COVID-19 vaccination does not affect male sexual functions.

BACKGROUND: COVID-19 infection has been linked with erectile dysfunction, which has also raised apprehensions about the impact of COVID-19 vaccination on male sexual functions. The purpose of this study was to investigate the impact of COVID-19 vaccination on male sexual functions, such as erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. METHODS: We used International Index of Erectile Function (IIEF) questionnaire for data collection. Mixed methods were adopted for this study, which consisted of Google online form distribution and the distribution of hard copies of the form to those who were not internet friendly. All data were entered in a spreadsheet and scores were assigned to each response according to the standard scores given in the IIEF questionnaire. Fifteen questions, one corresponding to each question in the IIEF questionnaire, were included to assess the impact of COVID-19 vaccination on each sexual function. RESULTS: In the first part of analysis, we calculated sexual function scores and men reporting low sexual function scores (~ 15%) were excluded, providing us with 465 individuals for further analysis. Regarding the impact of COVID-19 vaccination on male sexual functions, 71% individuals reported no impact, 3% reported a decline, 2.7% reported an improvement, and 23.3% could not assess the impact. We also performed analysis on the basis of age-groups of the participants and the duration after vaccination, finding that there was no impact irrespective of the age of subjects or the length of period after vaccination. CONCLUSIONS: COVID-19 vaccination does not affect male sexual functions, including erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall sexual satisfaction.

Relationship between visual and neurodevelopmental measures at 2 years with visual acuity and stereopsis at 4.5 years in children born at risk of neonatal hypoglycaemia.

PURPOSE: Mild to moderate vision loss affects many children and can negatively impact a child's early literacy and academic achievement. Nevertheless, there is no consensus on which factors present in early childhood indicate the need for long-term ophthalmic follow up, particularly in children with a history of perinatal adversity. This study identified the relationship between visual, cognitive, motor and demographic factors at 2 years of age and visual acuity (VA) and stereoacuity at 4.5 years of age. METHODS: Five hundred sixteen children identified as being at risk of neonatal hypoglycaemia were recruited soon after birth. At 2 years of age, binocular VA, stereoacuity and non-cycloplegic refraction were measured and a clinical neuro-developmental assessment with the Bayley Scales of Infant Development III (BSID-III) was conducted by a trained examiner. Monocular VA and stereoacuity were measured at 4.5 years of age. RESULTS: Three hundred twenty-eight children completed both the 2 and 4.5 year vision and neurodevelopmental assessments. Multiple linear regression showed oblique astigmatism and motor function at 2 years were significantly associated with VA at 4.5 years of age, while spherical equivalent refraction, motor scores and stereoacuity at 2 years were significantly associated with stereoacuity at 4.5 years of age. BSID-III motor scores had the best sensitivity (81.8%) and specificity (51.5%) for identifying impaired stereoacuity at 4.5 years. However, all measures at 2 years were poorly associated with VA at 4.5 years old. CONCLUSION: Vision and neurodevelopmental measures at 2 years were poorly associated with visual function at 4.5 years of age. However, lower scores on tests of motor function at 2 years may be associated with vision abnormalities, particularly reduced stereopsis, at 4.5 years of age and referral for comprehensive vision assessment for these children may be warranted.

Family-acquired photographs for the evaluation of pediatric head shape via telemedicine: an analysis of photograph quality.

OBJECTIVE: Telemedicine can be an effective tool for the evaluation of the pediatric patient with a cranial deformity, but it increases the reliance of neurosurgical providers on data provided by patients and families. Family-acquired photographs, in particular, can be used to augment the evaluation of pediatric head shape abnormalities via telemedicine, but photographs of sufficient quality are necessary. Here, the authors systematically reviewed the quality and utility of family-acquired photographs for patients referred to their pediatric neurosurgery clinic for telemedicine-based head shape evaluations. METHODS: All telemedicine encounters that were completed for head shape abnormalities at the authors' institution between May 2020 and December 2021 were retrospectively reviewed. Instructions were sent to families prior to each visit with examples of ideal photographs. Three orthogonal views of the patient's head-frontal, lateral, and vertex-were requested. Data were collected regarding demographics, diagnosis, follow-up, and photograph quality. Quality variables included orthogonality of each requested view, appropriate distance, appropriate lighting, presence of distracting elements, and whether hair obscured the head shape. RESULTS: Overall, 565 patients had 892 visits during the study period. A total of 1846 photograph requests were made, and 3335 photographs were received for 829 visits. Of 2676 requested orthogonal views, 1875 (70%) were received. Of these, 1826 (97%) had adequate lighting, 1801 (96%) had appropriate distance, and 1826 (97%) had no distracting features. Hair did not obscure the head shape on the vertex view in 557 visits with orthogonal vertex views (82%). In-person follow-up was requested for further medical evaluation in 40 visits (5%). CONCLUSIONS: The family-acquired photographs in this series demonstrated high rates of adequate lighting and distance, without distracting features. Lack of orthogonality and obscuration of the head shape by hair, however, were more common issues. Family education prior to the visit may improve the quality of family-acquired photographs but requires an investment of time by medical staff. Efforts to further improve photographic quality will facilitate efforts to perform craniometric evaluations through telemedicine visits.

Transcranial random noise stimulation and exercise do not modulate ocular dominance plasticity in adults with normal vision.

Short-term deprivation of one eye by monocular patching causes a temporary increase in the contribution of that eye to binocular vision when the eye patch is removed. This effect, known as ocular dominance plasticity, provides a model of neuroplasticity within the human binocular visual system. We investigated whether physical exercise and the non-invasive brain stimulation technique transcranial random noise stimulation (tRNS), two interventions that may increase visual cortex neuroplasticity, enhance ocular dominance plasticity when delivered individually or in combination. Ocular dominance was measured using a grating rivalry test and a dichoptic letter contrast polarity judgment test. We observed robust ocular dominance changes for both outcome measures following 2-hour monocular deprivation; however, the magnitude of the effect was not influenced by exercise or tRNS. Ocular dominance plasticity may already be maximal after 2 hours of monocular deprivation in those with normal vision and therefore cannot be augmented by interventions designed to enhance neuroplasticity.

Continuous theta burst TMS of area MT+ impairs attentive motion tracking.

Attentive motion tracking deficits measured using multiple object tracking (MOT) tasks have been identified in a number of neurodevelopmental disorders such as amblyopia and autism. These deficits are often attributed to the abnormal development of high-level attentional networks. However, neuroimaging evidence from amblyopia suggests that reduced MOT performance can be explained by impaired function in motion-sensitive area MT+ alone. To test the hypothesis that a subtle disruption of MT+ function could cause MOT impairment, we assessed whether continuous theta burst stimulation (cTBS) of MT+ influenced MOT task accuracy in individuals with normal vision. The MOT stimulus consisted of four target and four distractor dots and was presented at ±10° eccentricity (right/left hemifield). fMRI-guided cTBS was applied to left MT+. Participants (n = 13, age: 27 ± 3) attended separate active and sham cTBS sessions where the MOT task was completed before, 5-min post- and 30-min post-cTBS. Active cTBS significantly impaired MOT task accuracy relative to baseline for the right (stimulated) hemifield 5-min (10 ± 2% reduction) and 30-min (14 ± 3% reduction) post-stimulation. No impairment occurred within the left (control) hemifield after active cTBS or for either hemifield after sham cTBS. These results highlight the importance of lower level motion processing for MOT, suggesting that a minor disruption of MT+ function alone is sufficient to cause a deficit in MOT performance.

Arsenic exposure from drinking water and staple food (rice): A field scale study in rural Bengal for assessment of human health risk.

Arsenic is a well-known carcinogen with emerging reports showing a range of health outcomes even for low to moderate levels of exposure. This study deals with arsenic exposure and associated increased lifetime cancer risk for populations in arsenic-endemic regions of rural Bengal, where arsenic-safe drinking water is being supplied at present. We found a median total exposure of inorganic arsenic to be 2. 9 µg/Kg BW/day (5th and 95th percentiles were 1.1 µg/Kg BW/day and 7.9 µg/Kg BW/day); with major contribution from cooked rice intake (2.4 µg/Kg BW/day). A significant number of households drank arsenic safe water but used arsenic-rich water for rice cooking. As a result, 67% participants had inorganic arsenic intake above the JEFCA threshold value of 3 µg/Kg BW/day for cancer risk from only rice consumption when arsenic contaminated water was used for cooking (median: 3.5 µg/Kg BW/day) compared to 29% participants that relied on arsenic-free cooking water (median: 1.0 µg/kg BW/day). Arsenic in urine samples of study participants ranged from 31.7 to 520 µg/L and was significantly associated with the arsenic intake (r = 0.76); confirming the preponderance of arsenic exposure from cooked rice. The median arsenic attributable cancer risks from drinking water and cooked rice were estimated to be 2.4 × 10-5 and 2.7 × 10-4 respectively, which further emphasized the importance of arsenic exposure from staple diet. Our results show that any mitigation strategy should include both drinking water and local staple foods in order to minimize the potential health risks of arsenic exposure.

Wnt5a Signaling Promotes Host Defense against Leishmania donovani Infection.

Leishmania donovani infects macrophages, disrupting immune homeostasis. The underlying mechanism that sustains infection remains unresolved. In view of the potential of Wnt5a signaling to support immune homeostasis, we evaluated the interrelationship of Wnt5a signaling and Leishmania donovani infection. Upon infecting macrophages separately with antimony drug-sensitive and -resistant L. donovani, we noted disruption in the steady-state level of Wnt5a. Moreover, inhibition of Wnt5a signaling by small interfering RNA transfection in vitro or by use of inhibitor of Wnt production in vivo led to an increase in cellular parasite load. In contrast, treatment of macrophages with recombinant Wnt5a caused a decrease in the load of antimony-sensitive and -resistant parasites, thus confirming that Wnt5a signaling antagonizes L. donovani infection. Using inhibitors of the Wnt5a signaling intermediates Rac1 and Rho kinase, we demonstrated that Wnt5a-mediated inhibition of parasite infection in macrophages is Rac1/Rho dependent. Furthermore, phalloidin staining and reactive oxygen species estimation of Wnt5a-treated macrophages suggested that a Wnt5a-Rac/Rho-mediated decrease in parasite load is associated with an increase in F- actin assembly and NADPH oxidase activity. Moreover, live microscopy of L. donovani-infected macrophages treated with Wnt5a demonstrated increased endosomal/lysosomal fusions with parasite-containing vacuoles (parasitophorous vacuoles [PV]). An increase in PV-endosomal/lysosomal fusion accompanied by augmented PV degradation in Wnt5a-treated macrophages was also apparent from transmission electron microscopy of infected cells. Our results suggest that, although L. donovani evades host immune response, at least in part through inhibition of Wnt5a signaling, revamping Wnt5a signaling can inhibit L. donovani infection, irrespective of drug sensitivity or resistance.

The effect of mild traumatic brain injury on the visual processing of global form and motion.

Cortical visual processing involves the ventral stream (form perception) and the dorsal stream (motion perception). We assessed whether mild traumatic brain injury (TBI) differentially affects these two streams. Eleven adults with mild TBI (28 ± 9 yrs, 17 ± 5 months post injury) and 25 controls (25 ± 5 yrs) participated. Participants completed tests of global processing involving Glass patterns (form) and random dot kinematograms (motion), measurement of contrast thresholds for motion direction discrimination, a comprehensive vision screening and the Post-Concussion Symptom Inventory (PCSI). Our results showed that the mild TBI group had significantly higher (worse) global form (mean ± SD: TBI 25 ± 6%, control 21 ± 5%) and motion (TBI 14 ± 7%, control 11 ± 3%) coherence thresholds than controls. The magnitude of the mild TBI group deficit did not differ between the two tasks. Contrast thresholds for motion direction discrimination did not differ between the groups, but were positively correlated with PCSI score (r2 = 0.51. p = 0.01) in the mild TBI group. The mild TBI group had worse outcomes than controls for all clinical measurements of vision except distance visual acuity. In conclusion, mild TBI affects processing in both the dorsal and ventral cortical processing streams equally. In addition, spatiotemporal contrast sensitivity may be related to the symptoms of mild TBI.

Duplications in 19p13.3 are associated with male infertility.

PURPOSE: To identify genomic imbalances and candidate loci in idiopathic male infertility. METHODS: Affymetrix CytoScan 750K Array was used to analyze genomic imbalances and candidate loci in 34 idiopathic infertile cases of different phenotypes (hypo-spermatogenesis, n = 8; maturation arrest, n = 7; and Sertoli cell-only syndrome, n = 13, severe oligozoospermia, n = 6, and 10 normozoospermic fertile men). Ten ethnically matched controls were screened for comparison. RESULTS: The cytogenetic array analysis detected a genomic gain at the 19p13.3 region in 9 (26.47%) cases, with the highest frequency in patients with Sertoli cell-only syndrome (SCOS) (38%). Its complete absence in the control group suggests its likely pathogenic nature. In addition to Y-classical, micro, and partial deletions, the duplication in 19p13.3 could serve as a unique biomarker for evaluation of infertility risk. The common region across the individuals harboring the duplication identified STK11, ATP5D, MIDN, CIRBP, and EFNA2 genes which make them strong candidates for further investigations. The largest duplicated region identified in this study displayed a major network of 7 genes, viz., CIRBP, FSTL3, GPX4, GAMT, KISS1R, STK11, and PCSK4, associated with reproductive system development and function. The role of chance was ruled out by screening of ethnically matched controls. CONCLUSION: The result clearly indicates the significance of 19p13.3 duplication in infertile men with severe testicular phenotypes. The present study underlines the utility and significance of whole genomic analysis in the cases of male infertility which goes undiagnosed due to limitations in the conventional cytogenetic techniques and for identifying genes that are essential for spermatogenesis.

SNPs in ERCC1, ERCC2, and XRCC1 genes of the DNA repair pathway and risk of male infertility in the Asian populations: association study, meta-analysis, and trial sequential analysis.

PURPOSE: We investigated if substitutions in the ERCC1, ERCC2, and XRCC1 genes of the DNA repair pathway correlate with non-obstructive azoospermia and male infertility. METHODS: A total of 548 azoospermic infertile males and 410 fertile controls were genotyped for XRCC1 399A > G, 280G > A, and ERCC1 C > A 3' UTR and 541 azoospermic infertile males and 416 fertile controls were genotyped for ERCC2 751A > C using iPLEX Gold Assay. Meta-analyses were performed on XRCC1 399A > G (1022 cases and 1004 controls), ERCC1 C > A 3' UTR (879 cases and 1059 controls), and ERCC2 751A > C (914 cases and 850 controls) polymorphisms to quantitatively estimate the significance of the association between these polymorphisms and the risk of infertility. RESULTS: Statistically significant association between ERCC2 751A > C SNP and male infertility was found using the codominant model (p = 0.03). Results of meta-analysis suggested a lack of correlation with male infertility risk, which could be due to pooling of studies from different ethnic populations. Due to limited the number of studies, a stratified analysis for different ethnic groups could not be performed. CONCLUSION (S): In conclusion, AA genotype of 751A > C SNP in ERCC2 correlated with a higher risk of male infertility and may contribute to an increased risk of azoospermia and male infertility in Indian men.

Excess iodine-induced lymphocytic impairment in adult rats.

Altered lymphocytic activity and its subset ratio found responsible for initiating abnormal autoimmune responses in men and animals after excess iodine exposure. Study objective is to reveal excess iodine-induced impairment of peripheral blood lymphocytes (PBL), its functional status, antioxidant balance, DNA damage, proliferation assay, and serum cytokine levels (IL6 and TNF α)in adult male rats to understand the onset of autoimmune alterations if any indirectly that is unexplored. Experimental animals were grouped depending on doses of iodine(KI) treatment with moderately excess-7 mg/kg bw (100EI) and excessively excess-35 mg/kg bw (500EI)for 30 days to analyze IL6 and TNF α, hematological indices, oxidative stress, lymphocytic DNA damage, and proliferation status. Significant impairment in superoxide dismutase, catalase, GPx activities including elevated NO, LPO in lymphocytes of treated group, with increased IL6 and TNF α level, lymphocyte proliferation and DNA damage depending on doses of iodine. Therefore, excess iodine consumption leads to lymphocytic impairment that may be the potential cause of autoimmune thyroid diseases in long run. Highlights Excess iodine triggers the oxidative stress in lymphocytes. Excess iodine promotes the activity of pro-inflammatory cytokines. Excess iodine causes impairment of functional status of lymphocytes leading to immune-cytotoxicity. Excess iodine exacerbates the autoimmunity.

Influence of iodine in excess on seminiferous tubular structure and epididymal sperm character in male rats.

Excess iodine induced public health problems are now emerging in many iodine sufficient regions for indiscriminate intake of iodine through various iodized products. It has been reported that excess iodine can disrupt overall male reproductive physiology by generating oxidative stress in the testis. However, information on the possible effect of iodine in excess on spermatozoa found less. In the present investigation flow cytometric techniques and scanning electron microscopy (SEM) have been used to study the spermatozoal functional as well as structural status under the influence of excess iodine; generation of ROS in the spermatozoa as evident by DCFDA, altered acrosomal integrity as observed by fluorescence lectin staining method and depolarized mitochondrial membrane potential (ΔΨm ) noticed by JC-1 staining. Ultrastructure of seminiferous tubule after excess iodine exposure indicated severe deterioration of seminiferous tubular surface architecture. Significant increase in spermatozoal DNA fragmentation and apoptotic sperms were found by acridine orange and Annexin V, respectively, however the plasma membrane integrity/viability was decreased as evident by propidium iodide staining in various incremental doses and durations under iodine excess. The study reveals that excess iodine could cause apoptosis of spermatozoal cells by inducing ROS that ultimately affects male fertility potential.

Cross-talk between endoplasmic reticulum (ER) stress and the MEK/ERK pathway potentiates apoptosis in human triple negative breast carcinoma cells: role of a dihydropyrimidone, nifetepimine.

Triple negative breast cancers (TNBC) are among the most aggressive and therapy-resistant breast tumors and currently possess almost no molecular targets for therapeutic options in this horizon. In the present study we discerned the molecular mechanisms of potential interaction between the endoplasmic reticulum (ER) stress response and the MEK/ERK pathway in inducing apoptosis in TNBC cells. Here we observed that induction of ER stress alone was not sufficient to trigger significant apoptosis but simultaneous inhibition of the MEK/ERK pathway enhanced ER stress-induced apoptosis via a caspase-dependent mechanism. Our study also demonstrated nifetepimine, a dihydropyrimidone derivative as a potent anti-cancer agent in TNBC cells. Nifetepimine down-regulated the MEK/ERK pathway in MDAMB-231 and MDAMB-468 cells and resulted in blockage of ER stress-mediated GRP78 up-regulation. Detailed mechanistic studies also revealed that nifetepimine by down-regulating pERK expression also declined the promoter binding activity of TFII-I to the GRP78 promoter and in turn regulated GRP78 transcription. Studies further extended to in vivo Swiss albino and SCID mice models also revalidated the anti-carcinogenic property of nifetepimine. Thus our findings cumulatively suggest that nifetepimine couples two distinct signaling pathways to induce the apoptotic death cascade in TNBC cells and raises the possibility for the use of nifetepimine as a potent anti-cancer agent with strong immune-restoring properties for therapeutic intervention for this group of cancer bearers.

Wnt5a-Rac1-NF-κB homeostatic circuitry sustains innate immune functions in macrophages.

Macrophages play a critical role in innate immunity. Differentiation Ags present on macrophages such as CD14 orchestrate the first line of defense against infection. The basal/homeostatic signaling scheme that keeps macrophages thus groomed for innate immune functions remains unresolved. Wnt5a-Fz5 signaling being a primordial event during cell differentiation, we examined the involvement of Wnt5a-Fz5 signaling in the maintenance of innate immune functions. In this study, we demonstrate that innate immune functions of macrophages ensue at least partly through a homeostatic Wnt5a-Fz5-NF-κB (p65) circuit, which is Rac1 dependent. The autocrine/paracrine Wnt5a-Fz5-Rac1-p65 signaling cascade not only maintains basal levels of the immune defense modulating IFNs and CD14; it also supports macrophage survival. Wnt5a-Fz5-Rac1 signaling mediated p65 homeostasis in turn sustains Wnt5a expression in a feed-forward mode. The natural immune response of macrophages to Escherichia coli/LPS and virus is accordingly sustained. The depiction of sustenance of innate immune functions as an outcome of a homeostatic Wnt5a-p65 axis unfolds previously unidentified details of immune regulation and provides new insight into homeostatic cell signaling.

Formulation and antitumorigenic activities of nanoencapsulated nifetepimine: A promising approach in treating triple negative breast carcinoma.

Triple negative breast cancer (TNBC) is one of the most common invasive malignancies among women, associated with poor prognosis. Standard chemotherapy targets all dividing cells, resulting in dose-limiting toxicities. In this study, we demonstrated a strategy of encapsulating a hydrophobic synthetic compound, nifetepimine, having anticancer properties, in poly (lactic-co-glycolic acid) nanoparticles to increase selectivity of drug to cancerous cells with minimum toxicity towards normal cells. Nanoencapsulated nifetepimine (30-100nm) having loading and encapsulation efficiency of 7.45% and 75% respectively, was successfully internalized inside TNBC cells upon sustained release resulting in apoptosis. An in vivo bio-distribution study indicated that nanonifetepimine selectively accumulated into breast tumor sites of mice, primarily due to prolonged blood circulation time and binding of nifetepimine to epidermal growth factor receptor that remains overexpressed in most of the TNBC tumors. Moreover, we observed significant reduction in breast tumor volume with improved survival implying high tumor targetability of nanonifetepimine.

Synergic actions of polyphenols and cyanogens of peanut seed coat (Arachis hypogaea) on cytological, biochemical and functional changes in thyroid.

In animals, long-term feeding with peanut (Arachis hypogaea) seed coats causes hypertrophy and hyperplasia of the thyroid gland. However, to date there have been no detailed studies. Here, we explored the thyroidal effects of dietary peanut seed coats (PSC) in rats. The PSC has high levels of pro-goitrogenic substances including phenolic and other cyanogenic constituents. The PSC was mixed with a standard diet and fed to rats for 30 and 60 days, respectively. Animals fed with the PSC-supplemented diet showed a significant increase in urinary excretion of thiocyanate and iodine, thyroid enlargement, and hypertrophy and/or hyperplasia of thyroid follicles. In addition, there was inhibition of thyroid peroxidase (TPO) activity, 5'-deiodinase-I (DIO1) activity, and (Na+-K+)-ATPase activity in the experimental groups of rats as compared to controls. Furthermore, the PSC fed animals exhibited decreased serum circulating total T4 and T3 levels, severe in the group treated for longer duration. These data indicate that PSC could be a novel disruptor of thyroid function, due to synergistic actions of phenolic as well as cyanogenic constituents.

Exploiting N-Centered Umpolung Reactivity of α-Iminomalonates for the Synthesis of N-Sulfenylimines and Sulfonamides.

An efficient and interesting N-centered umpolung method has been disclosed to construct beneficial S-N bonds, furnishing N-sulfenylimines, which can readily be converted into the corresponding sulfonamide derivatives in a one-pot sequential operation. N-Sulfenylimines are potent intermediates in organic synthesis, whereas sulfonamides are of major molecular interest due to their rich biological activities and wide applicability in medicinal chemistry. Owing to the simple reaction conditions and setup, this protocol displays a broad and versatile substrate scope, resulting in excellent functional group tolerability toward the synthesis of both N-sulfenylimines and sulfonamides. A density functional theory (DFT) computed and experimentally supported convenient mechanism has been proposed for this unique method.

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection.

How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in macrophages mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (MPC1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (ERRα). Consequently, ERRα exhibits weakened binding to the MPC1 promoter. This outcome arises from the impaired interaction between ERRα and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of MPC1 and ERRα and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedented mechanism of host tolerance to infection involving the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.

Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds.

Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum-sensing transcription factor MvfR (multiple virulence factor regulator) by interrogating, 5 days post-infection, its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs adenosine triphosphate generation, oxidative phosphorylation, and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR-mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients. IMPORTANCE: Skeletal muscle, pivotal for many functions in the human body, including breathing and protecting internal organs, contains abundant mitochondria essential for maintaining cellular homeostasis during infection. The effect of Pseudomonas aeruginosa (PA) infections on skeletal muscle remains poorly understood. Our study delves into the role of a central quorum-sensing transcription factor, multiple virulence factor regulator (MvfR), that controls the expression of multiple acute and chronic virulence functions that contribute to the pathogenicity of PA. The significance of our study lies in the role of MvfR in the metabolic perturbances linked to mitochondrial functions in skeletal muscle and the effectiveness of the novel MvfR inhibitor and the mitochondrial-targeted peptide SS-31 in alleviating the mitochondrial disturbances caused by PA in skeletal muscle. Inhibiting MvfR or interfering with its effects can be a potential therapeutic strategy to curb PA virulence.

Skeletal Muscle Mitochondrial Dysfunction Mediated by Pseudomonas aeruginosa Quorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds.

Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum sensing (QS) transcription factor MvfR by interrogating five days post-infection its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs ATP generation, oxidative phosphorylation (OXPHOS), and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR- mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.