Cardiorenal syndrome (CRS) represents a complex interplay of pathophysiological processes that create a self-perpetuating cycle of heart and kidney dysfunction. While it is clearly understood how hemodynamic changes connect pathogenesis in the two organs, other processes are also in play. Some are the structural changes involving both the cellular and extracellular compartments that precede functional alterations. Fibrosis, which is initiated by an inflammatory response triggering myofibroblast activation and excessive extracellular matrix production, is a common denominator of heart and kidney pathology in CRS. This review focuses on fibroblast activities as a crucial factor in disease onset and progression in CRS. We explore how fibrosis in one organ can trigger or worsen dysfunction in the other organ, and we describe the key pathological signaling pathways of cardiorenal fibrosis, the extracellular matrix-derived biomarkers that can aid clinical management and drug development, and the therapeutic opportunities that can be beneficial in CRS by targeting fibroblast activities.

The discovery of leptin as an adipocyte-secreted hormone encoded by the ob gene whose absence produces severe obesity that is corrected by leptin repletion in both mice and humans was a transformative event in metabolic science. Leptin's discovery in 1994 accelerated the identification of central neuronal circuitry responsive to peripheral signals that regulate energy balance as well as metabolic, neuroendocrine, and other vital functions. Leptin's primary physiological role was initially viewed as preventing obesity by its levels rising, but subsequent research has emphasized the key role of falling levels to signal starvation. Resistance to leptin action, though partial, characterizes common forms of obesity. Despite much being learned about leptin signal transduction over 30 years, the precise molecular mechanisms for leptin resistance and common obesity remain unclear. Leptin therapy is effective in rare patients with congenital leptin deficiency and other low leptin conditions but not common obesity. Interestingly, reducing hyperleptinemia may prove useful in treating common obesity.

Most scenarios that seek to predict the responses of terrestrial mammals to climate change focus on the direct thermal effects of higher ambient temperatures. Measurements from free-living mammals reveal that the physiological challenge for many terrestrial mammals facing climate change will arise from the compound effects of higher heat loads, reduced water, and reduced energy intake. Deaths from climate change, particularly for large mammals, are more likely to result from starvation than from heat stroke. The extent of heterothermy exhibited by a mammal, which results from the relaxation of temperature regulation in response to demands from competing homeostatic systems, provides an index of its physiological welfare and, therefore, a tool to assess sensitivity and responses to climate change. Studies of responses to heat in laboratory or captive individuals can identify what mammals can achieve physiologically, but they do not necessarily reveal what an animal will actually do in its natural habitat.

Cell division is essential for organismal growth and development and is associated with changes in signaling dynamics, including Ca2+ signaling, to meet structural, functional, and energetic needs. The process of cell division must ensure equal separation of both the genetic material and cellular organelles. Organelle segregation to the daughter cells is in most cases associated with their remodeling to support equal distribution. Here, we review the concurrent remodeling of organelles and Ca2+ signaling during cell division. Interesting patterns emerge, showing that organelle dynamics, specifically the plasma membrane, endoplasmic reticulum, and mitochondria, underlie Ca2+ signaling remodeling during cell division.

Clearance of waste products from brain metabolism and by-products of brain injury is a fundamental aspect of normal brain function. Impaired clearance may cause accumulation of proteins and other substances that are harmful to the brain. Abnormal protein aggregation due to clearance failure is a hallmark of neurodegenerative and dementia diseases. Cerebral clearance processes rely on multiple mechanisms; in recent years, it has become increasingly evident that brain fluids, primarily by the exchange of cerebrospinal fluid (CSF) and interstitial fluid, are essential for removing cerebral waste products. These fluids are integral to the glymphatic clearance system operating along perivascular pathways and clearance via meningeal lymphatic pathways. Translational human imaging research has bridged observations from animals to humans but also revealed species differences. CSF influx to the brain is enhanced by a compartmentalized subarachnoid space, and solute efflux from brain is highly dependent on CSF efflux, mainly to meningeal lymphatic vessels.

Hypertrophic cardiomyopathy (HCM) is the most common myocardial genetic disease characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction with preserved or elevated ejection fraction. Thirty-five years after the identification of the first genetic variant in myosin heavy chain 7, other variants have been discovered in numerous components of the sarcomere, pointing to a primary defect in cardiomyocyte contractility. Still, a large portion of HCM patients does not have a pathogenic variant and others present with LVH of another genetic origin. Research has uncovered a primary driver of hypercontractility at the sarcomere level and diverse molecular and cellular mechanisms contributing to HCM, including alterations of calcium handling and proteolysis, microtubule modifications, energy deficiency, and the impact of noncardiomyocyte cell types. These discoveries have fueled preclinical and translational research, leading to the development of myosin inhibitors, which are now on the market, and gene-based therapeutic products. This review summarizes current knowledge on the genetics, mechanisms, and targeted treatments of HCM.

Polycyclic aromatic hydrocarbons (PAHs) are released into the environment primarily through industrial processes and the incomplete combustion of organic matter. Their persistence in air, water, and soil facilitates widespread environmental distribution and exposure that directly impact the health of humans, other animals, and ecosystems. In recent years, the 3-ringed PAH phenanthrene has drawn particular interest for its specific cardiotoxicity. Phenanthrene can be transformed in the environment and within the body, leading to metabolites that can also influence heart function. Phenanthrene and its derivatives alter the electrical activity of the heart by inhibiting repolarizing (e.g., I K) currents and inhibiting depolarizing (e.g., I Na and I Ca) currents, which increase the probability of arrhythmias. Phenanthrene and its derivatives also impact cardiac contractility by reducing the amplitude of the intracellular Ca2+ transient in all species examined to date. This review begins by describing the sources and sinks of environmental phenanthrene and how it enters and accumulates within organisms. It then focuses on the potential for, and mechanisms of, modulation of cardiac activity by phenanthrene and its derivatives at the molecular, cellular, intact heart, and whole organism levels. The results provide a comprehensive summary of the propensity of phenanthrene to modulate vertebrate cardiac function, from fish exposed via crude oil to humans breathing polluted air.

Optogenetics and chemogenetics have transformed how physiologists interrogate biological systems by enabling precise control over protein activity and cellular function. Optogenetics uses light-sensitive proteins for rapid and localized control, while chemogenetics employs small molecules to trigger or block specific pathways with systemic and sustained effects. These tools have advanced research in areas such as brain function, heart rhythm, immune response, and gene regulation. They have been applied to disease models that include epilepsy, metabolic and cardiovascular diseases, immunoinflammatory disorders, and cancer. Clinical applications are emerging, such as optogenetic therapies for vision restoration and chemogenetic safety switches in engineered immune cells. In this review, we categorize these tools by their mechanisms of action, compare their advantages and limitations, and discuss strategies to improve their precision, efficiency, and translational capability. As these technologies continue to evolve, they offer powerful approaches to dissect complex physiological processes and drive innovative therapeutic interventions.

Life on earth evolved under daily cycles of sunlight, and all species developed mechanisms for detecting and responding to solar wavelengths reaching the surface of the earth. Early phototransduction studies found that our eyes detect visible wavelengths using light-activated G protein-coupled receptors named opsins. Many years after discovering the mechanisms by which rhodopsin (opsin 2) and the cone opsins (opsin 1) mediate vision, three other members of the opsin family (opsins 3, 4, and 5) were identified and, surprisingly, found to be expressed in the brain and peripheral organs. Named nonvisual opsins (NVOs), these receptors mediate physiological light responses, such as pupillary light reflex and circadian rhythms. NVOs have been the focus of an increasing number of extraocular phototransduction studies, illuminating novel ways in which light modulates human physiology. This review summarizes our current knowledge on signaling mechanisms mediating nonvisual photoreception and their physiological functions.