Mitochondrial autophagy plays an important role in maintaining the complexity of mitochondrial functions and removing damaged mitochondria, of which the PINK1-Parkin signal pathway is one of the most classical pathways. Thus, a comprehensive and in-depth interpretation of the PINK1-Parkin signal pathway might deepen our understanding on the impacts of mitochondrial autophagy. Alzheimer\'s disease (AD) is a classical example of neurodegenerative disease. Research on the pathogenesis and treatments of AD has been a focus of scientific research because of its complexity and the limitations of current drug therapies. It was reported that the pathogenesis of AD might be related to mitochondrial autophagy due to excessive deposition of Aβ protein and aggravation of the phosphorylation of Tau protein. Two key proteins in the PINK1-Parkin signaling pathway, PINK1 and Parkin, have important roles in the folding and accumulation of Aβ protein and the phosphorylation of Tau protein. In addition, the intermediate signal molecules in the PINK1-Parkin signal pathway also have certain effects on AD. In this paper, we first described the role of PINK1-Parkin signal pathway on mitochondrial autophagy, then discussed and analyzed the effect of the PINK1-Parkin signal pathway in AD and other metabolic diseases. Our aim was to provide a theoretical direction to further elucidate the pathogenesis of AD and highlight the key molecules related to AD that could be important targets used for AD drug development.

UNASSIGNED: RIPK1 is a critical mediator of inflammation and cell death, which is associated with extensive neurodegenerative and inflammatory diseases. Recently, RIPK1 has aroused the interests of pharmaceutical industry and research institutions.
UNASSIGNED: This review focuses on patent literature covering small-molecule inhibitors of RIPK1 since 2018. SciFinder and PubMed databases were used for patent and literature searching.
UNASSIGNED: Studies of RIPK1 inhibitors for the necroptosis pathway have increased dramatically in recent years. To date, dozens of RIPK1 inhibitors have been reported, and several have entered clinical studies. However, the development of RIPK1 inhibitors is still at a preliminary stage. An understanding of the dosage and disease indications of RIPK1 inhibitors, rational structural optimization, and the optimal clinical setting for new structures will require feedback from further clinical trials. Recently, compared with type III inhibitors, the patents on type II inhibitors have dramatically increased. Most of them contain hybrid structures of type II/III inhibitors occupying the ATP-binding pocket and the back hydrophobic pocket of RIPK1. Patents of RIPK1 degraders were also disclosed, but the role of RIPK1 kinase- independent and dependent in promoting cell death and diseases must be considered.

The p-21-activated kinase 1 (PAK1) protein, encoded by the PAK1 gene, is an evolutionarily conserved serine/threonine-protein kinase that regulates key cellular developmental processes. To date, seven de novo PAK1 variants have been reported to cause the Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). In addition to the namesake features, other common characteristics include structural brain anomalies, delayed development, hypotonia, and dysmorphic features. Here, we report a de novo PAK1 NM_002576.5: c.1409 T > A variant (p.Leu470Gln) identified by trio genome sequencing (GS) in a 13-year-old boy with postnatal macrocephaly, obstructive hydrocephalus, medically refractory epilepsy, spastic quadriplegia, white matter hyperintensities, profound developmental disabilities, and a horseshoe kidney. This is the first recurrently affected residue identified in the protein kinase domain. Combined assessment of the eight pathogenic PAK1 missense variants reveal that the variants cluster in either the protein kinase or autoregulatory domains. Although interpretation of the phenotypic spectrum is limited by the sample size, neuroanatomical alterations were found more often in individuals with PAK1 variants in the autoregulatory domain. In contrast, non-neurological comorbidities were found more often in individuals with PAK1 variants in the protein kinase domain. Together, these findings expand the clinical spectrum of PAK1-associated IDDMSSD and reveal potential correlations with the affected protein domains.

Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the DMPK gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.

CIPKs are a subclass of serine/threonine (Ser/Thr) protein kinases. CBLs are ubiquitous Ca2+ sensors that interact with CIPK with the aid of secondary Ca2+ messengers for regulation of growth and development and response to stresses faced by plants. The divergent roles of the CIPK-CBL interaction in plants include responding to environmental stresses (salt, cold, drought, pH, ABA signaling, and ion toxicity), ion homeostasis (K+, NH4 +, NO3 -, and microelement homeostasis), biotic stress, and plant development. Each member of this gene family produces distinct proteins that help plants adapt to diverse stresses or stimuli by interacting with calcium ion signals. CIPK consists of two structural domains-an N-terminal domain and a C-terminal domain-connected by a junction domain. The N-terminal domain, the site of phosphorylation, is also called the activation domain and kinase domain. The C-terminal, also known as the regulatory domain of CIPK, further comprises NAF/FISL and PPI. CBL comprises four EF domains and conserved PFPF motifs and is the site of binding with the NAF/FISL domain of CIPK to form a CBL-CIPK complex. In addition, we also performed a bibliometric analysis of the CIPK gene family of data extracted from the WoSCC. A total of 95 documents were retrieved, which had been published by 47 sources. The production over time was zigzagged. The top key terms were gene, CIPK, abiotic stress, and gene expression. Beijing Forestry University was the top affiliation, while The Plant Cell was the top source. The genomics and metabolomics of this gene family require more study.

Eryptosis is a coordinated non-lytic cell death of erythrocytes characterized by cell shrinkage, cell membrane scrambling, Ca2+ influx, ceramide accumulation, oxidative stress, activation of calpain and caspases. Physiologically, it aims at removing damaged or aged erythrocytes from circulation. A plethora of diseases are associated with enhanced eryptosis, including metabolic diseases, cardiovascular pathology, renal and hepatic diseases, hematological disorders, systemic autoimmune pathology, and cancer. This makes eryptosis and eryptosis-regulating signaling pathways a target for therapeutic interventions. This review highlights the eryptotic signaling machinery containing several protein kinases and its small molecular inhibitors with a special emphasis on casein kinase 1α (CK1α), a serine/threonine protein kinase with a broad spectrum of activity. In this review article, we provide a critical analysis of the regulatory role of CK1α in eryptosis, highlight triggers of CK1α-mediated suicidal death of red blood cells, cover the knowledge gaps in understanding CK1α-driven eryptosis and discover the opportunity of CK1α-targeted pharmacological modulation of eryptosis. Moreover, we discuss the directions of future research focusing on uncovering crosstalks between CK1α and other eryptosis-regulating kinases and pathways.

Therapeutic ultrasound (TUS) is the ultrasound modality widely used in physical therapy for the treatment of acute and chronic injuries of various biological tissues. Its thermal and mechanical effects modify the permeability of the plasma membrane, the flow of ions and molecules and cell signaling and, in this way, promote the cascade of physiological events that culminate in the repair of injuries. This article is a review of the biochemical and physiological effects of TUS with parameters commonly used by physical therapists. Integrins can translate the mechanical signal of the TUS into a cellular biochemical signal for protein synthesis and modification of the active site of enzymes, so cell function and metabolism are modified. TUS also alters the permeability of the plasma membrane, allowing the influx of ions and molecules that modulate the cellular electrochemical signaling pathways. With biochemical and electrochemical signals tampered with, the cellular response to damage is then modified or enhanced. Greater release of pro-inflammatory factors, cytokines and growth factors, increased blood flow and activation of protein kinases also seem to be involved in the therapeutic response of TUS. Although a vast number of publications describe the mechanisms by which TUS can interact with the biological system, little is known about the metabolic possibilities of TUS because of the lack of standardization in its application.

Phosphorylation facilitates the regulation of all fundamental biological processes, which has triggered extensive research of protein kinases and their roles in human health and disease. In addition to their phosphotransferase activity, certain kinases have evolved to adopt additional catalytic functions, while others have completely lost all catalytic activity. We searched the Universal Protein Resource Knowledgebase (UniProtKB) database for bifunctional protein kinases and focused on kinases that are critical for bacterial and human cellular homeostasis. These kinases engage in diverse functional roles, ranging from environmental sensing and metabolic regulation to immune-host defense and cell cycle control. Herein, we describe their dual catalytic activities and how they contribute to disease pathogenesis.

Drugs that modulate previously unexplored targets could potentially slow or halt the progression of neurodegenerative diseases. Several candidate proteins lie within the dark kinome, those human kinases that have not been well characterized. Much of the kinome (~80%) remains poorly studied, and these targets likely harbor untapped biological potential.
This review highlights the significance of kinases as mediators of aberrant pathways in neurodegeneration and provides examples of published high-quality small molecules that modulate some of these kinases.
There is a need for continued efforts to develop high-quality chemical tools to illuminate the function of understudied kinases in the brain. Potent and selective small molecules enable accurate pairing of an observed phenotype with a protein target.
The examples discussed herein support the premise that validation of therapeutic hypotheses surrounding kinase targets can be accomplished via small molecules and they can serve as the basis for disease-focused drug development campaigns.

Schistosoma mansoni worms are under a milieu of external and internal signaling pathways. The life-cycle stages are exposed to enormous stimuli within the mammalian and the snail hosts and as free-living stages in the fresh water. Furthermore, there is a unique interplay between the male and the female worms involving many stimuli from the male essential for full development of the female. PI3K/Akt/mTOR is an evolutionarily divergent signal transduction pathway universal to nearly every multicellular organism. This work reviews the Schistosoma mansoni PI3K/Akt/mTOR signal pathways and the involvement of the signal in the worms\' physiology concerning the uptake of glucose, reproduction and survival. The inhibitors of the signal pathway used against Schistosoma mansoni were summarized. Given the importance of the PI3K/Akt/mTOR signal pathway, its inhibition could be a promising control strategy against schistosomiasis.