Mitochondrial permeability transition pore: a promising target for the treatment of Parkinson’s disease

Among the neurodegenerative diseases (ND), Parkinson’s disease affects 6.3 million people worldwide characterized by the progressive loss of dopaminergic neurons in substantia nigra. The mitochondrial permeability transition pore (mtPTP) is a non-selective voltage-dependent mitochondrial channel whose opening modifies the permeability properties of the mitochondrial inner membrane. It is recognized as a potent pharmacological target for diseases associated with mitochondrial dysfunction and excessive cell death including ND such as Parkinson’s disease (PD). Imbalance in Ca²⁺ concentration, change in mitochondrial membrane potential, overproduction of reactive oxygen species (ROS), or mutation in mitochondrial genome has been implicated in the pathophysiology of the opening of the mtPTP. Different proteins are released by permeability transition including cytochrome c which is responsible for apoptosis. This review aims to discuss the importance of PTP in the pathophysiology of PD and puts together different positive as well as negative aspects of drugs such as pramipexole, ropinirole, minocyclin, rasagilin, and safinamide which act as a blocker or modifier for mtPTP. Some of them may be detrimental in their neuroprotective nature.     

Alzheimer’s disease and gut microbiota

Alzheimer’s disease (AD) is a most common neurodegenerative disorder, which associates with impaired cognition. Gut microbiota can modulate host brain function and behavior via microbiota-gut-brain axis, including cognitive behavior. Germ-free animals, antibiotics, probiotics intervention and diet can induce alterations of gut microbiota and gut physiology and also host cognitive behavior, increasing or decreasing risks of AD. The increased permeability of intestine and blood-brain barrier induced by gut microbiota disturbance will increase the incidence of neurodegeneration disorders. Gut microbial metabolites and their effects on host neurochemical changes may increase or decrease the risk of AD. Pathogenic microbes infection will also increase the risk of AD, and meanwhile, the onset of AD support the “hygiene hypothesis”. All the results suggest that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention will probably become a new treatment for AD.     

Crohn’s disease of the colon: ultrastructural changes in submuscular interstitial cells of Cajal

Interstitial cells of Cajal (ICC) at the submuscular border of the human colon (ICC-SMP) are the proposed pacemaker cells of the musculature. In patients with Crohn’s disease (CD) of the colon, ICC-SMP showed characteristic cytological changes from controls. The changes comprised secondary lysosomes in connection with lipid droplets and cytoplasmic vacuoles or multiple empty, confluent and often outbulging vacuoles merging with cisterns of granular endoplasmic reticulum and clusters of glycogen granules. These changes were most pronounced in patients with macroscopical mucosal inflammation but were also demonstrable in uninvolved colonic segments. Relationships of ICC to other cells were undisturbed. The changes were selective to ICC-SMP, as glial cells, muscle cells and fibroblast-like cells at the submuscular border showed no cytological alterations compared with controls. Varicosities of the submuscular plexus were often empty and dilated. Fibroblast-like cells selectively encased macrophages and mast cells. The cytological changes in ICC-SMP in CD are thus similar to changes seen in ulcerative colitis and may be of pathophysiological significance with regard to the motility and sensory disturbances seen in patients with CD.     

Emerging targets and new small molecule therapies in Parkinson’s disease treatment

Parkinson’s disease (PD) is a common chronic degenerative disease of the central nervous system. Due to a rapidly aging society worldwide, PD morbidity is on the rise; however, the treatment of PD with conventional drugs carries serious adverse reactions and cannot fix the root cause of PD, the degeneration of dopaminergic neurons, which limits conventional drug usage in clinical practice. In recent years, research on the pathogenesis of PD and its clinical manifestations has led to the discovery of an increasing number of novel targets in PD, including several small molecule targeted compounds. In this paper, we analyze and summarize the most recently published PD literature and review several recently discovered novel targets in PD and their small molecule targeted pharmacologically active agents based on their mechanisms of action and pharmacodynamic profiles.     

Peculiarities of L-DOPA treatment of Parkinson’s disease

Summary. L-Dihydroxyphenylalanine (L-DOPA), the anti-parkinsonian drug affording the greatest symptomatic relief of parkinsonian symptoms, is still misunderstood in terms of its neurotoxic potential and the mechanism by which generated dopamine (DA) is able to exert an effect despite the absence of DA innervation of target sites in basal ganglia. This review summaries important aspects and new developments on these themes. On the basis of L-DOPA therapy in animal models of Parkinsons disease, it appears that L-DOPA is actually neuroprotective, not neurotoxic, as indicated by L-DOPAs reducing striatal tissue content of the reactive oxygen species, hydroxyl radical (HO), and by leaving unaltered the extraneuronal in vivo microdialysate level of HO. In addition, the potential beneficial anti-parkinsonian effect of L-DOPA is actually increased because of the fact that the basal ganglia are largely DA-denervated. That is, from in vivo microdialysis studies it can be clearly demonstrated that extraneuronal in vivo microdialysate DA levels are actually higher in the DA-denervated vs. the intact striatum of rats – owing to the absence of DA transporter (i.e., uptake sites) on the absent DA nerve terminal fibers in parkinsonian brain. In essence, there are fewer pumps removing DA from the extraneuronal pool. Finally, the undesired motor dyskinesias that commonly accompany long-term L-DOPA therapy, can be viewed as an outcome of L-DOPAs sensitizing DA receptors (D₁–D₅), an effect easily replicated by repeated DA agonist treatments (especially agonist of the D₂ class) in animals, even if the brain is not DA-denervated. The newest findings demonstrate that L-DOPA induces BDNF release from corticostriatal fibers, which in-turn enhances the expression of D₃ receptors; and that this effect is associated with motor dyskinesias (and it is blocked by D₃ antagonists). The recent evidence on mechanisms and effects of L-DOPA increases our understanding of this benefical anti-parkinsonian drug, and can lead to improvements in L-DOPA effects while providing avenues for reducing or eliminating L-DOPAs deleterious effects.     

Medical,ethical, and legal aspects of hematopoietic stem cell transplantation for Crohn’s disease in Brazil

Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract. The etiology of CD is unknown; however, genetic, epigenetic, environmental, and lifestyle factors could play an essential role in the onset and establishment of the disease. CD results from immune dysregulation due to loss of the healthy symbiotic relationship between host and intestinal flora and or its antigens. It affects both sexes equally with a male to female ratio of 1.0, and its onset can occur at any age, but the diagnosis is most commonly observed in the range of 20 to 40 years of age. CD diminishes quality of life, interferes with social activities, traumatizes due to the stigma of incontinence, fistulae, strictures, and colostomies, and in severe cases, affects survival when compared to the general population. Symptoms fluctuate between periods of remission and activity in which complications such as fistulas, strictures, and the need for bowel resection, surgery, and colostomy implantation make up the most severe aspects of the disease. CD can be progressive and the complications recurrent despite treatment with anti-inflammatory drugs, corticosteroids, immunosuppressants, and biological agents. However, over time many patients become refractory without treatment alternatives, and in this scenario, hematopoietic stem cell transplantation (HSCT) has emerged as a potential treatment option. The rationale for the use of HSCT for CD is anchored in animal studies and human clinical trials where HSCT could reset a patient's immune system by eliminating disease-causing effector cells and upon immune recovery increase regulatory and suppressive immune cells. Autologous HSCT using a non-myeloablative regimen of cyclophosphamide and anti-thymocyte globulin without CD34+ selection has been to date the most common transplant conditioning regimen adopted. In this review we will address the current situation regarding CD treatment with HSCT and emphasize the medical, ethical, and legal aspects that permeate the procedure in Brazil.     

Cellular trafficking in trypanosomatids: a new target for therapies?

Pathogenic trypanosomatids cause a plethora of diseases marked by the lack of efficient vaccines and therapies. As a consequence, studies are being conducted that are geared towards the understanding of basic mechanisms and various biological aspects of these parasites that might be used as targets for new developments in these areas. One such aspect is the understanding of specific cellular trafficking mechanisms that might be attacked with the intention of disease control. In this paper, we give an overview of our current knowledge of cellular targeting mechanisms in trypanosomatids, with special emphasis on our data related to lysosomal targeting of cysteine proteinases in Leishmania.     

BAG3: a new therapeutic target of human cancers?

Bcl-2-associated athanogene (BAG) family proteins share the BAG domain, which is characterized by their interaction with a variety of partners (heat shock proteins, steroid hormone receptors, Raf-1 and others) and is involved in regulating a number of cellular processes. BAG3, also known as CAIR-1 or Bis, mediates protein delivery to proteasome and modulates apoptosis by interfering with cytochrome c release, apoptosome assembly and other events in the cellular death program. Moreover, it takes part in the processes of cell adhesion and migration. It has been shown that, in human cancer cells, including lymphocytic and myeloblastic leukemic cells, BAG3 sustains cell survival and underlies resistance to chemotherapy, through down-modulation of apoptosis. BAG3 knocking down could enhance the effectiveness of chemotherapy. This review summarizes the physiological and pathological roles of BAG3 in cancer cells and its potential as a therapeutic target of human malignancies.     

Histone methyltransferases: a new class of therapeutic targets in cancer treatment?

Epigenetic gene regulation contributes, together with genetic alterations, to cancer development and progression. In contrast to genetic disorders, the possibility of reversing epigenetic alterations has provided original targets for therapeutic application. In the last years, work has been focused on the pharmacological restoration of epigenetic regulation balance using epidrugs which yield hopes for novel strategy in cancer therapy. Histone acetylation and DNA methylation are epigenetic modifications which have been closely linked to the pathology of human cancers, and inhibitors of both enzyme classes for clinical use are at hands. Novel findings accumulated during the last years both in chemistry and biomedical applications give rise to new targeted treatments against cancer. Since their links with pathogenesis and progression of cancer were recognized, histone methyltransferases emerge as promising therapeutic targets in cancer treatment.     

Chemokine blockade: a new era in the treatment of rheumatoid arthritis?

Blockade of chemokines or chemokine receptors is emerging as a new potential treatment for various immune-mediated conditions. This review focuses on the therapeutic potential in rheumatoid arthritis, based on studies in animal models and patients. Several knockout models as well as in vivo use of chemokine antagonists are discussed. Review of these data suggests that this approach might lead to novel therapeutic strategies in rheumatoid arthritis and other chronic inflammatory disorders.     

A review of major Crohn’s disease susceptibility genes and their role in disease pathogenesis

Crohn’s disease (CD) is a chronic inflammatory bowel disease whose relevance is increasing in industrialized society. Recent genome wide association studies revealed over seventy one loci associated with disease penetrance. Several variants that increase disease risk encode for altered proteins that diminish bacterial host defense. NOD2 alters intracellular bacterial sensing while ATG16L1 is thought to diminish bacterial clearance by impairing autophagy. Additionally, changes in the IBD5 locus are thought to diminish barrier function. Alternatively, recent data indicate a gain of function genetic variant of IL23R is protective amongst European CD patients. These recent genetic discoveries contradict historical theories that Crohn’s disease results from overactive auto-aggressive responses. Rather, new genetic data suggest disease-associated variants encode for dysfunctional proteins that diminish essential innate immune responses against commensal organisms. This review provides an overview of these critical discoveries and places them in their biological context.     

The impact of new emerging drugs in the treatment of multiple myeloma: is there still a role for PBSC transplantation?

High-dose therapy with the rescue of autologous stem cells represents today the standard approach for multiple myeloma patients aged <65 years. Several studies, in fact, have demonstrated the superiority of high-dose therapy with respect to conventional chemotherapy in younger patients. Peripheral blood stem cells (PBSCs) provide a rapid and effective hematopoietic recovery after the administration of supra maximal chemotherapy and mainly for this reason have become the preferred source of stem cells for autologous transplantation. Recently, however, a number of new drugs have appeared in the armamentarium of the hematologist. Among these, thalidomide has been the first antiangiogenetic drug effectively adopted firstly in refractory-relapsed patients and now also as first line treatment with better results respect to VAD or VAD-like regimens. Inhibitors of proteasome, such as bortezomib, and other immunomodulatory agents, such as lenalidomide, have been also studied more recently in myeloma patients. In particular, bortezomib has shown to be very effective as single agent or in combination with high-dose dexamethasone. In this review, we try to define the potential role of these new drugs, how and when they can be included in the therapeutic program designed for younger and older patients, and mostly if and how these new agents could jeopardize the central role of autologous stem cell transplantation in the treatment of multiple myeloma.     

Visceral pain: gut microbiota,a new hope?

Background

Visceral pain is a complex and heterogeneous disorder, which can range from the mild discomfort of indigestion to the agonizing pain of renal colic. Regulation of visceral pain involves the spinal cord as well as higher order brain structures. Recent findings have linked the microbiota to gastrointestinal disorders characterized by abdominal pain suggesting the ability of microbes to modulate visceral hypersensitivity and nociception to pain.

Main body

In this review we describe the neuroanatomical basis of visceral pain signaling and the existing evidence of its manipulation exerted by the gut microbiota. We included an updated overview of the potential therapeutic effects of dietary intervention, specifically probiotics and prebiotics, in alleviating hypersensitivity to visceral pain stimuli.

Conclusions

The gut microbiota dramatically impacts normal visceral pain sensation and affects the mechanisms mediating visceral nociception. Furthermore, manipulation of the gut microbiota using prebiotics and probiotics plays a potential role in the regulation of visceral pain disorders.

     

Perianal Crohn’s disease and hidradenitis suppurativa: a possible common immunological scenario

Background

Crohn’s disease (CD) and Hidradenitis suppurativa (HS) are both chronic inflammatory diseases. The pathogenesis of these diseases is multifactorial, due to the interaction of genetic and environmental factors leading to a deregulated local immune response where T lymphocytes play a major role. To the best of our knowledge, no previous study has clarified whether the pathogenetic mechanism of perianal CD and HS is the same. We therefore analyzed the cellular expression pattern and the cytokine repertoire in three patients suffering from both perianal CD and HS.

Methods

We evaluated three patients affected by concurrent HS and CD with fistulizing perianal disease. Surgical specimens have been fixed and embedded in paraffin prior to sectioning for histological examination. Inflammatory tissue curettages have been recovered during intervention from perianal fistulas and HS lesions in order to analyze the phenotypic and functional characteristics of infiltrating T cells. In particular we evaluated T cells, by flow cytometry, for cytokine production profile and expression of surface markers. Moreover, analysis of the T cell repertoire was performed by means of spectratyping, in only one patient.

Results

A higher frequency of CD4+ CD161+ T lymphocytes has been detected in CD fistulas and in HS lesions than in peripheral blood (PB) samples. In the patient in whom we derived enough cells from the three sources, we found higher frequency of CD4+ IL-17- producing cells in HS lesion and fistula lesion compared to PB. It is noteworthy that the same clonotypes were expanded in this patient in T cells derived from both HS lesion and fistula lesion.

Conclusion

The presence of numerous CD4+ CD161+ lymphocytes in fistula and HS lesion curettages suggests that these cells may play a pathogenic role, and candidates CD161 as a possible biological target for medical treatment.