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Background Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett’s multiple comparison test. Results We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration ( n  ≥ 3, p  < 0.05) and invasion ( n  ≥ 3, p  < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model ( p  < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content ( n  ≥ 3, p  < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 ( p  < 0.05) or 21 days ( p  < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

HIV infection results in a neurodegenerative disorder for which currently there is no effective therapy available. Currently, available antiretroviral therapy has no impact on the production of early regulatory HIV proteins once the virus is integrated. Of these proteins, Tat was shown to be toxic to neurons. We, thus, used an in vitro neuronal culture system to determine if immunophilin ligands could protect against Tat-induced neurotoxicity. We found that GPI 1046 had potent neuroprotective effects in this model. The compound was able to protect the neurons even though it only partially obliterated Tat-induced oxidative stress in neurons, suggesting that other mechanisms may be important in mediating its neuroprotective effect. Furthermore, GPI 1046 showed inhibition of HIV replication and Tat-mediated long terminal repeat (LTR) activation suggesting that this class of compounds may be worthy of further exploration as a potential treatment for HIV dementia.

Objectives The purpose was to investigate the role of immunophilin ligands in ischemia/reperfusion (I/R)-induced germ cell apoptosis in the rat. Materials and methods Sprague–Dawley rats were divided into five groups with ten animals in each. In animals undergoing torsion/detorsion, right testes were rotated 720º for 1 h. A baseline group was for basal normal values. The sham-operated group served as a control group. The TD group underwent torsion/detorsion surgery alone; the cyclosporine-A group (TD-CsA) received intravenous cyclosporine injection (5 mg/kg) at the time of detorsion, and the FK-506 group (TD-FK) received intravenous FK-506 (3.5 mg/kg) at the time of detorsion. For measurement of lipid peroxidation and antioxidant enzyme activities, the right testes of five animals in each group were excised after 4-h reperfusion. Germ cell apoptosis indices were determined 24 h following detorsion in the right testes of the remaining five animals in each group. Results Malondialdehyde (MDA) levels in the TD group were significantly higher compared to control and baseline groups. Moreover, testicular MDA values in TD-CsA and TD-FK groups were significantly lower than in TD. There were also significant decreases in catalase and superxide dismutase activities in the TD group compared to control and baseline groups. These values in TD-CsA and TD-FK groups were significantly higher than in TD. The mean germ cell apoptosis scores were significantly higher in TD animals compared to control and baseline groups; however, CsA and FK-506 treatment significantly reduced the apoptosis compared with the TD group. Conclusion We have shown that administration of immunophilin ligands in testicular torsion decreases ischemia/reperfusion (I/R) cellular damage. The results of biochemical studies suggest that reduction of oxidative stress along with attenuated neutrophil accumulation by immunophilin ligands may have a major role in their cytoprotective effects.

FKBPL has been implicated in processes associated with cancer, including regulation of tumor growth and angiogenesis with high levels of FKBPL prognosticating for improved patient survival. Understanding how FKBPL levels are controlled within the cell is therefore critical. We have identified a novel role for RBCK1 as an FKBPL-interacting protein, which regulates FKBPL stability at the post-translational level via ubiquitination. Both RBCK1 and FKBPL are upregulated by 17-β-estradiol and interact within heat shock protein 90 chaperone complexes, together with estrogen receptor-α (ERα). Furthermore, FKBPL and RBCK1 associate with ERα at the promoter of the estrogen responsive gene, pS2 , and regulate pS2 levels. MCF-7 clones stably overexpressing RBCK1 were shown to have reduced proliferation and increased levels of FKBPL and p21. Furthermore, these clones were resistant to tamoxifen therapy, suggesting that RBCK1 could be a predictive marker of response to endocrine therapy. RBCK1 knockdown using targeted small interfering RNA resulted in increased proliferation and increased sensitivity to tamoxifen treatment. Moreover, in support of our in vitro data, analysis of mRNA microarray data sets demonstrated that high levels of FKBPL and RBCK1 correlated with increased patient survival, whereas high RBCK1 predicted for a poor response to tamoxifen. Our findings support a role for RBCK1 in the regulation of FKBPL with important implications for estrogen receptor signaling, cell proliferation and response to endocrine therapy.

FK506 binding protein 51 (FKBP51, also called FKBP5) belongs to a family of immunophilins, FK506 binding proteins (FKBPs). Members of this family are targets for drugs such as rapamycin and cyclosporine. Although FKBP5 shares characteristics with other FKBPs, it also has unique features, especially its role in the regulation of multiple signalling pathways and in tumourigenesis and chemoresistance. In this review, we will focus on the recently discovered role of FKBP5 in cancer aetiology and response to antineoplastic therapy.

Nephrotic focal segmental glomerulosclerosis (FSGS) represents a difficult therapeutic challenge. FSGS has long been considered a subset of idiopathic nephrotic syndrome, lumping together FSGS and minimal change disease (MCD). The time-honored ‘Shalhoub hypothesis’ has led to treating FSGS as a T-cell-driven condition in which a lymphokine, considered without proof as being the ‘glomerular permeability factor,’ induces proteinuria and podocyte functional and structural derangement. This has led to trying, in addition to steroids, every new drug marketed in the field of organ transplantation, first cyclosporine (CsA) and then other immunophilin modulators. The fact that alkylating agents and mycophenolate mofetil have obtained a poor and inconstant favorable effect, and that rituximab may obtain remissions, although inconstantly, has not led to reconsidering the T-cell hypothesis. This wrong thinking has fostered innumerable, mostly uncontrolled, treatment trials with various immunosuppressive agents. In fact, clinicians have not considered the fact that some but not all immunophilin modulators may be effective as nonspecific antiproteinuric agents, rather than as immunosuppressive drugs, and that treatment success does not exclude a non-immunologic pathophysiology. Recent findings on the mode of action of CsA and FK-506 have lent support to this concept. This review should be considered as a plea to reconsider the pathogenesis of nephrotic FSGS, applying all efforts to the identification of the factor, or factors, responsible for nephrotic FSGS, and to fund treatment to counteract the ‘factor,’ rather than pursuing costly and non-evidence-based immunosuppressive therapeutic trials.

This study evaluated the utility of combinational therapy, coupling delayed posttraumatic hypothermia with delayed FK506 administration, on altered cerebral vascular reactivity, axonal injury, and blood–brain barrier (BBB) disruption seen following traumatic brain injury (TBI). Animals were injured, subjected to various combinations of hypothermic/FK506 intervention, and equipped with cranial windows to assess pial vascular reactivity to acetylcholine. Animals were then processed with antibodies to the amyloid precursor protein and immunoglobulin G to assess axonal injury and BBB disruption, respectively. Animals were assigned to five groups: (1) sham injury plus delayed FK506, (2) TBI, (3) TBI plus delayed hypothermia, (4) TBI plus delayed FK506, and (5) TBI plus delayed hypothermia with FK506. Sham injury plus FK506 had no impact on vascular reactivity, axonal injury, or BBB disruption. Traumatic brain injury induced dramatic axonal injury and altered pial vascular reactivity, while triggering local BBB disruption. Delayed hypothermia or FK506 after TBI provided limited protection. However, TBI with combinational therapy achieved significantly enhanced vascular and axonal protection, with no BBB protection. This study shows the benefits of combinational therapy, using posttraumatic hypothermia with FK506 to attenuate important features of TBI. This suggests that hypothermia not only protects but also extends the therapeutic window for improved FK506 efficacy.

Advances in the neurobiology of growth factors, neural development, and prevention of cell death have resulted in a heightened clinical interest for the development of protective and regenerative neuromodulatory strategies for the cavernous nerves （CNs）, as therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function. Nitric oxide released from the axonal end plates of these nerves within the corpora cavernosa causes relaxation of smooth muscle, initiating the haemodynamic changes of penile erection as well as contributing to maintained tumescence; the loss of CN function is primarily responsible for the development of erectile dysfunction （ED） after pelvic surgery and serves as the primary target for potential neuroprotective or regenerative strategies. Evidence from pre-clinical studies for select neuromodulatory approaches is reviewed, including neurotrophins, glial cell line-derived neurotrophic factors （GDNF）, bone morphogenic proteins, immunophilin ligands, erythropoetin （EPO）, and stem cells.

Cyclosporine A (CsA) is an immunosuppressive cyclic peptide that binds with a high affinity to 18 kDa human cyclophilin-A (hCyPA). CsA and its several natural derivatives have some pharmacological potential in treatment of diverse immune disorders. More than 20 paralogues of CyPA are expressed in the human body while expression levels and functions of numerous ORFs encoding cyclophilin-like sequences remain unknown. Certain derivatives of CsA devoid of immunosuppressive activity may have some potential in treatments of Alzheimer diseases, Hepatitis C and HIV infections, amyotrophic lateral sclerosis, congenital muscular dystrophy, asthma and various parasitic infections. Here, we discuss structural and functional aspects of the human cyclophilins and their interaction with various intra-cellular targets that can be under the control of CsA or its complexes with diverse cyclophilins that are selectively expressed in different cellular compartments. Some molecular aspects of the cyclophilins expressed in parasites invading humans and causing diseases were also analyzed.