Differentially expressed protein-coding genes in ankylosing spondylitis: Emerging insights into pathogenesis and therapeutic approaches

Ankylosing spondylitis (AS) is a chronic, progressive inflammatory rheumatic disease affecting the spine, axial skeleton, and sacroiliac joints. Pathogenesis of AS encompasses enthesitis, synovitis, and osteoproliferation, leading to the formation of syndesmophytes, ankylosis, and spinal rigidity. Bioinformatics, an interdisciplinary field combining computer science, mathematics, and biology, enables the analysis of complex biological data for investigating AS pathogenesis. This review summarizes differentially expressed protein-coding genes in peripheral blood or local tissues of AS patients compared with healthy controls and comprehensively reviews currently available therapeutic agents. The objective is to enhance the understanding of AS pathogenesis, inform diagnosis, identify novel therapeutic targets, and facilitate personalized medicine. This review contributes to a deeper understanding of AS pathogenesis and provides a foundation for developing innovative therapeutic approaches.     

Animal models of systemic sclerosis: insights into systemic sclerosis pathogenesis and potential therapeutic approaches

PURPOSE OF REVIEW: Animal models have been extremely valuable in contributing to a better understanding of the pathogenesis of systemic sclerosis. Discussed here are recent studies that have examined the molecular pathways and potential therapeutic approaches for systemic sclerosis using animal models. RECENT FINDINGS: Reported evidence further indicates that the immune system plays a role in modulating the fibrosis observed in the tight skin-1/+ mouse model for systemic sclerosis. CD19, interleukin-6, and interleukin-4 are involved. The injection of spleen cells into immune-compromised mice resulted in fibrotic, vascular, and immunologic alterations quite similar to those of systemic sclerosis. Transforming growth factor-beta and its signaling pathway (JAK kinase and STAT-6, Smad2/3, and Smad7) appear to play a central role in the development of fibrosis as well as monocyte chemoattractant protein-1, CCR-2, platelet-derived growth factor C, and excessive apoptosis. Viruses were shown to be possible cofactors. The therapeutic agents hepatocyte growth factor and halofuginone were shown to prevent fibrosis in animal models of systemic sclerosis. SUMMARY: The transforming growth factor-beta signaling pathway is a common mechanism of tissue fibrosis in animal models of systemic sclerosis, although numerous additional molecules modulate this pathway or have a direct effect on fibrosis.     

从机体清除乙型肝炎病毒的规律探讨抗病毒治疗的新策略

乙型肝炎患者自体每日可清除外周血中大量乙型肝炎病毒（ＨＢＶ）根据最近对ＨＢＶ在人体内动力学研究,ＨＢＶ的半衰期为 ２６．４ ｈ,病毒存活期为 ３６．６ ｈ,日更新率为４８％,所以控制人体病毒感染的关键在于清除ＨＢＶ ＣＣＣ ＤＮＡ,抑制病毒复制［１,２］。根据目前研究,可能通过两种途径清除 ＨＢＶ ｃｃｃＤＮＡ,即非溶细胞性及溶细胞性,而且以前者为主［３］。至于其具体途径目前尚不完全了解。但是肝脏及肝细胞在清除 ＨＢＶ ｃｃｃ ＤＮＡ过程中具有重要作用是无庸置疑的。 一、非溶细胞性清除ＨＢＶ和细胞因子 自从…     

New approaches to the pathogenesis of peptic ulcer based on the protective action of saliva

Epidemiologic studies have shown differences in the prevalence of peptic ulcer disease among various communities to be related to variations in diet and eating patterns. Results of studies of the effect of diet and pattern of eating on saliva, on gastric juice, and on the amount of bile are reviewed. It is suggested that bile, and not hydrochloric acid, plays the causative role in pathogenesis of peptic ulceration. The role of saliva in the prevention of peptic ulcer is emphasized. The salivary mucus swallowed with food is protective because it decreases the flow rate of bile which, when held in the gallbladder longer, loses its alkalinity and therefore its ability to damage the mucous cells. When food is well masticated, resulting in an increase in the amount of salivary mucus, peptic ulceration may be prevented and cured and relapses may be prevented. This does not require a big change in the pattern of diet but only a change in the manner of eating so that meal-scamping is avoided and food is chewed well. The pattern of diet, especially the relative dietary preponderance of short-chain fatty acids, such as those present in milk, yogurt and other fermented milk products, has a protective action; the short-chain fatty acids retard gallbladder contraction and thus diminish the amount of bile entering the duodenal lumen.     

Idiopathic intestinal inflammations--contemporary therapeutic approaches

Current pharmacotherapy of idiopathic intestinal inflammations can benefit from standard (conventional) therapies based on results of controlled studies, non-standard (unconventional) therapies based on pilot and uncontrolled studies, or can be a subject of clinical experiments. Clinical experimental area is a way to a progress in traditional treatment methods. Currently it includes a group of new drugs (immunosuppressives tacrolimus mycophenolate, thalidomide, biologic therapy, probiotics, neuroinflammation blockers), new treatment techniques (cytaphereses, sequential immunosuppression, immunosuppression with high doses), and finally new indications (chemoprophylaxis).     

New therapeutic approaches for spondyloarthritis

PURPOSE OF REVIEW: Tumor necrosis factor alpha antagonists are effective for signs and symptoms of ankylosing spondylitis. Recent studies have evaluated the efficacy of these agents for structural disease modification. We critically review recent radiographic data suggesting that tumor necrosis factor alpha inhibition may have structure-modifying effects in ankylosing spondylitis, and may thereby alter the disease course. RECENT FINDINGS: Recent studies employing MRI suggest that therapy with tumor necrosis factor alpha antagonists significantly reduces spinal inflammation in active ankylosing spondylitis when compared to placebo; there was no comparable improvement in the severity of chronic stigmata, such as syndesmyophytes and vertebral bridging. These studies were of relatively short duration and small size. SUMMARY: Despite insufficient evidence to conclude definitively that tumor necrosis factor alpha-antagonist therapy provides durable and effective structure modification in ankylosing spondylitis, the data strongly suggest a benefit, at least in the short term. In the future, MRI data coupled with clinical outcomes in larger cohorts followed for longer durations may result in a paradigm shift for ankylosing spondylitis treatment similar to that undergone for rheumatoid arthritis, where patients with ankylosing spondylitis are offered therapy early in the disease course to arrest and prevent structural disease progression.     

Modern therapeutic approaches to osteoporosis

Therapeutic strategies for osteoporosis treatment encompass both prophylaxis against age, menopausal-or medication-related bone loss, and promotion of a significant increase in bone mass following the onset of fractures. This article details the classification and screening procedures, various treatment methods, and research directions.     

Novel therapeutic approaches for haemophilia

The major therapy for haemophilia is plasma derived or recombinant clotting factors which are evolving steadily to increase potency, stability and half‐life. Research in the area of haemophilia therapeutics, however, is not restricted only to modifications in the recombinant products, but alternate therapeutic strategies are being developed which are in different phases of experimental and clinical trials. This chapter reviews the diverse molecular innovations which are being developed for alternate therapeutic approaches in haemophilia. The data is mainly extracted from the literature and the Conference abstracts. Some of the novel therapeutic approaches include inhibition of anticoagulant pathway factors (activated protein C, antithrombin, tissue factor pathway inhibitor) by monoclonal antibodies, peptide inhibitors, DNA or RNA aptamers, use of variant coagulation factors (factor Xa, factor Va) which are more resistant to inactivation or enzymatically more active and antibody‐mediated therapy including a humanized anti‐factor IXa/X bispecific antibody mimicking factor VIII. Other approaches include nonsense mutation suppression, induction of prothrombotic microparticles by P‐selectin‐immunoglobulin chimeras, suppression of fibrinolytic potential either by antifibrinolytics or by the use of mutant molecules of fibrinolytic inhibitors. Few products are proposed as ‘stand alone’ treatment for haemophilia, while a few can be used as adjuvant therapies to recombinant factors with an aim to reduce the amount of factor intake. All efforts are underway to produce an alternate, novel drug for haemophilia which will have an increased half‐life, subcutaneously injectable, non‐immunogenic and effective both in the presence and absence of inhibitors.     

Curative therapeutic approaches to APL

Acute promyelocytic leukemia (APL) has become the most curable subtype of acute myeloid leukemia in adults. It represents the only established example of successful differentiation therapy. With current therapy which includes all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy for induction, anthracycline-based consolidation and maintenance with ATRA and/or low-dose chemotherapy, approximately 75-85% of patients with acute promyelocytic leukemia (APL) remain alive and disease-free at 5 years, and most patients are likely to be cured, an unprecedented achievement in the field of hematologic malignancies. However, several causes for failure to be cured need to be addressed. The first is early death which occurs in approximately 10% and is frequently attributable to hemorrhage due to the characteristic coagulopathy. The second is relapse, particularly in intermediate- and high-risk patients. Analyses of new prognostic factors may permit refinement of current risk classification and identify patients warranting alternative therapy. Finally, long-term consequences of current treatment will be important to recognize, including delayed cardiomyopathy, extramedullary relapse related to sanctuary sites, and the potential for second malignancies. For patients who do relapse, arsenic trioxide appears to be the treatment of choice since the majority of patients achieve a second complete morphologic, cytogenetic, and even molecular remission. While some patients achieving a second complete remission have prolonged disease-free survival with consolidation and maintenance arsenic, high-dose chemotherapy with autologous hematopoietic stem cell transplantation appears to offer the highest likelihood of cure. Such a strategy or anti-CD33 antibodies, recently shown to be active in APL, might be considered for high-risk patients in first remission.     

Newer therapeutic approaches: gout

Newer approaches to the treatment of gout have included modifications and further attention to aspects of current therapies, and development of interesting new therapies. Colchicine prophylaxis appears to be needed longer than previously recognized after introduction of a urate-lowering agent. Diet has received attention, though most dietary effects are small. New agents under investigation include pegylated formulations of uricase and a new potent xanthine oxidase inhibitor, febuxostat. Some cardiovascular drugs have been shown to be uricosuric.     

Kennedy's disease: pathogenesis and clinical approaches

Kennedy's disease, also known as spinal and bulbar muscular atrophy, is a progressive degenerative condition affecting lower motor neurons. It is one of nine neurodegenerative disorders caused by a polyglutamine repeat expansion. Affecting only men, Kennedy's disease is the only one of these conditions that follows an X-linked mode of inheritance. The causative protein in Kennedy's disease, with a polyglutamine expansion residing in the first N-terminal domain, is the androgen receptor. Research in this field has made significant advances in recent years, and with the increased understanding of pathogenic mechanisms, feasible approaches to treatments are being investigated. In Kennedy's disease research, the most significant issue to emerge recently is the role of androgens in exacerbating the disease process. On the basis of animal experiments, a viable hypothesis is that higher circulating levels of androgens in men could trigger the degeneration of motor neurons causing this disease, and that lower levels in heterozygous and homozygous women are protective. This is a major issue, as treatment of individuals affected by Kennedy's disease with testosterone has been considered a reasonable therapy by some neurologists. The rationale behind this approach relates to the fact that Kennedy's disease is accompanied by mild androgen insensitivity. It was therefore believed that treatment with high doses of testosterone might compensate for this loss of androgen action, with the added benefit of preventing muscle wasting. The current review provides an overview of recent advances in the field of Kennedy's disease research, including approaches to treatment.     

Novel therapeutic approaches to post-infarction remodelling

Adverse cardiac remodelling is a major cause of morbidity and mortality following acute myocardial infarction (MI). Mechanical and neurohumoral factors involved in structural and molecular post-infarction remodelling were important targets in research and treatment for years. More recently, therapeutic strategies that address myocardial regeneration and pathophysiological mechanisms of infarct wound healing appear to be useful novel tools to prevent progressive ventricular dilation, functional deterioration, life-threatening arrhythmia, and heart failure. This review provides an overview of future and emerging therapies for cardiac wound healing and remodelling after MI.     

Current therapeutic approaches to hyperthyroidism.

Treatment of hyperthyroidism varies, depending upon the underlying etiology of thyrotoxicosis. Antithyroid drugs may be administered to patients with Graves' hyperthyroidism for prolonged periods in an attempt to obtain a remission. Alternatively, a short course of antithyroid drugs may be administered to patients with Graves' disease or toxic adenoma to achieve euthyroidism prior to definitive therapy with radioiodine or surgery. Radioiodine is the preferred therapy for most adult patients, however, large goiters, especially i f obstructive symptoms are present, are best treated with surgery.     

Controversial and so-called alternative therapeutic approaches

In spite of intensive research, it has not yet been possible to produce a complete explanation of the aetiology and pathology of rheumatoid arthritis (R.A.). Therapeutic measures are possible in many phases of the pathogenetic concept, and often produce good, modifying results, improving the course of the disease. No causal therapy of R.A. exists--we do not know the aetiology of this disease. Frustration with conventional medicine on the one side, and the predominating spirit of the times on the other--back to biological methods and the old forms of therapy--are the reasons why chronic polyarthritics drift into the sphere of para-medicine. In the judgement of para-medical methods, "risk/benefit relationship", "superfluous and no longer up-to-date", "controversial--absence of scientific evidence", "controversial", and "controversial--not scientifically acceptable" present some of the decision criteria. Treatment with mussel extracts, beta-sitosterins, THX, and substitution with various substances, as well as anthroposophically-oriented high-potency homeopathy, are to be allocated to the "controversial--not scientifically acceptable" category. If one weighs up the "risk/benefit relationship" of cell therapy, this treatment concept also cannot be supported. Moreover, precisely documented scientific results of this form of therapy do not exist. Methods standing on scientifically-hypothetically interesting ground, but which were tested on too small a group and cannot yet be accepted as sufficiently proven, are therapy with Vitamin E, the use of Thymopoietin, in which, for example, dose-finding and mode of application are not yet firmly established, and therapy with enzyme mixtures. Interferon results, initially extolled in the lay press, have not been confirmed in the most recent studies. Thymopoietin treatments, via the laborious road to the correct application (oral, subcutaneous, intramuscular, intravenous as bolus, intravenous--fractionated), show encouraging successes. As tissue-localized immune complexes (which sort?) play a role in the pathogenesis of R.A., but enzyme mixtures, apart from the problems of absorption, only influence circulating immune complexes, and moreover, in many diseases neither the aetiology nor the pathogenesis is connected with the immune complexes, this therapy concept can be regarded neither as causal nor as scientifically guaranteed. In summary: from the start-point that healing is the ideal aim, it has been forgotten that there are many human sufferings which medicine can ease and ameliorate, but not yet cure.(ABSTRACT TRUNCATED AT 400 WORDS)