Bax is an essential mediator of mitochondria-dependent programed cell death. Bax belongs to the Bcl-2 family of proteins and its activities are regulated through interaction with other member proteins in the Bcl-2 family. To date, several apoptosis-inducing drugs activating Bax have been developed, and some of them are already in the market as therapeutics against cancer. However, at present, there are no clinically effective pharmacological Bax inhibitors protecting essential cells. Previously, we developed Bax-Inhibiting Peptides (BIPs) that belong to the peptide group of Cell-Penetrating Peptides (CPPs). CPPs have the ability to deliver cargo molecules into the cell. In this review, we will describe the mechanism of action of BIPs together with the recent applications of BIPs in disease models in vitro and in vivo. However, BIPs have several limitations in their use to treat human diseases, and other types of Bax inhibitors need to be developed for future therapeutics. Recently, several groups reported the successful development of novel small compounds inhibiting Bax. We will review these Bax inhibitors to discuss current strategies to develop pharmacological Bax inhibitors. Impact statement Bax induces mitochondria-dependent programed cell death. While cytotoxic drugs activating Bax have been developed for cancer treatment, clinically effective therapeutics suppressing Bax-induced cell death rescuing essential cells have not been developed. This mini-review will summarize previously reported Bax inhibitors including peptides, small compounds, and antibodies. We will discuss potential applications and the future direction of these Bax inhibitors.
Eye movements are frequently considered diagnostic markers indicating involvement of the cerebellum. Impaired amplitude of saccades (saccade dysmetria), impaired gaze holding function (horizontal or downbeat nystagmus), and interrupted (choppy) pursuit are typically considered hallmarks of cerebellar disorders. While saccade dysmetria is a frequently considered abnormality, the velocity of saccades are rarely considered part of the constellation of cerebellar involvement. Reduced saccade velocity, frequently called “slow saccades” are typically seen in a classic disorder of the midbrain called progressive supranuclear palsy. It is also traditionally diagnostic of spinocerebellar ataxia type 2. In addition to its common causes, the slowness of vertical saccades is not rare in cerebellar disorders. Frequently this phenomenology is seen in multisystem involvement that substantially involves the cerebellum. In this review we will first discuss the physiological basis and the biological need for high saccade velocities. In subsequent sections we will discuss disorders of cerebellum that are known to cause slowing of saccades. We will then discuss possible pathology and novel therapeutic strategies.
Objectives Pancreatic cancer has a five year survival rate of less than 5%, partly due to limited chemotherapeutic options, thereby highlighting the need for novel therapies. Triptolide, a diterpene triepoxide derived from a Chinese herb has shown great promise in preclinical testing against pancreatic cancer using immune compromised animals. Results In this study, we tested the ability of triptolide to induce cell death in cell lines derived from a primary tumor and adjacent liver metastases of immuno-competent animals (KRasG12D; Trp52R172H; Pdx-1 Cre (KPC)). Both cell lines were more aggressive in their ability to form tumors when compared to other pancreatic cancer cell lines, and showed constitutive activation of the NFkB pathway. Triptolide induced apoptotic cell death in both cell lines, as evidenced by decreased cell viability and increased caspase 3/7 activity, Annexin V positivity, and increased TUNEL positivity in tumors from KPC animals treated with Minnelide. Additionally, triptolide decreased levels of HSP70, its transcription factor HSF1, and the anti-apoptotic proteins Bcl-xL, Bcl-2 and Mcl-1, known to be up-regulated in pancreatic cancer. Conclusion The ability of triptolide to cause cell death in cell lines derived from immune-competent animals further validates its potential as a novel agent against pancreatic cancer.
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