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Summary: Background: Insulin resistance and lipotoxicity are extremely interconnected but fundamental in setting the stage for the development of MASLD/MASH. Aim/Methods: A comprehensive literature search was performed and key themes were synthesised to provide insight into the underlying molecular mechanisms of insulin resistance and lipotoxicity in the liver, muscle, pancreas and adipose tissue and how organ cross‐talk is fundamental to driving disease pathogenesis. Results: Classical thinking postulates that excess FFA load exceeds the storage capacity of adipose tissue, which is predicated upon both genetic and environmental factors. This results in insulin resistance and compensatory hyperinsulinaemia by pancreatic beta cells to overcome target organ insulin resistance. As adipocyte dysfunction worsens, not only are excess FFA delivered to other organs, including skeletal muscle, pancreas and liver but a pro‐inflammatory milieu is established with increases in IL‐6, TNF‐α and changes in adipokine levels (increased leptin and decreased adiponectin). With increased intramuscular lipid accumulation, lipotoxic species decrease insulin signalling, reduce glucose uptake by downregulation of GLUT4 and decrease glycogen synthesis. With this additional reduced capacity, hyperglycaemia is further exacerbated and increased FFA are delivered to the liver. The liver has the largest capacity to oxidise fat and to adapt to these stressors and, therefore, has become the last line of defence for excess lipid storage and utilisation, the capacity of which may be impacted by genetic and environmental factors. However, when the liver can no longer keep up with increasing FFA delivery and DNL, lipotoxic species accumulate with ensuing mitochondrial dysfunction, increased ER stress, oxidant stress and inflammasome activation, all of which drive hepatocyte injury and apoptosis. The resulting wound healing response, marked by stellate cell activation, drives collagen accumulation, progressive fibrosis, and, ultimately, end organ failure and death. This vicious cycle and complex interplay between insulin resistance, hyperinsulinaemia, lipotoxicity and multi‐directional cross‐talk among different target organs are critical drivers of MASLD/MASH. Conclusions: Targeting tissue‐specific insulin resistance and hyperinsulinaemia while decreasing FFA load (lipotoxicity) through dietary and lifestyle changes remain the best upstream interventions. [ABSTRACT FROM AUTHOR]

Background: Vestibular evoked myogenic potential (VEMP) is a test to assess the functioning of otolith organs of the inner ear. Cervical VEMPs (cVEMPs) assess the saccule and the inferior vestibular nerve, whereas ocular VEMPs (oVEMPs) assess the utricle and superior vestibular nerve. In individuals with sensorineural hearing loss, disturbances of cochlear function could accompany vestibular impairment since both these parts of the inner ear are anatomically related. The aim of the present study was to find out the prevalence of cVEMPs and oVEMPs in individuals with congenital severe to profound sensorineural hearing loss. Material and methods: There were 46 participants in the present study: 23 with normal hearing and 23 with bilateral severe to profound hearing loss, and cVEMPs and oVEMPs were recorded from all of them. Results: cVEMPs were present in 100% of subjects, both in the control and experimental groups; oVEMPs were present in 100% of the control and 66% of the experimental group. In hearing impaired individuals no correlation was found between cVEMPs and oVEMPs, although a Mann-Whitney test revealed that the amplitude of cVEMPs and oVEMPs were significantly smaller in the hearing impaired group compared to normals. Conclusions: The results indicate impairment of both utricular and saccular function in individuals with severe to profound hearing loss. Also oVEMPs were absent in more individuals compared to cVEMPs, which suggests that utricular function is more linked with the cochlea compared to that of the saccule. [ABSTRACT FROM AUTHOR]

Abstract: The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the αv-integrins αvβ3 and αvβ5 is described. High-throughput screening of an extensive series of ECLiPS™ compound libraries led to the identification of compound 1 as a dual inhibitor of the αv-integrins αvβ3 and αvβ5. Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the αvβ3 and αvβ5 integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile. [Copyright &y& Elsevier]

Conformationally restricted 2'-spironucleosides and their prodrugs were synthesized as potential anti-HCV agents. Although the replicon activity of the new agents containing pyrimidine bases was modest, the triphosphate of a 2'-oxetane cytidine analogue demonstrated potent intrinsic biochemical activity against the NS5B polymerase, with IC50 = 8.48 μM. Activity against NS5B bearing the S282T mutation was reduced. Phosphoramidate prodrugs of a 2'-oxetane 2-amino-6-O-methyl-purine nucleoside demonstrated potent anti-HCV activity in vitro, and the corresponding triphosphate retained similar potent activity against both wild-type and S282T HCV NS5B polymerase.

Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1alpha (MIP-1alpha) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC(50) of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.