Background/Objectives: Diabetes mellitus is known to exacerbate neural degeneration and impair regenerative capacity following injury. This study aimed to investigate the effects of Garcinia kola and curcumin on spinal cord morphology and neural structure in a diabetic sciatic nerve injury model. Methods: Spinal cord tissues were obtained from male Wistar albino rats subjected to sciatic nerve transection and diabetes induction in a previously established experimental model. Animals had been assigned to five experimental groups (n = 7 per group): control group, transected sciatic nerve group, transected sciatic nerve + diabetes mellitus (DM), transected sciatic nerve + diabetes mellitus + curcumin (DM + Cur), and transected sciatic nerve + diabetes mellitus + Garcinia kola (DM + GK). Curcumin (300 mg/kg/day) and Garcinia kola (200 mg/kg/day) were administered orally. All animals were sacrificed at three months post-injury. Cervical (C3-C5) spinal cord segments were processed for histological evaluation, and quantitative assessments were performed using unbiased stereological methods to estimate neuronal and structural parameters. Microscopic analyses were conducted to assess morphological alterations. Results: Diabetes combined with sciatic nerve transection induced marked structural alterations in the spinal cord, including reductions in neuronal density and disruption of tissue organization. The DM group showed a significantly lower number of motor neurons than the other groups; similarly, it showed a significant decrease in soma area compared to the Cont and Sham groups. Conclusions: Both the curcumin and Garcinia kola treatment groups exhibited partial preservation of spinal cord morphology. This study provides evidence that Garcinia kola and curcumin exert protective effects not only at the peripheral nerve level, but also in the spinal cord following diabetic nerve injury.

Sensory neurons express extrasynaptic GABAA receptors in their soma and axon, tonically activated by ambient GABA, modulating their excitability. However, the specific glial or neuronal origin of endogenous GABA that modulates this excitability has yet to be identified. We investigated the expression and function of enzymes involved in GABA synthesis via the ornithine-putrescine and glutamic acid pathways, and the effects of inhibiting these enzymes on the compound action potential (cAP) of primary afferent fibers. PCR analysis revealed that the dorsal root ganglia (DRG) express transcripts for ornithine decarboxylase (ODC), monoamine oxidase B (MAOB), diamine oxidase (DAO), and GAD65/67. Immunofluorescence assays confirmed the expression of ODC, MAOB, DAO, and GAT-3 proteins, as well as GABA in satellite glial cells (SGC). In contrast, neurons express DAO and ODC. However, despite the presence of GAD65 and GAD67 mRNAs, their corresponding proteins were not detected. Inhibition of ODC and MAOB, but not DAO or GAD, prevented the accumulation of GABA induced by the GABA transaminase (GABA-T) inhibitor aminooxy acetic acid in SGC cultures. Additionally, the Best1 channel blocker CaCCinh suppressed the K[+]-induced release of [[3]H]GABA in DRG and SGC cultures. Blocking GABAA receptors with picrotoxin, inhibiting MAOB, and blocking Best1 all increased cAP. However, allylglycine, a GAD inhibitor, failed to elicit this effect. Likewise, the use of selegiline and CaCCinh on cAP occluded the effects of picrotoxin. These results support that GABA synthesized and released by satellite glial cells activates extrasynaptic GABAA receptors, thereby modulating the excitability of sensory neurons.

The voltage-gated sodium channel NaV1.7 is a pain target supported by human genetics, and many compounds have been developed to inhibit NaV1.7 but have disappointed in clinical trials due to cardiovascular effects. Because some recent reports suggest that pharmacological inhibition of NaV1.7 in the rodent spinal dorsal horn can achieve pain relief, we sought to better understand NaV1.7 expression in the human spinal cord. We report that NaV1.7 mRNA is expressed in putative projection neurons (NK1R+, GPR83+) in the human spinal dorsal horn, predominantly in lamina I and II, as well as in deep dorsal horn neurons. NaV1.7 mRNA was also detected in preganglionic parasympathetic and sympathetic neurons, motor neurons in the ventral horn, and ependymal cells lining the central canal. NaV1.7 protein was predominantly found in the central axons of sensory neurons terminating in lamina I-II and colocalized, in part, with presynaptic markers like Bassoon and CGRP. Postsynaptically, NaV1.7 protein was detectable in the soma of motor neurons but was more elusive in dorsal horn populations due to the abundance of presynaptic signal. However, NaV1.7 protein was detected in the axon initial segment of some resident dorsal horn neurons and in axons entering the anterior commissure. Given that projection neurons are critical for conveying nociceptive information from the dorsal horn to the brain, these data support that dorsal horn NaV1.7 expression may play an unappreciated role in pain phenotypes observed in humans with genetic SCN9A mutations.

Venom peptides are key to the evolutionary success of most venomous animals, including stinging ants. The stingless ant subfamily Formicinae is thought to rely solely on formic acid in their venoms, despite early, unsubstantiated hints of proteinaceous venom constituents. Here, we show that carpenter ants, the largest formicine genus, produce a diverse venom peptide arsenal. Mass spectrometry and transcriptomics across eight geographically distant species uncovered 35 peptides, formicitoxins, belonging to two gene families. Several formicitoxins display antifungal activity. Application to pupae delays fungal outgrowth, suggesting a role of the peptides in colony hygiene. Genome analyses revealed that formicitoxins are widespread but variable across the Formicinae. Our findings overturn the paradigm of formicine venoms as simple acid sprays and establish them as a source of bioactive peptides.

Bioethanol dehydrogenation is a promising route for clean and renewable hydrogen production, aligning with low-carbon economy goals. Additionally, it promotes the synthesis of valuable organic compounds from bioethanol. This study investigated the use of green-synthesized NiO nanoparticles as a catalyst for ethanol dehydrogenation. The highest selectivity for hydrogen production (97.4%) was achieved using 10% NiO at 260 °C. However, at 10% NiO and 280 °C, the fuel gas mixture yielded a higher calculated calorific value (1,231.6 kJ). This condition was used to evaluate the reaction's kinetic over a period of 1 to 8 reaction-hours. During these experiments, a progressive increase in gas volume was observed, along with a transition in the gas products from propane to hydrogen, followed by methane. These changes correlated with ethanol conversion to organic compounds (1,1-diethoxyethane and 1-butanol) in the liquid phase, as well as catalyst's crystal structure alterations, from Ni[2+] face-centered-cubic (FCC) to metallic nickel FCC and hexagonal close-packed (HCP) phase.

After aspirin ingestion, salicylic acid is excreted into breastmilk, with higher doses resulting in disproportionately higher milk levels. Long-term, high-dose maternal aspirin ingestion probably caused metabolic acidosis in one breastfed infant. Reye's syndrome is associated with aspirin administration to infants with viral infections, but the risk of Reye's syndrome from salicylate in breastmilk is unknown. An alternate drug is preferred over continuous high-dose, aspirin therapy. With low-dose aspirin (75 to 325 mg daily), no aspirin is excreted into breastmilk and salicylate levels are low. If a nursing mother uses aspirin, monitor the infant for bruising and bleeding.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) has summarized and re-evaluated the data for 2-mercaptobenzothiazole [149-30-4] considering all toxicological end points. Relevant studies were identified from a literature search and also unpublished study reports were used. The critical effect in humans and animals is sensitization. Data for chronic inhalation exposure are not available. The most sensitive systemic end point observed in a 13-week gavage study in rats was an increase in relative liver weights. The female rat was found to be the most sensitive species. A LOAEL of 188 mg/kg body weight and day was derived, which corresponds to a concentration in the air of 27.5 mg/m[3]. No conclusions can be drawn for systemic toxicity from a 2-year gavage study in rats because of the high spontaneous incidence of different pathological effects observed in the control group. As there are no data for inhalation exposure to the poorly soluble substance, a particle effect in the lungs cannot be excluded. Additionally, epidemiological and animal data suggest a carcinogenic potential. As a result, the present maximum concentration at the workplace (MAK value) has been suspended. 2-Mercaptobenzothiazole is not mutagenic in bacteria. Mutagenic and clastogenic effects in mammalian cells are observed only at high, mostly cytotoxic concentrations. In vivo data do not provide evidence of genotoxic effects in soma cells or male germ cells, even at concentrations that cause systemic toxicity. Overall, the data from epidemiological studies are not sufficient to draw definite conclusions about whether 2-mercaptobenzothiazole is a human carcinogen. A carcinogenicity study with gavage administration in rats observed adenomas of the pancreas, preputial glands and pituitary gland as well as fibromas and phaeochromocytomas. However, the increased incidence of tumours is neither clear evidence for nor against a carcinogenic potential because of a number of uncertainties inherent in the study. Thus, 2-mercaptobenzothiazole remains classified in Carcinogen Category 3 for suspected carcinogens. Dermal absorption is not expected to contribute significantly to systemic toxicity. 2-Mercaptobenzothiaziole is a known contact allergen. Therefore, the "Sh" designation has been retained. There are no data for respiratory sensitization.

The German Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) has evaluated the data for tetrabromobisphenol A [79-94-7] considering all toxicological end points. Relevant studies were identified from a literature search, epidemiological studies of tetrabromobisphenol A are not available. After repeated administration by gavage, the target organs of toxicity were the endocrine system in male and female rats with decreased total T4 concentrations and the kidneys in male mice with cytoplasmic changes in the tubules. Tetrabromobisphenol A induces uterine tumours in female Wistar-Han rats and hepatoblastomas and haemangiosarcomas in male B6C3F1/N mice. Due to its non-genotoxic mechanism of action, it is assumed that a NAEL (no adverse effect level) can be determined for carcinogenic effects. Therefore, tetrabromobisphenol A could be classified in Carcinogen Category 4. However, there are no data that can be used to establish a NOAEL for atypical hyperplasia (preneoplasia) in the endometrium, to clarify whether the observed uterine tumours are specific to the strain, and to further characterize the mechanism of tumourigenesis. Therefore, a maximum concentration at the workplace (MAK value) cannot be established and tetrabromobisphenol A has been classified in Carcinogen Category 2 and given the footnote "Prerequisite for Category 4 in principle fulfilled, but insufficient data available for the establishment of a MAK or BAT value". Tetrabromobisphenol A is not mutagenic in bacteria or clastogenic in mammalian cells. In vivo data do not provide evidence of genotoxic effects in soma cells, even at concentrations that cause systemic toxicity. In vivo studies suggest that transdermal uptake may be relevant. As tetrabromobisphenol A has been classified as a Category 2 carcinogen and no threshold for the carcinogenic effects can be established at present, the substance has provisionally been designated with "H". Data for humans, animals and from in vitro studies show no sensitizing potential.

The evolution of reproductive specialization, in which somatic cells forfeit reproduction, represents a fundamental innovation in complex multicellular life. This specialization imposes a fitness cost: because somatic cells do not produce offspring, organisms that invest in soma have reduced fecundity. The magnitude of this cost might be expected to depend simply on the proportion of cells allocated to soma. Here, we show that these costs also decrease with the logarithm of organism size, because larger organisms require proportionally more cell divisions for development, diluting the rate at which reproductive costs compound across multicellular generations. We derive this result analytically and validate it with data from the volvocine green algae. When somatic cells provide a compensating survival benefit, a positive feedback emerges: larger organisms can afford greater somatic investment, which in turn favors further size increases. This size-scaling relationship helps explain the broad association between large organism size and multicellular complexity.

Dual leucine-zipper kinase (DLK) is implicated in at least two distinct processes that drive neurodegeneration: retrograde (axon-to-soma) signaling to activate pro-degenerative transcription programs, and axon-intrinsic action to drive Wallerian and Wallerian-like axon degeneration. Inhibiting DLK-dependent signaling is thus an attractive neuroprotective strategy, but compounds that inhibit all cellular pools of DLK cause unintended side effects. We recently successfully deployed a complementary approach to identify compounds that selectively block DLK retrograde (axon-to-soma) signaling and subsequent neurodegeneration by inhibiting acute, axonal palmitoylation of DLK. Here, we explored chemical space for one of our two most effective compounds and identified multiple analogs that are equally neuroprotective in a model of transcription-dependent neurodegeneration that requires DLK-dependent retrograde signaling. In contrast, our original hits and these additional analogs had minimal effect in two models of DLK-dependent, but transcription-independent, distal axon degeneration. Moreover, our original hits did not phenocopy the stabilization of axon survival factor proteins that is a well-described effect of conventional DLK kinase domain inhibitors. These findings reveal additional potential neuroprotective compounds and further support the notion that the pool of DLK that conveys axonal retrograde signals can be selectively targeted therapeutically.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron degeneration in the substantia nigra and striatum. Current treatments are largely palliative and frequently associated with adverse effects. This study aimed to evaluate the neuroprotective potential of an aqueous extract of Bacopa procumbens (B. procumbens) and the NAPEL formulation-composed of five neuroactive compounds (Naringenin, Apigenin, Paeoniflorin, (-)-Epicatechin, and Lupeol)-in a murine model of MPTP-induced parkinsonism. Behavioral, histological, and molecular parameters were examined to elucidate underlying mechanisms of neuroprotection. Male mice received MPTP to induce parkinsonism, followed by oral administration of B. procumbens extract or NAPEL. Motor function was assessed through open-field-related parameters. Substantia nigra neuronal morphology was analyzed histologically. Molecular analyses focused on the Keap1/Nrf2/ARE pathway, HSF1, HIF-1α, antioxidant enzymes, and lipid peroxidation. Additionally, in silico analyses (GeneMANIA, STRING) were performed to explore regulatory networks associated with Nrf2, HSF1, and HIF-1α. The aqueous extract significantly improved motor performance, increased rearing events, enhanced central exploration, and increased total distance traveled. It preserved neuronal number and soma diameter in the substantia nigra. Molecularly, the extract activated the Keap1/Nrf2/ARE axis and induced HSF1 and HIF-1α, accompanied by increased SOD-1, CAT, and GSR expression and reduced lipid peroxidation. NAPEL also produced behavioral and histological improvements but did not activate Nrf2, HSF1, or HIF-1α nor notably elevate antioxidant enzymes, except for CAT in the striatum. In silico analyses identified Nrf2, HSF1, and HIF-1α as central nodes integrating oxidative stress, proteostasis, hypoxia, inflammation, and apoptotic responses. These findings support the neuroprotective potential of both B. procumbens aqueous extract and the NAPEL formulation, highlighting their value as promising therapeutic candidates for Parkinson's disease.

De novo fatty acid synthesis produces the acyl units needed to generate phospholipids, lipoproteins, enzyme prosthetic factors, polyketides, and mycolic acids in mycobacterium tuberculosis (Mtb). Here, we identified sALT629, a butoxyphenyl-tetrazole-acetamide compound that inhibits de novo lipid synthesis in Mtb. This compound disrupts the Mtb lipidome and prevents incorporation of metabolic tracers into acyl chains of Mtb lipids. Unexpectedly, we also found that sALT629 treatment significantly depleted triacylglycerol (TAG) pools as a metabolic compensation mechanism when de novo fatty acid synthesis was inhibited. Resistance to sALT629 was mediated by loss of function mutations in HadC, the non-essential hydroxyacyl- acyl carrier protein -dehydratase subunit involved in the synthesis of long-chain oxygenated mycolic acids. Inactivating HadC rescued sALT629-mediated inhibition by sustaining TAG pools to fulfill Mtb's biosynthetic demand for acyl chains. Lastly, loss of function HadC resistance mutations resulted in cell wall perturbations that confer fitness defects in vitro and in vivo suggesting that this specific resistance mechanism is unlikely to arise in Mtb in a clinical setting. Significance. Having effective antibiotics to treat tuberculosis underpins our ability to control this disease. The spread of antibiotic-resistant tuberculosis has prompted a need to identify new drug candidates with new mechanisms of action. Here we describe an antitubercular that targets de novo fatty acid synthesis in Mtb, a critical process required to generate multiple essential lipid and lipid-based factors in the bacteria. One resistance mechanism to this inhibitor is associated with perturbations to mycolic acid synthesis resulting in Mtb attenuation. These findings demonstrate that de novo fatty acid synthesis in Mtb is an actionable drug target, and uncovered a compensatory metabolic resistance network between TAGs and mycolic acids.

Redox regulation is a key mechanism supporting tumor survival and an attractive therapeutic target. In this study, we screened 1161 FDA-approved compounds to identify agents that induce reactive oxygen species (ROS) accumulation in head and neck squamous cell carcinoma (HNSCC) cells. Pimozide, a dopamine D2 receptor antagonist, emerged as the most potent ROS inducer. It selectively suppresses the growth of HNSCC cells with high oxidative stress resistance while exhibiting only modest effects on less resistant cells and normal keratinocytes. Notably, pimozide exhibited anti-tumor effects as a monotherapy and in combination with paclitaxel at clinically relevant doses. Mechanistic analysis revealed that pimozide rapidly induced ROS accumulation via a mechanism distinct from its known action on dopamine D2 receptors and STAT3/5. To identify markers of ROS-induced responses, we examined ROS-responsive genes and found that early growth response 1 (EGR1) was selectively induced in sensitive cells and correlated with pimozide responsiveness. Functional analysis revealed that EGR1 knockdown suppressed pimozide-induced cytotoxicity, suggesting its role as a functional pharmacodynamic marker of pimozide sensitivity. In a patient-derived xenograft model of HNSCC, pimozide significantly reduced the tumor burden alone and in combination with paclitaxel. While tumor volume reduction in the combination group was not statistically greater than that in the monotherapy group, fluorescence immunohistochemistry revealed a marked decrease in undifferentiated tumor cells, indicating enhanced therapeutic effects of combination treatment. Taken together, these findings indicate that pimozide is a promising candidate for repurposing as a novel therapeutic agent against HNSCC.

The kynurenine pathway is the principal route of tryptophan metabolism in the brain, generating several neuroactive metabolites, including kynurenic acid (KYNA). KYNA functions as both a neuromodulator and a neuroprotective compound, and its dysregulation has been associated with numerous neurological and psychiatric disorders. Kynurenine aminotransferase-2 (KAT-2) is the key enzyme responsible for KYNA synthesis, yet its precise cellular localization in the mouse brain remains insufficiently characterized. In this study, we systematically compared KAT-2 expression in primary astrocytic, microglial, and neuronal cultures derived from mouse brain, complemented by in situ immunolabeling of brain sections. Immunocytochemistry combined with quantitative colocalization analysis revealed that KAT-2 is expressed in all three major brain cell types, with significant overlap with cell type-specific markers. Furthermore, KAT-2 immunoreactivity was largely restricted to the soma, showing a perinuclear distribution in glial cells and partial extension into dendritic compartments in neurons. These findings provide the first parallel characterization of KAT-2 distribution across astrocytes, microglia, and neurons in the mouse brain. Overall, our results indicate that KAT-2 is widely expressed in neural cells, a finding that supports the hypothesis that KAT-2 contributes broadly to kynurenine metabolism. Taken together, our findings provide a foundation for future studies aimed at defining the cell type-specific functional roles of KAT-2.