Treatment and prevention of pathological mitochondrial dysfunction in retinal degeneration and in photoreceptor injury.

Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.

Pathogenic mitochondrial dysfunction and metabolic abnormalities.

Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs.

In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.

A New Approach to Treating Neurodegenerative Otologic Disorders.

Hearing loss, the most common neurological disorder and the fourth leading cause of years lived with disability, can have profound effects on quality of life. The impact of this "invisible disability," with significant consequences, economic and personal, is most substantial in low- and middle-income countries, where >80% of affected people live. Given the importance of hearing for communication, enjoyment, and safety, with up to 500 million affected globally at a cost of nearly $800 billion/year, research on new approaches toward prevention and treatment is attracting increased attention. The consequences of noise pollution are largely preventable, but irreversible hearing loss can result from aging, disease, or drug side effects. Once damage occurs, treatment relies on hearing aids and cochlear implants. Preventing, delaying, or reducing some degree of hearing loss may be possible by avoiding excessive noise and addressing major contributory factors such as cardiovascular risk. However, given the magnitude of the problem, these interventions alone are unlikely to be sufficient. Recent advances in understanding principal mechanisms that govern hearing function, together with new drug discovery paradigms designed to identify efficacious therapies, bode well for pharmaceutical intervention. This review surveys various causes of loss of auditory function and discusses potential neurological underpinnings, including mitochondrial dysfunction. Mitochondria mitigate cell protection, survival, and function and may succumb to cumulative degradation of energy production and performance; the end result is cell death. Energy-demanding neurons and vestibulocochlear hair cells are vulnerable to mitochondrial dysfunction, and hearing impairment and deafness are characteristic of neurodegenerative mitochondrial disease phenotypes. Beyond acting as cellular powerhouses, mitochondria regulate immune responses to infections, and studies of this phenomenon have aided in identifying nuclear factor kappa B and nuclear factor erythroid 2-related factor 2/antioxidant response element signaling as targets for discovery of otologic drugs, respectively, suppressing or upregulating these pathways. Treatment with free radical scavenging antioxidants is one therapeutic approach, with lipoic acid and corresponding carnitine esters exhibiting improved biodistribution and other features showing promise. These compounds are also histone deacetylase (HDAC) inhibitors, adding epigenetic modulation to the mechanistic milieu through which they act. These data suggest that new drugs targeting mitochondrial dysfunction and modulating epigenetic pathways via HDAC inhibition or other mechanisms hold great promise.

Gut Microbiota and Salivary Diagnostics: The Mouth Is Salivating to Tell Us Something.

The microbiome of the human body represents a symbiosis of microbial networks spanning multiple organ systems. Bacteria predominantly represent the diversity of human microbiota, but not to be forgotten are fungi, viruses, and protists. Mounting evidence points to the fact that the "microbial signature" is host-specific and relatively stable over time. As our understanding of the human microbiome and its relationship to the health of the host increases, it is becoming clear that many and perhaps most chronic conditions have a microbial involvement. The oral and gastrointestinal tract microbiome constitutes the bulk of the overall human microbial load, and thus presents unique opportunities for advancing human health prognosis, diagnosis, and therapy development. This review is an attempt to catalog a broad diversity of recent evidence and focus it toward opportunities for prevention and treatment of debilitating illnesses.

Epigenetic Treatment of Neurodegenerative Ophthalmic Disorders: An Eye Toward the Future.

Eye disease is one of the primary medical conditions that requires attention and therapeutic intervention in ageing populations worldwide. Further, the global burden of diabetes and obesity, along with heart disease, all lead to secondary manifestations of ophthalmic distress. Therefore, there is increased interest in developing innovative new approaches that target various mechanisms and sequelae driving conditions that result in adverse vision. The research challenge is even greater given that the terrain of eye diseases is difficult to landscape into a single therapeutic theme. This report addresses the burden of eye disease due to mitochondrial dysfunction, including antioxidant, autophagic, epigenetic, mitophagic, and other cellular processes that modulate the biomedical end result. In this light, we single out lipoic acid as a potent known natural activator of these pathways, along with alternative and potentially more effective conjugates, which together harness the necessary potency, specificity, and biodistribution parameters required for improved therapeutic outcomes.

Microbiota and Neurological Disorders: A Gut Feeling.

In the past century, noncommunicable diseases have surpassed infectious diseases as the principal cause of sickness and death, worldwide. Trillions of commensal microbes live in and on our body, and constitute the human microbiome. The vast majority of these microorganisms are maternally derived and live in the gut, where they perform functions essential to our health and survival, including: digesting food, activating certain drugs, producing short-chain fatty acids (which help to modulate gene expression by inhibiting the deacetylation of histone proteins), generating anti-inflammatory substances, and playing a fundamental role in the induction, training, and function of our immune system. Among the many roles the microbiome ultimately plays, it mitigates against untoward effects from our exposure to the environment by forming a biotic shield between us and the outside world. The importance of physical activity coupled with a balanced and healthy diet in the maintenance of our well-being has been recognized since antiquity. However, it is only recently that characterization of the host-microbiome intermetabolic and crosstalk pathways has come to the forefront in studying therapeutic design. As reviewed in this report, synthetic biology shows potential in developing microorganisms for correcting pathogenic dysbiosis (gut microbiota-host maladaptation), although this has yet to be proven. However, the development and use of small molecule drugs have a long and successful history in the clinic, with small molecule histone deacetylase inhibitors representing one relevant example already approved to treat cancer and other disorders. Moreover, preclinical research suggests that epigenetic treatment of neurological conditions holds significant promise. With the mouth being an extension of the digestive tract, it presents a readily accessible diagnostic site for the early detection of potential unhealthy pathogens resident in the gut. Taken together, the data outlined herein provide an encouraging roadmap toward important new medicines and companion diagnostic platforms in a wide range of therapeutic indications.

Effective Precursors for Sulfur Monoxide Formation.

When triphenylmethanesulfenyl chloride (12) (or its thio 13 or dithio homolog 14) are treated with hindered olefins 15 and 16, thiiranes 10 and 11 are produced in high isolated yields (ca. 94%). Treatment of 10 and 11 with m-chloroperoxybenzoic acid (m-CPBA) leads to the formation of thiirane 1-oxides 8 and 9 (99% isolated yields). The structures of 8-11 were established by (1)H and (13)C NMR, mass spectrometry as well as by X-ray. Thermal decomposition of either 8 or 9 smoothly delivers sulfur monoxide to various 1,3-dienes giving cyclic sulfoxides in good yield. A variety of conditions were employed to optimize the yield of the trapped adducts.

Investigation of sulfur extrusion from a cyclic dialkoxy disulfide.

The relationship of cyclic dialkoxy disulfide 11, its thionosulfite isomer 12, and the related sulfoxylate 13 has been examined. Investigations demonstrate an interconversion between thionosulfite 12 and sulfoxylate 13. This sequential transformation brings evidence that a branched-bond sulfur structure is likely involved in sulfur extrusion.

Synthesis of new cyclic dialkoxy disulfides.

Five new cyclic dialkoxy disulfides have been synthesized and fully characterized. An X-ray structure was obtained for the 2,3-furandimethylene dialkoxy disulfide.

Crossover point between dialkoxy disulfides (ROSSOR) and thionosulfites ((RO)2S=S): prediction, synthesis, and structure.

Isomeric preference between cyclic dialkoxy disulfides and thionosulfites is governed by the ring size of the heterocycle. Rings smaller than seven atoms prefer the thionosulfite connectivity, whereas larger rings or acyclic analogues favor the unbranched dialkoxy disulfide structure. Density functional calculations were employed to predict the crossover point at which both constitutional isomers are of comparable stability. Follow-up synthesis provides the previously unknown eight-membered ring dialkoxy disulfide 14 and seven-membered ring thionosulfite 15 from the same reaction. X-ray crystallography for all but one of the reaction products and complementary NMR analysis furnishes insights into both solid-state and solution conformations. A long-standing issue regarding the concerted vs catalyzed isomerization pathway between XSSX and X(2)S=S has been addressed for X = RO and shown to be acid dependent.

Generalized synthesis and physical properties of dialkoxy disulfides.

A substrate study was undertaken in order to probe the scope of S(2)Cl(2) coupling of alcohols to form dialkoxy disulfides. Compounds 1b and 1f are new; along with 1a, 1c, 1h, and 1j, all of the title compounds are fully characterized, and the yields of 1a and 1c have been optimized from previously reported syntheses. The effect of the R-substituent about the OSSO moiety has been carefully probed as yields vary. A substrate and a solvent study of the coalescence behavior of this class was carried out. The origin of the inherently large barrier to rotation and the resultant thermal decomposition pathway is discussed. Both phenomena are shown to be solvent independent; hindered rotation is substrate independent. The decomposition of 1a is ca. 7 kcal/mol higher than the barrier to rotation about the S-S bond. The combined evidence suggests acyclic unsymmetric homolytic cleavage of the dialkoxy disulfide.

Optimization of the synthesis of symmetric aromatic tri- and tetrasulfides.

The reaction of aromatic thiols with sulfur dichloride and sulfur monochloride to form the corresponding aromatic trisulfides, 2a-d, and tetrasulfides, 3a-d, has been optimized with respect to yield and purity. The use of pyridine as an amine base and the use of freshly distilled sulfur monochloride (S(2)Cl(2)) serve as important alterations to the synthetic method. Their physical properties have been characterized, revealing some discrepancies with the literature.

Synthesis of new cyclic thionosulfites.

The reaction of a series of 1,2-diols with S(2)Cl(2), 1,1'-thiobisbenzimidazole (4a), and 1,1'-dithiobisbenzimidazole (4b) provides the corresponding thionosulfites, ROS(S)OR (2), in moderate to good yield.

Insertion of SO(2) into the S-S bond of Cp(2)MoS(2) and Cp(2)MoS(2)O to give molybdocene dithiosulfate and bis(O-alkylthiosulfates).

Cp(2)MoS(2), 3, reacts with SO(2) in CH(2)Cl(2)/EtOH mixtures to give Cp(2)MoS(3)O(2), 4, wherein the SO(2) has inserted into the S-S bond to give a dithiosulfate ligand. Crystal data for 4: P2(1)/n, a = 7.6782(6) A, b = 14.580(3) A, c = 10.2730(10) A, beta = 92.04(1) degrees, V = 1149(3) A(3), Z = 4. Cp(2)MoS(2)O, 5, reacts with SO(2) in CH(2)Cl(2) to give low yields of 4 plus other identified products. 5 reacts with SO(2) in MeOH and EtOH to give the corresponding bis(O-alkylthiosulfate), 6a and 6b, respectively. Crystal data for 6a: P 1 macro, a = 8.3226(13) A, b = 8.4736(11) A, c = 12.382(2) A, alpha = 87.803(11) degrees, beta = 77.758(11) degrees, gamma = 86.383(12) degrees, V = 851.4(2) A(3), Z = 2.

Identification of carbonyl sulfide and sulfur dioxide in porcine coronary artery by gas chromatography/mass spectrometry, possible relevance to EDHF.

Incubation of porcine coronary artery rings and cardiac muscle tissue in Krebs buffer followed by GC/MS analysis of the headspace gas revealed two gases, carbonyl sulfide (COS) and sulfur dioxide (SO(2)). The gases were identified by characteristic ions obtained by electron ionization, and by comparison of the retention time on a chromatographic column (GS GasPro) with standards of these gases. Stimulation of the arterial rings with acetylcholine and calcium ionophore A23187 increased the levels of SO(2) and COS in the vascular tissue. We also provide evidence that SO(2) could originate from disproportionation of a very unstable gas, sulfur monoxide (S=O). We suggest potential origins of these gases and discuss their relevance to endothelium-derived hyperpolarizing factor.

Dicubyl disulfide.

Dicubyl disulfide (1) has been prepared in six steps from commercially available dimethyl-1,4-cubanedicarboxylate in 47% overall yield. In the final step, the previously unknown cubanethiol 2 was oxidized to disulfide 1. X-ray crystallography for 1 reveals the shortest tetragonal C-S bond on record (1.771 A). In contrast to previous generalizations, density functional theory calculations predict a low S-S rotation barrier similar to that for t-BuSSBu-t. Low-temperature (13)C NMR (600 MHz) confirms the prediction.