ρ′Vcyt/Vt was always further higher than ρValt/Vt during the entire measuration. All these results indicated that the development and operation of the alternative pathway played important roles in endodormancy induction, but the cytochrome pathway was the main pathway for mitochondrial electron transport in buds during endodormancy induction.

Targeting the alternative bile acid synthetic pathway for metabolic diseases

The gut microbiota is profoundly involved in glucose and lipid metabolism,in part by regulating bile acid(BA)metabolism and affecting multiple BA-receptor signaling pathways.BAs are synthesized in the liver by multi-step reactions catalyzed via two distinct routes,the classical pathway(producing the 12α-hydroxylated primary BA,cholic acid),and the alternative pathway(producing the non-12α-hydroxylated primary BA,chenodeoxycholic acid).BA synthesis and excretion is a major pathway of cholesterol and lipid catabolism,and thus,is implicated in a variety of metabolic diseases including obesity,insulin resistance,and nonalcoholic fatty liver disease.Additionally,both oxysterols and BAs function as signaling molecules that activate multiple nuclear and membrane receptor-mediated signaling pathways in various tissues,regulating glucose,lipid homeostasis,inflammation,and energy expenditure.Modulating BA synthesis and composition to regulate BA signaling is an interesting and novel direction for developing therapies for metabolic disease.In this review,we summarize the most recent findings on the role of BA synthetic pathways,with a focus on the role of the alternative pathway,which has been under-investigated,in treating hyperglycemia and fatty liver disease.We also discuss future perspectives to develop promising pharmacological strategies targeting the alternative BA synthetic pathway for the treatment of metabolic diseases.

Very early onset perinatal constipation:Can it be cow’s milk protein allergy?

Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung’s disease(HD),meconium ileus due to Cystic Fibrosis,etc.The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis,such as anorectal manometry or rectal suction biopsy.What if there was another etiology of perinatal constipation,that is far lesser known?Cow’s milk protein allergy(CMPA)is often diagnosed in infants within the first few weeks of life,however,there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero,therefore allowing symptoms to show as early as day one of life.The presentation is more atypical,with perinatal constipation rather than with bloody stools,diarrhea,and vomiting.The diagnosis and management would be avoidance of cow's milk protein within the diet,with results and symptom improvement in patients immediately.Therefore,we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients.This entails first ruling out CMPA with safe,noninvasive techniques with diet modification,and if unsuccessful,then moving forward with further diagnostic modalities.

Distinct roles of alternative oxidase pathway during the greening process of etiolated algae

The vital function of mitochondrial alternative oxidase(AOX) pathway in optimizing photosynthesis during plant de-etiolation has been well recognized. However, whether and how AOX impacts the chloroplast biogenesis in algal cells remains unclear. In the present study, the role of AOX in regulating the reassembly of chloroplast in algal cells was investigated by treating Auxenochlorella protothecoides with salicylhydroxamic acid(SHAM), the specific inhibitor to AOX, in the heterotrophy to autotrophy transition process. Several lines of evidences including delayed chlorophyll accumulation, lagged reorganization of chloroplast structure, altered PSI/PSII stoichiometry, and declined photosynthetic activities in SHAM treated cells indicated that the impairment in AOX activity dramatically hindered the development of functioning chloroplast in algal cells. Besides, the cellular ROS levels and activities of antioxidant enzymes were increased by SHAM treatment, and the perturbation on the balance of NAD+/NADH and NADP+/NADPH ratios was also observed in A. protothecoides lacking AOX activity, indicating that AOX was essential in promoting ROS scavenging and keeping the redox homeostasis for algal chloroplast development during greening. Overall, our study revealed the essentiality of mitochondrial AOX pathway in sustaining algal photosynthetic performance and provided novel insights into the physiological roles of AOX on the biogenesis of photosynthetic organelle in algae.

C3 Glomerulopathy and Therapeutic Potential of C5 Complement Inhibitors

C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology characterized by accumulation of C3 with absent or scanty immunoglobulin deposition. The keystone defect in both of these pathologies is the unregulated hyperactivity of alternative complement pathway. Specifically, in C3 glomerulopathy patients, there exists a prolongation of C3 cleavage which causes the uncontrolled alternative pathway activation. Many treatments have been investigated for treating C3 glomerulopathy to little or no avail, including calcineurin inhibitors, plasmapharesis, and anti-CD20 monoclonal antibodies. The next logical step is exploring the efficacy of anti-C5 monoclonal antibody therapy in C3 glomerulopathies to target the specific pathophysiology of this particular disease. Eculizumab is an anti-C5 monoclonal antibody that blocks the terminal step of complement activation. This drug has proven to be an effective treatment in other nephrologic pathologies that are caused by complement dysregulation. Here in this paper we discuss and present various case studies and clinical trials available that experiment with Eculizumab in patients with either dense deposit disease or C3 glomerulonephritis. In most of these patients, treatment with Eculizumab has demonstrated clinical and biochemical improvements in kidney function. These results provide encouraging evidence that suggest Eculizumab as a promising therapy for patients with C3 glomerulopathy and warrant that more extensive clinical trials can be designed as a next step.

Inhibition of vertebrate complement system by hematophagous arthropods: inhibitory molecules, mechanisms, physiological roles, and applications

In arthropods,hematophagy has arisen several times throughout evolution.This specialized feeding behavior offered a highly nutritious diet obtained during blood feeds.On the other hand,blood-sucking arthropods must overcome problems brought on by blood intake and digestion.Host blood complement acts on the bite site and is still ac-tive after ingestion,so complement activation is a potential threat to the host's skin feed-ing environment and to the arthropod gut enterocytes.During evolution,blood-sucking arthropods have selected,either in their saliva or gut,anticomplement molecules that inac-tivate host blood complement.This review presents an overview of the complement sys-tem and discusses the arthropod's salivary and gut anticomplement molecules studied to date,exploring their mechanism of action and other aspects related to the arthropod-host-pathogen interface.The possible therapeutic applications of arthropod's anticomplement molecules arealsodiscussed.

The Response Difference of Mitochondria in Recalcitrant Antiaris toxicaria Axes and Orthodox Zea mays Embryos to Dehydration Injury

Long-term preservation of recalcitrant seeds is very difficult because the physiological basis on their desiccation sensitivity is poorly understood. Survival of Antiaris toxicaria axes rapidly decreased and that of immature maize embryos very slowly decreased with dehydration. To understand their different responses to dehydration, we examined the changes in mitochondria activity during dehydration. Although activities of cytochrome （Cyt） c oxidase and malate dehydrogenase of the A. toxicaria axis and maize embryo mitochondria decreased with dehydration, the parameters of maize embryo mitochondria were much higher than those of A. toxicaria, showing that the damage was more severe for the A. toxicaria axis mitochondria than for those of maize embryo. The state I and III respiration of the A. toxicaria axis mitochondria were higher than those of maize embryo, the former rapidly decreased, and the latter slowly decreased with dehydration. The proportion of Cyt c pathway to state III respiration for the A. toxicaria axis mitochondria was low and rapidly decreased with dehydration, and the proportion of alternative oxidase pathway was high and slightly increased with dehydration. In contrast, the proportion of Cyt c pathway for maize embryo mitochondria was high, and that of alternative oxidase pathway was low. Both pathways decreased slowly with dehydration.