The present invention relates to use of an aminomethylenecyclohexane-1,3-dione compound, more particularly to use of a compound shown in the following formula (I) or a pharmaceutically acceptable salt thereof alone or in combination with other drug in preparing a drug for regulating or treating a disease related to autophagy, especially mammalian ATG8 homologous proteins. ##STR00001##

The present disclosure provides pharmaceutical combinations comprising at least one spliceosome modulator and at least one inhibitor chosen from BCL2, BCL2/BCLxL, and BCLxL inhibitors. Also provided are methods of treating cancer comprising administering a therapeutically effective amount of at least one spliceosome modulator and a therapeutically effective amount of at least one inhibitor chosen from BCL2, BCL2/BCLxL, and BCLxL inhibitors.

The present disclosure provides pharmaceutical combinations comprising at least one spliceosome modulator and at least one inhibitor chosen from BCL2, BCL2/BCLxL, and BCLxL inhibitors. Also provided are methods of treating cancer comprising administering a therapeutically effective amount of at least one spliceosome modulator and a therapeutically effective amount of at least one inhibitor chosen from BCL2, BCL2/BCLxL, and BCLxL inhibitors.

A method for preventing or reducing adverse effects such as profuse sweating, nausea and vomiting, which normally are associated with subcutaneous and intravenous administration of glucagon-like peptide 1 (GLP-1) therapy is provided. In particular, the method comprises the rapid administration of a GLP-1 formulation into the pulmonary circulation such as by inhalation, directly into pulmonary alveolar capillaries using a dry powder drug delivery system.

A method for preventing or reducing adverse effects such as profuse sweating, nausea and vomiting, which normally are associated with subcutaneous and intravenous administration of glucagon-like peptide 1 (GLP-1) therapy is provided. In particular, the method comprises the rapid administration of a GLP-1 formulation into the pulmonary circulation such as by inhalation, directly into pulmonary alveolar capillaries using a dry powder drug delivery system.

Heart failure with preserved ejection fraction (HFpEF) which results from diastolic dysfunction is a growing epidemiologic problem. However, the pathophysiology of this disease is poorly understood. Our goal is to investigate whether microvessel disease may promote HFpEF. To do so we have used Leptin receptor deficient (Lepr.sup.db/db) female mice as a model of HFpEF and performed a transcriptomic analysis via RNA sequencing of the cardiac vascular fraction of both these mice and their control Lepr.sup.db/+littermates. In Lepr.sup.db/db female mice, end diastolic pressure (EDP) signing diastolic dysfunction is significantly increased from 3 month of age. It is correlated with a cardiac and cardiomayocyte hypertrophy, vascular leakage, endothelial cell activation and leucocyte infiltration. As expected, the RNA sequencing analysis confirmed endothelial dysfunction. Besides, it also revealed a strong increase in several mast cell markers. We confirmed, via histology, an accumulation of mast cells in the heart of Lepr.sup.db/db mice. Importantly, it was associated with increased levels of circulating IgE. Lepr.sup.db/db mice were then treated or not with Cromolyn sodium, an inhibitor of mast cell degranulation. After a month treatment, EDP was significantly reduced in Lepr.sup.db/db mice demonstrating the critical role of mast cell in the development of diastolic dysfunction in diabetic obese mice.

Heart failure with preserved ejection fraction (HFpEF) which results from diastolic dysfunction is a growing epidemiologic problem. However, the pathophysiology of this disease is poorly understood. Our goal is to investigate whether microvessel disease may promote HFpEF. To do so we have used Leptin receptor deficient (Lepr.sup.db/db) female mice as a model of HFpEF and performed a transcriptomic analysis via RNA sequencing of the cardiac vascular fraction of both these mice and their control Lepr.sup.db/+littermates. In Lepr.sup.db/db female mice, end diastolic pressure (EDP) signing diastolic dysfunction is significantly increased from 3 month of age. It is correlated with a cardiac and cardiomayocyte hypertrophy, vascular leakage, endothelial cell activation and leucocyte infiltration. As expected, the RNA sequencing analysis confirmed endothelial dysfunction. Besides, it also revealed a strong increase in several mast cell markers. We confirmed, via histology, an accumulation of mast cells in the heart of Lepr.sup.db/db mice. Importantly, it was associated with increased levels of circulating IgE. Lepr.sup.db/db mice were then treated or not with Cromolyn sodium, an inhibitor of mast cell degranulation. After a month treatment, EDP was significantly reduced in Lepr.sup.db/db mice demonstrating the critical role of mast cell in the development of diastolic dysfunction in diabetic obese mice.

Compounds of formulae (I) and (II), compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo.

##STR00001##

Compounds of formulae (I) and (II), compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo.

##STR00001##

Provided herein are methods and formulations for reducing viability of a cancer or enhancing susceptibility of a cancer to an anti-cancer agent. The method includes administering to the subject an effective amount of an anti-parasitic agent and an autophagy inhibitor to the subject. Additionally or optionally, the method further includes administering to the subject the anti-cancer agent. Also provided herein are formulations for the treatment of cancers, particularly cancers that are unresponsive to anti-cancer agents. The formulation includes at least two agents selected from the group consisting of an anti-parasitic agent, an autophagy inhibitor and an HDAC inhibitor; and a pharmaceutically acceptable excipient.