Metformin is the first-line oral anti-hyperglycemic agent for the treatment of type 2 diabetes mellitus due to its effectiveness, cost-efficiency, and acceptable safety profile. Although metformin possesses a favorable safety profile, a rare but serious adverse event known as metformin-associated lactic acidosis (MALA) may occur, particularly in patients with impaired renal clearance or predisposing comorbidities that favor drug retention. High anion-gap metabolic acidosis, increased concentrations of lactate (>5 mmol/L), and arterial pH of less than 7.35 are the hallmarks of MALA. MALA has a multifactorial pathophysiology, driven primarily by mitochondrial complex I inhibition, leading to an altered intracellular redox state and decreased hepatic lactate clearance. Crucially, MALA is fundamentally an accumulation disorder precipitated by an acute decline in kidney function rather than an intrinsic toxicity of metformin at therapeutic concentrations. Many precipitating factors, including acute kidney injury (AKI), chronic kidney disease (CKD), hepatic impairment, sepsis, hypoxia, and dehydration, substantially predispose individuals to this complication. Early identification of clinical signs, such as metabolic acidosis, tachypnea, hypotension, and altered mental status, is essential to a better patient outcome. Diagnostic assessment is based on arterial blood gas values, serum lactate, and renal function tests. Management aims at stopping metformin immediately, providing supportive care, and eliminating the medication through renal replacement therapy (RRT) in severe instances. Prevention measures focus on appropriate patient selection, renal monitoring, dose adjustment, and proactive temporary drug withdrawal during acute intercurrent illnesses ("sick-day rules"). MALA is not highly prevalent, and contemporary evidence demonstrates that mortality is highly context-dependent, with prompt extracorporeal interventions yielding robust survival rates.

Metformin-associated lactic acidosis (MALA) is a rare phenomenon mostly described in the setting of impaired renal elimination or following an acute overdose. While metformin is first-line treatment for type 2 diabetes mellitus, glucagon-like peptide-1 (GLP-1) receptor agonists and glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 dual receptor agonists are frequent add-on agents. Both classes of medications share common gastrointestinal adverse reactions, including decreased appetite, nausea, vomiting, and abdominal pain. We present a series of four critically ill patients with type 2 diabetes mellitus on high-dose metformin who presented with severe MALA following the introduction or dose escalation of a GLP-1 or GIP/GLP-1 dual receptor agonist, or during an acute gastrointestinal illness while also on a maintenance dose of a GLP-1 receptor agonist, requiring acute renal replacement therapy. Prudence must be exercised when co-prescribing these 2 classes of medications with close monitoring of kidney function, possible reduction in metformin dose, and emphasis on sick day rule teaching.

Acute high-altitude hypoxia (AHH) disrupts systemic homeostasis and alters the pharmacokinetic (PK) profiles of drugs, yet the role of the organic anion transport network in mediating altered drug disposition and the link to regulation by the Remote Sensing and Signaling Theory remain unclear. Moreover, the underlying mechanisms governing the PK of acetazolamide (ACZ), an FDA-approved therapeutic agent for high-altitude illness, remain unelucidated. This study aimed to clarify the effects of AHH on the PK of ACZ, identify the organic anion transport network involved, and characterize perturbations in renal metabolism. Results demonstrated that AHH markedly altered ACZ PK: with a 3.27-fold increase in AUC0-∞ and a 2.62-fold prolongation in t1/2. For the first time, ACZ was confirmed as a specific substrate of organic anion transporter 1, multidrug resistance-related protein (MRP4), and breast cancer resistance protein. Mechanistically, AHH dysregulated these transporters, including upregulating breast cancer resistance protein, downregulating organic anion transporters, organic anion transporting polypeptides, MRPs, and P-glycoprotein via transcriptional regulation of nuclear receptors (hypoxia-inducible factor-1α, Pregnane X receptor, constitutive androstane receptor, and hepatocyte nuclear factor-4α), a finding validated in acute hypoxic Caco-2 cells and AHH rat models. Renal metabolomics further revealed profound perturbations in organic anion metabolism, notably, indoxyl sulfate, hippuric acid, and kynurenic acid were decreased by 56.84%, 88.53%, and 69.77%, respectively, whereas estrone glucuronide was elevated 4.78-fold, and these 4 metabolites were identified as novel renal tissue-specific biomarkers of AHH-induced renal organic anion transport network dysfunction. Collectively, this study elucidates organic anionic drug disposition mechanisms under AHH, validates Remote Sensing and Signaling Theory by linking organic anion transport network to drug metabolism crosstalk, and provides evidence for personalized pharmacotherapy of high-altitude sickness. SIGNIFICANCE STATEMENT: This study uncovers how acute high-altitude hypoxia dysregulates the organic anion transport network to disrupt acetazolamide (ACZ) disposition and renal metabolic homeostasis. It first identifies ACZ as an organic anion transporter 1/multidrug resistance-related protein 4/breast cancer resistance protein substrate and defines indoxyl sulfate, hippuric acid, kynurenic acid, and estrone glucuronide as endogenous renal tissue-specific biomarkers for organic anion transport network dysfunction. Filling the gap in understanding acute high-altitude hypoxia-mediated organic anion transport network regulation, this work validates the Remote Sensing and Signaling Theory and provides critical insights for optimizing ACZ pharmacotherapy and exploring metabolic homeostasis in high-altitude environments.

Two mixed-anion chalcohalides, Pb4Sb4S9Cl2 and Pb4Sb4Se9Cl2, which crystallize in the orthorhombic space group Pbam (No. 55), were synthesized by a solid-state reaction. Their structures consist of puckered two-dimensional 2∞[Pb4Sb4Q9Cl][+] layers (Q = S, Se) constructed from NaCl-type ribbon motifs of Pb- and Sb-centered polyhedra, with Cl[-] ions located between the layers. Single-crystal X-ray diffraction and synchrotron powder X-ray diffraction confirm the structural models and support the presence of mixed chalcogen/halogen occupancies at selected anion sites. X-ray photoelectron spectroscopy confirms the presence of Pb[2+], Sb[3+], Q[2-] (Q = S, Se), and Cl[-]. Diffuse-reflectance measurements indicate indirect optical band gaps of 1.55 eV for the sulfide and 1.01 eV for the selenide, in agreement with density functional theory calculations that reproduce the indirect-gap character and the band-gap narrowing upon S to Se substitution. Both compounds exhibit low thermal conductivity at 300 K, with values of 1.1 W m[-1] K[-1] for Pb4Sb4S9Cl2 and 0.7 W m[-1] K[-1] for Pb4Sb4Se9Cl2, and the thermal conductivity decreases slightly with increasing temperature. This behavior is attributed to structural complexity, bonding heterogeneity associated with the mixed-anion framework, stereochemically active lone-pair cations, and partial halogen occupancy. These results clarify the structure-property relationships in Pb4Sb4Q9Cl2 and highlight mixed-anion design as a useful strategy for developing layered semiconducting chalcohalides with low thermal conductivity.

The structure-property relationship investigations constitute a fundamental paradigm for the rational design and synthesis of high-performance functional materials. Herein, four guanidinopropionates (C4H10N3O2)X (X = Cl- (GPC), Br[-] (GPB), [HSeO3][-] (GPSe), and [NH2SO3][-] (GPMS)) were reported. Anion-size-dependent modulation of the C2─C3 single bond rotation (linking guanidino and carboxylic π-conjugated groups) induces a reduction of the dihedral angle between the two π-conjugated planes (α) from 175° to 65°. With such a coplanarity reduction, the optical anisotropy property (birefringence, Δn) decreases from an excessive 0.20 in GPC to a favorable 0.11 in GPMS. Remarkably, GPMS also exhibits a large band gap (5.63 eV) and an enhanced second-harmonic generation (SHG) response (3.3 × KH2PO4). DFT reveals these four conformations are nearly degenerated, and the HOMO-LUMO gap, polarizability anisotropy, and hyperpolarizability across these four conformers are broadly tunable. This work first demonstrates how conformational folding control of flexible π-conjugated units effectively modulates and optimally balances three critical yet mutually restrictive parameters essential for high-performance SHG materials.

Volume-activated chloride current (VACC), the most common and abundant anion current in organisms, is involved in various physiological and pathological processes. However, its expression and characteristics in preadipocytes remain unclear. Whole-cell patch clamp technique was used to investigate the presence and properties of VACC in 3T3-L1 preadipocytes, as well as the effects of chloride channel blockers (NPPB, DIDS, and tamoxifen) on this current under different osmotic conditions. Additionally, 3T3-L1 preadipocytes were treated with the chloride channel blocker TMEM16A to observe its effect on cell differentiation. Hypotonic stimulation significantly induced whole-cell currents in 3T3-L1 preadipocytes, which exhibited obviously outward-rectifying and volume-activated characteristics. Under hypotonic stimulation, NPPB, DIDS, and tamoxifen all inhibited the current, with NPPB showing a significantly stronger inhibitory effect than DIDS and tamoxifen. Moreover, growth-arrested 3T3-L1 preadipocytes at 2 days post-confluence were successfully induced, with mRNA levels of C/EBPα, C/EBPβ, PPARγ and FABP4 peaking on day 3 and decreasing by day 14. Protein levels of PPARγ, perilipin 1 and LRRC8A were significantly upregulated during differentiation. Treatment with TMEM16A significantly reduced adipocyte lipid droplet formation and FABP4 mRNA/protein levels, but increased C/EBPα and PPARγ mRNA levels, as well as LRRC8A protein levels after 3 days. Collectively, our results clarify the characteristics of VACC in 3T3-L1 preadipocytes, confirm the inhibitory effect of chloride channel blockers on 3T3-L1 preadipocyte differentiation, fill the gap in the understanding of VACC in preadipocytes, and lay a preliminary experimental foundation for further exploring the role of VACC in adipocyte differentiation.

The Lewis pairing between existing dopant molecules offers great potential for developing new organic dopants with exceptional doping strength and stability. However, the high reactivity of Lewis-paired dopants complicates doping-level control, while the use of non-orthogonal solvents can damage organic semiconductor (OSC) films, hindering device applications. Here, the dopant reactivity is controlled by regulating the association-dissociation kinetics among pairing dopants and solvent molecules, which are strongly influenced by solvent polarity. In highly polar solvents, Lewis acid-solvent adducts predominantly form, suppressing the generation of Lewis-paired dopants. As solvent polarity decreases, the dissociation rate of the Lewis acid-solvent adduct increases, establishing a dynamic equilibrium between the Lewis acid and the solvent and thereby optimizing reactivity. Consequently, the optimally processed Lewis-paired dopant enables efficient doping of various OSCs with finely tunable doping levels, simultaneously achieving a high thermoelectric power factor (170 µW m[-1] K[-2]) and Seebeck coefficient (227 µV K[-1]). These performances surpass those of the conventional salt-type FeCl3 dopant and exhibit markedly improved doping stability under ambient and elevated-temperature conditions. This study provides a practical strategy for utilizing Lewis-paired dopants by elucidating their doping mechanisms, paving the way to overcome long-standing limitations in OSC doping.

Background: Valproic acid (VPA) poisoning has a dynamic clinical course and may require extracorporeal toxin removal (ECTR) in severe cases. Intermittent hemodialysis is the preferred ECTR technique; however, clinical experience with expanded hemodialysis (HDx) using medium cut-off (MCO) membranes in acute VPA intoxication is scarce. We describe a case of severe VPA poisoning managed with intermittent HDx and outline the clinical rationale and kinetic response. Case Report: A 54-year-old woman presented to the emergency department after accidental presumably ingesting approximately 4 g of VPA, with depressed consciousness (Glasgow Coma Scale 7) and metabolic acidosis (pH 7.10, HCO3[-] 13 mmol/L, PCO2 50 mmHg, lactate 2.8 mmol/L, ionized calcium 0.8 mmol/L, elevated anion gap). Initial plasma VPA was 262.99 µg/mL, ammonia was 14 µmol/L, and cranial computed tomography showed no acute abnormalities. ECTR was initiated in the intensive care unit as intermittent HDx using an MCO dialyzer for 4 h. Serial VPA concentrations were obtained before treatment, at 2 h, and at the end of the session to guide real-time prescription adjustment, with an increase in blood flow from 200 to 230 mL/min. Results: VPA decreased from 262.99 µg/mL pre-HD to 141.48 µg/mL at 2 h (46.2% reduction) and 97.81 µg/mL at 4 h (62.8% reduction), with clear improvement in the level of consciousness. A mild post-dialysis rebound was observed (100.07 µg/mL at 14 h). The patient recovered without additional ECTR and was discharged with normalized VPA levels on follow-up. Conclusions: In this patient, intermittent HDx with an MCO membrane was feasible, well tolerated, and associated with rapid VPA clearance and neurological recovery. Serial drug monitoring enabled bedside optimization of the dialysis prescription and post-treatment evaluation. A single HDx session was sufficient, and VPA therapy was safely reintroduced under close monitoring.